Cyclic Peptides That Govern Signal Transduction Pathways: From Prokaryotes to Multi-Cellular Organisms

May combine two claims.

Short peptide sequences are easier to transport but lack specificity and exhibit only moderate affinity to their target due to their ability to adopt a high number of conformations.

“On the other hand, short peptide sequences are easier to transport, but they lack specificity and only exhibit moderate affinity to their target due to their ability to adopt a high number of conformations.”

Probably not a substantial claim: may not pass S4 (based).

In eukaryotic systems, cyclic peptide hormones play a key role in regulation of the overall function of multicellular organisms, mainly through the endocrine system.

“In the more evolved eukaryotic systems, cyclic peptide hormones play a key role in the regulation of the overall function of multicellular organisms, mainly through the endocrine system.”

Classified as probably not a substantial claim.

Peptide cyclization is a widely used method of creating unique conformational constraints necessary for effective and specific receptor binding.

“Peptide cyclization is a widely used method of creating unique conformational constraints necessary for effective and specific receptor binding.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Biologically active cyclic peptides are naturally formed through diverse ring-closure methods including head-to-tail, side-chain-to-side-chain, head-to-side-chain, and side-chain-to-tail cyclization, and by utilizing various chemical bonds such as amide, lactone, thioester, or disulfide bonds.

“Biologically active cyclic peptides are naturally formed through diverse ring-closure methods, including head-to-tail, side-chain-to-side-chain, head-to-side-chain, and side-chain-to-tail cyclization, and by utilizing various chemical bonds such as amide, lactone, thioester, or disulfide bonds.[3]”

• cites [3] Joo SH Cyclic peptides as therapeutic agents and biochemical tools Biomol Ther 2012 20 1 19 26 PMC3792197 24116270Not checked yet

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May combine two claims.

Many genera of Gram-positive bacteria utilize cyclic peptides to assess their population density, and at high cell number synchronize to initiate group behavior phenotypes.

“In particular, many genera of Gram-positive bacteria utilize cyclic peptides to assess their population density, and at high cell number synchronize to initiate group behavior phenotypes.[4–6]”

• cites [4] Ji G Beavis RC Novick RP Cell density control of staphylococcal virulence mediated by an octapeptide pheromone Proc Natl Acad Sci U S A 1995 92 26 12055 12059 8618843 PMC40295Not checked yet

  Not checked in the free run.

• cites [5] Waters CM Bassler BL Quorum sensing: cell-to-cell communication in bacteria Annu Rev Cell Dev Biol 2005 21 319 346 16212498Not checked yet

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• cites [6] Ng W-L Bassler BL Bacterial quorum-sensing network architectures Annu Rev Genet 2009 43 197 222 19686078 PMC4313539Not checked yet

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May combine two claims.

Large peptide (15 to 50 amino acids) and protein (greater than 50 amino acids) scaffolds possess optimal pharmacological properties for signal transduction messengers because they form many contacts with their target receptor, leading to high affinity and specificity, while being efficiently inactivated and cleared.

“Large peptide, 15 to 50 amino acids, and protein, greater than 50 amino acids, scaffolds possess optimal pharmacological properties required for dynamic signal transduction messengers since they form a high number of contacts with their target receptor, leading to high affinity and specificity, while at the same time they are efficiently inactivated and cleared from the environment to prevent over”

May combine two claims.

The mature AIP is a short 7-12 amino acid peptide with a five-amino acid cyclic ring connected via a thiolactone bridge between the C-terminus of the peptide and a conserved cysteine (in Staphylococcus intermedius the AIP was identified as a lactone-containing signal).

“The mature AIP is a short 7–12 amino acid peptide with a five-amino acid cyclic ring connected via a thiolactone bridge between the C-terminus of the peptide and a conserved cysteine (in the case of Staphylococcus intermedius the AIP was identified as a lactone-containing signal, Figure 2).[4, 21, 25, 31]”

• cites [4] Ji G Beavis RC Novick RP Cell density control of staphylococcal virulence mediated by an octapeptide pheromone Proc Natl Acad Sci U S A 1995 92 26 12055 12059 8618843 PMC40295Not checked yet

  Not checked in the free run.

• cites [21] Ji G Beavis R Novick RP Bacterial interference caused by autoinducing peptide variants Science 1997 276 5321 2027 2030 9197262Not checked yet

  Not checked in the free run.

• cites [25] Ji G Pei W Zhang L Qiu R Lin J Benito Y Lina G Novick RP Staphylococcus intermedius produces a functional agr autoinducing peptide containing a cyclic lactone J Bacteriol 2005 187 9 3139 3150 15838041 PMC1082806Not checked yet

  Not checked in the free run.

• cites [31] Wang B Zhao A Novick RP Muir TW Key driving forces in the biosynthesis of autoinducing peptides required for staphylococcal virulence Proc Natl Acad Sci U S A 2015 112 34 10679 10684 26261307 PMC4553796Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Pathogenic staphylococci species cause disease due to their ability to colonize within host tissues and secrete toxins that create damage and impair the host immune system.

“Pathogenic staphylococci species cause disease due to their ability to colonize within host tissues and secrete toxins that not only create damage, but also impair the host immune system.[22, 26]”

• cites [22] Lowy FD Staphylococcus aureus infections N Engl J Med 1998 339 8 520 532 9709046Not checked yet

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• cites [26] Foster T Medical Microbiology 4 Baron S Galveston (TX) 1996Not checked yet

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May combine two claims.

The basic QS signaling mechanism consists of a synthase and a receptor; the synthase produces small signaling molecules secreted outside the cell, and upon reaching a threshold concentration they bind and activate the cognate receptor to trigger expression of group-related genes.

“The most basic of these signaling mechanisms consists of a synthase and a receptor. The synthase produces small signaling molecules that are secreted outside of the cell, and upon reaching a threshold concentration (corresponding to high bacterial density), the signaling molecules effectively bind and activate the cognate receptor to trigger the expression of genes involved in group-related”

• cites [5] Waters CM Bassler BL Quorum sensing: cell-to-cell communication in bacteria Annu Rev Cell Dev Biol 2005 21 319 346 16212498Not checked yet

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• cites [13] Gerdt JP Blackwell HE Competition studies confirm two major barriers that can preclude the spread of resistance to quorum-sensing inhibitors in bacteria ACS Chem Biol 2014 9 10 2291 2299 25105594 PMC4201345Not checked yet

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• cites [14] Bassler BL How bacteria talk to each other: regulation of gene expression by quorum sensing Curr Opin Microbiol 1999 2 6 582 587 10607620Not checked yet

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May combine two claims.

The diversity of autoinducers allows specific bacterial species to assess their own cell density within a complex bacterial population and differentiate between other Gram-positive or Gram-negative species.

“The diversity of these autoinducers can thus allow specific bacterial species to assess their own cell density within a complex bacterial population and differentiate between other Gram-positive or Gram-negative species.[17]”

• cites [17] Fuqua C Parsek MR Greenberg EP Regulation of gene expression by cell-to-cell communication: acyl-homoserine lactone quorum sensing Annu Rev Genet 2001 35 1 439 468 11700290Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Many species of staphylococci are opportunistic pathogens that cause infections such as skin infections, nosocomial infections of surgical wounds, food poisoning, toxic shock syndrome, urinary tract infections, and other serious ailments that may result in death if left untreated.

“However, many species of staphylococci are opportunistic pathogens that cause infections such as skin infections, nosocomial infections of surgical wounds, food poisoning, toxic shock syndrome (TSS), urinary tract infections, and other serious ailments that may result in death, if left untreated.[19, 26]”

• cites [19] Peng H Novick R Kreiswirth B Kornblum J Schlievert P Cloning, characterization, and sequencing of an accessory gene regulator (agr) in Staphylococcus aureus J Bacteriol 1988 170 9 4365 4372 2457579 PMC211451Not checked yet

  Not checked in the free run.

• cites [26] Foster T Medical Microbiology 4 Baron S Galveston (TX) 1996Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Autoinducer 2 (AI-2), a furanosyl borate diester, is used by both Gram-negative and Gram-positive bacteria for interspecies signaling.

“Furthermore, autoinducer 2 (AI-2), a furanosyl borate diester, is used by both Gram-negative and Gram-positive bacteria for interspecies signaling.[6]”

• cites [6] Ng W-L Bassler BL Bacterial quorum-sensing network architectures Annu Rev Genet 2009 43 197 222 19686078 PMC4313539Not checked yet

  Not checked in the free run.

May combine two claims.

The premature AIP is encoded by AgrD, which is proteolytically cleaved and secreted out of the cell by AgrB.

“The premature AIP is encoded by AgrD, which is proteolytically cleaved and secreted out of the cell by AgrB.[4, 25, 28–31]”

• cites [4] Ji G Beavis RC Novick RP Cell density control of staphylococcal virulence mediated by an octapeptide pheromone Proc Natl Acad Sci U S A 1995 92 26 12055 12059 8618843 PMC40295Not checked yet

  Not checked in the free run.

• cites [25] Ji G Pei W Zhang L Qiu R Lin J Benito Y Lina G Novick RP Staphylococcus intermedius produces a functional agr autoinducing peptide containing a cyclic lactone J Bacteriol 2005 187 9 3139 3150 15838041 PMC1082806Not checked yet

  Not checked in the free run.

• cites [28] Saenz HL Augsburger V Vuong C Jack RW Götz F Otto M Inducible expression and cellular location of AgrB, a protein involved in the maturation of the staphylococcal quorum-sensing pheromone Arch Microbiol 2000 174 6 452 455 11195102Not checked yet

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• cites [29] Thoendel M Horswill AR Identification of Staphylococcus aureus AgrD residues required for autoinducing peptide biosynthesis J Biol Chem 2009 284 33 21828 21838 19520867 PMC2756194Not checked yet

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• cites [30] Thoendel M Kavanaugh JS Flack CE Horswill AR Peptide signaling in the staphylococci Chem Rev 2011 111 1 117 151 21174435 PMC3086461Not checked yet

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• cites [31] Wang B Zhao A Novick RP Muir TW Key driving forces in the biosynthesis of autoinducing peptides required for staphylococcal virulence Proc Natl Acad Sci U S A 2015 112 34 10679 10684 26261307 PMC4553796Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Gram-positive QS circuits generally consist of four components: the oligopeptide autoinducer, an endopeptidase, a transmembrane histidine kinase receptor, and a response regulator.

“Generally, the Gram-positive QS circuits consist of four different components, the oligopeptide autoinducer, an endopeptidase, a transmembrane histidine kinase receptor, and a response regulator.”

Probably not a substantial claim: may not pass S3 (load-bearing).

There are two main classes of autoinducers that regulate QS: small signal molecules such as N-acyl-homoserine lactones (AHL), and oligopeptide autoinducers.

“There are two main classes of autoinducers that regulate QS: small signal molecules, such as N-acyl-homoserine lactones (AHL), and oligopeptide autoinducers.[6, 17]”

• cites [6] Ng W-L Bassler BL Bacterial quorum-sensing network architectures Annu Rev Genet 2009 43 197 222 19686078 PMC4313539Not checked yet

  Not checked in the free run.

• cites [17] Fuqua C Parsek MR Greenberg EP Regulation of gene expression by cell-to-cell communication: acyl-homoserine lactone quorum sensing Annu Rev Genet 2001 35 1 439 468 11700290Not checked yet

  Not checked in the free run.

May combine two claims.

AHL autoinducers bearing different fatty acid tails are utilized for intraspecies communication by Gram-negative bacteria, while oligopeptide autoinducers of varying sequences are utilized for intraspecies communication by Gram-positive bacteria.

“In general, AHL autoinducers bearing different fatty acid tails are utilized for intraspecies communication by Gram-negative bacteria, while oligopeptide autoinducers of varying sequences are utilized for intraspecies communication by Gram-positive bacteria.”

• cites [6] Ng W-L Bassler BL Bacterial quorum-sensing network architectures Annu Rev Genet 2009 43 197 222 19686078 PMC4313539Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Staphylococci are the most studied Gram-positive genus that utilize QS to cause bacterial infections in their human hosts.

“Staphylococci are the most studied Gram-positive genus that utilize QS to cause bacterial infections in their human hosts.[4, 19–25]”

• cites [4] Ji G Beavis RC Novick RP Cell density control of staphylococcal virulence mediated by an octapeptide pheromone Proc Natl Acad Sci U S A 1995 92 26 12055 12059 8618843 PMC40295Not checked yet

  Not checked in the free run.

• cites [19] Peng H Novick R Kreiswirth B Kornblum J Schlievert P Cloning, characterization, and sequencing of an accessory gene regulator (agr) in Staphylococcus aureus J Bacteriol 1988 170 9 4365 4372 2457579 PMC211451Not checked yet

  Not checked in the free run.

• cites [20] Novick R Projan S Kornblum J Ross H Ji G Kreiswirth B Vandenesch F Moghazeh S The agr P2 operon: An autocatalytic sensory transduction system in Staphylococcus aureus Mol Gen Genet 1995 248 4 446 458 7565609Not checked yet

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• cites [21] Ji G Beavis R Novick RP Bacterial interference caused by autoinducing peptide variants Science 1997 276 5321 2027 2030 9197262Not checked yet

  Not checked in the free run.

• cites [22] Lowy FD Staphylococcus aureus infections N Engl J Med 1998 339 8 520 532 9709046Not checked yet

  Not checked in the free run.

• cites [23] Lyon GJ Wright JS Christopoulos A Novick RP Muir TW Reversible and specific extracellular antagonism of receptor-histidine kinase signaling J Biol Chem 2002 277 8 6247 6253 11733525Not checked yet

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• cites [24] Lyon GJ Wright JS Muir TW Novick RP Key determinants of receptor activation in the agr autoinducing peptides of Staphylococcus aureus Biochemistry 2002 41 31 10095 10104 12146974Not checked yet

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• cites [25] Ji G Pei W Zhang L Qiu R Lin J Benito Y Lina G Novick RP Staphylococcus intermedius produces a functional agr autoinducing peptide containing a cyclic lactone J Bacteriol 2005 187 9 3139 3150 15838041 PMC1082806Not checked yet

  Not checked in the free run.

May combine two claims.

These group behaviors regulate symbiotic relationships with a bacterial host, such as bioluminescence and root nodulation, or coordinate bacterial pathogenicity including swarming, motility, competence, biofilm formation, and virulence factor production.

“These group behaviors regulate symbiotic relationships with a bacterial host, such as bioluminescence and root nodulation, or coordinate bacterial pathogenicity including swarming, motility, competence, biofilm formation, and virulence factor production.[7–9]”

• cites [7] Li Y-H Tian X Quorum sensing and bacterial social interactions in biofilms Sensors 2012 12 3 2519 2538 22736963 PMC3376616Not checked yet

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• cites [8] Miller MB Bassler BL Quorum sensing in bacteria Annu Rev Microbiol 2001 55 1 165 199 11544353Not checked yet

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• cites [9] Parsek MR Greenberg E Sociomicrobiology: the connections between quorum sensing and biofilms Trends Microbiol 2005 13 1 27 33 15639629Not checked yet

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May combine two claims.

The agr circuitry is conserved across staphylococci and is centered on a cyclic peptide signal (autoinducing peptide, AIP) that is secreted by the bacteria.

“The agr circuitry is conserved across staphylococci and is centered on a cyclic peptide signal (autoinducing peptide, AIP) that is secreted by the bacteria.[4, 21, 23, 24, 27]”

• cites [4] Ji G Beavis RC Novick RP Cell density control of staphylococcal virulence mediated by an octapeptide pheromone Proc Natl Acad Sci U S A 1995 92 26 12055 12059 8618843 PMC40295Not checked yet

  Not checked in the free run.

• cites [21] Ji G Beavis R Novick RP Bacterial interference caused by autoinducing peptide variants Science 1997 276 5321 2027 2030 9197262Not checked yet

  Not checked in the free run.

• cites [23] Lyon GJ Wright JS Christopoulos A Novick RP Muir TW Reversible and specific extracellular antagonism of receptor-histidine kinase signaling J Biol Chem 2002 277 8 6247 6253 11733525Not checked yet

  Not checked in the free run.

• cites [24] Lyon GJ Wright JS Muir TW Novick RP Key determinants of receptor activation in the agr autoinducing peptides of Staphylococcus aureus Biochemistry 2002 41 31 10095 10104 12146974Not checked yet

  Not checked in the free run.

• cites [27] Geisinger E George EA Muir TW Novick RP Identification of ligand specificity determinants in AgrC, the Staphylococcus aureus quorum-sensing receptor J Biol Chem 2008 283 14 8930 8938 18222919 PMC2276371Not checked yet

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May combine two claims.

Truncated tAIP-II is a pan-group QS inhibitor with higher IC50 values (260, 230, 4, and 150 nM against AgrC-I, -II, -III, and -IV respectively).

“In addition, the truncated version of AIP-II, tAIP-II (Figure 3), was also found to be a pan-group QS inhibitor, although with higher IC50 values (IC50 values of 260, 230, 4, and 150 nM against AgrC-I, -II, -III, and -IV respectively).[24]”

• cites [24] Lyon GJ Wright JS Muir TW Novick RP Key determinants of receptor activation in the agr autoinducing peptides of Staphylococcus aureus Biochemistry 2002 41 31 10095 10104 12146974Not checked yet

  Not checked in the free run.

May combine two claims.

Replacing the thioester linkage with an amide to afford lactam ring-containing analogs (AIP-III D4A Amide and tAIP-III D2A Amide) maintains high receptor affinities while enhancing pharmacological properties including metabolic and hydrolytic stability and water solubility.

“Lastly, they have also replaced the thioester linkage with an amide to afford a lactam ring-containing analogs, AIP-III D4A Amide and tAIP-III D2A Amide (Figure 3), and have shown that these analogs maintain their high receptor affinities while enhancing their pharmacological properties, including metabolic and hydrolytic stability as well as water solubility.[56]”

• cites [56] Tal-Gan Y Ivancic M Cornilescu G Yang T Blackwell HE Highly Stable, Amide-Bridged Autoinducing Peptide Analogues that Strongly Inhibit the AgrC Quorum Sensing Receptor in Staphylococcus aureus Angew Chem Int Ed Engl 2016 55 31 8913 8917 27276693 PMC4972187Not checked yet

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May combine two claims.

Activation of the TCSTS first upregulates RNAII transcription, resulting in autoinduction of the QS circuitry; later it activates the P3 promoter, leading to RNAIII transcription and expression of group behavior genes including hemolysins and exoproteins.

“The activation of the TCSTS first upregulates RNAII transcription, resulting in autoinduction of the QS circuitry necessary for behavioral change synchronization. At a later stage, the TCSTS also activates the P3 promoter, leading to RNAIII transcription and the expression of group behavior genes including hemolysins and exoproteins.[4, 25]”

• cites [4] Ji G Beavis RC Novick RP Cell density control of staphylococcal virulence mediated by an octapeptide pheromone Proc Natl Acad Sci U S A 1995 92 26 12055 12059 8618843 PMC40295Not checked yet

  Not checked in the free run.

• cites [25] Ji G Pei W Zhang L Qiu R Lin J Benito Y Lina G Novick RP Staphylococcus intermedius produces a functional agr autoinducing peptide containing a cyclic lactone J Bacteriol 2005 187 9 3139 3150 15838041 PMC1082806Not checked yet

  Not checked in the free run.

May combine two claims.

The agr system is activated during the post-exponential growth phase and is responsible for triggering staphylococcal pathogenesis.

“The agr system is activated during the post-exponential growth phase and is responsible for triggering staphylococcal pathogenesis.[4, 19]”

• cites [4] Ji G Beavis RC Novick RP Cell density control of staphylococcal virulence mediated by an octapeptide pheromone Proc Natl Acad Sci U S A 1995 92 26 12055 12059 8618843 PMC40295Not checked yet

  Not checked in the free run.

• cites [19] Peng H Novick R Kreiswirth B Kornblum J Schlievert P Cloning, characterization, and sequencing of an accessory gene regulator (agr) in Staphylococcus aureus J Bacteriol 1988 170 9 4365 4372 2457579 PMC211451Not checked yet

  Not checked in the free run.

May combine two claims.

Removal of the exocyclic tail in AIP-III D4A to form tAIP-III D2A does not reduce potency (IC50 values of 257, 900, 329, and 95.7 pM against AgrC-I, -II, -III, and -IV respectively), making these two analogs the most potent QS inhibitors known to date.

“In addition, they found that removal of the exocyclic tail in that analog to form tAIP-III D2A (Figure 3) does not reduce the potency of the peptide (IC50 values of 257, 900, 329, and 95.7 pM against AgrC-I, -II, -III, and -IV respectively), making these two peptide analogs the most potent QS inhibitors known to date.[45]”

• cites [45] Tal-Gan Y Stacy DM Foegen MK Koenig DW Blackwell HE Highly potent inhibitors of quorum sensing in Staphylococcus aureus revealed through a systematic synthetic study of the group-III autoinducing peptide J Am Chem Soc 2013 135 21 7869 7882 23647400Not checked yet

  Not checked in the free run.

May combine two claims.

The four agr groups strive in different niches and express different virulence factors, resulting in distinct disease profiles associated with each agr group.

“Moreover, the four groups were found to strive in different niches and express different virulence factors, resulting in distinct disease profiles associated with each agr group.”

• cites [42] Jarraud S Mougel C Thioulouse J Lina G Meugnier H Forey F Nesme X Etienne J Vandenesch F Relationships between Staphylococcus aureus genetic background, virulence factors, agr groups (Alleles), and human disease Infect Immun 2002 70 2 631 641 11796592 PMC127674Not checked yet

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• cites [43] Holtfreter S Grumann D Schmudde M Nguyen HTT Eichler P Strommenger B Kopron K Kolata J Giedrys-Kalemba S Steinmetz I Witte W Broker BM Clonal distribution of superantigen genes in clinical Staphylococcus aureus isolates J Clin Microbiol 2007 45 8 2669 2680 17537946 PMC1951235Not checked yet

  Not checked in the free run.

• cites [44] Limbago B Fosheim GE Schoonover V Crane CE Nadle J Petit S Heltzel D Ray SM Harrison LH Lynfield R Dumyati G Townes JM Schaffner W Mu Y Fridkin SK Characterization of Methicillin-Resistant Staphylococcus aureus Isolates Collected in 2005 and 2006 from Patients with Invasive Disease: a Population-Based Analysis J Clin Microbiol 2009 47 5 1344 1351 19321725 PMC2681881Not checked yet

  Not checked in the free run.

• cites [45] Tal-Gan Y Stacy DM Foegen MK Koenig DW Blackwell HE Highly potent inhibitors of quorum sensing in Staphylococcus aureus revealed through a systematic synthetic study of the group-III autoinducing peptide J Am Chem Soc 2013 135 21 7869 7882 23647400Not checked yet

  Not checked in the free run.

• cites [46] Goerke C Kümmel M Dietz K Wolz C Evaluation of intraspecies interference due to agr polymorphism in Staphylococcus aureus during infection and colonization J Infect Dis 2003 188 2 250 256 12854080Not checked yet

  Not checked in the free run.

May combine two claims.

Three additional AIP signals were identified in S. aureus, leading to classification of four specificity groups within the species (agr-I through -IV).

“Soon after, three additional AIP signals were identified in S. aureus, leading to the classification of four specificity groups within the species (termed agr-I through -IV).[21, 39, 40]”

• cites [21] Ji G Beavis R Novick RP Bacterial interference caused by autoinducing peptide variants Science 1997 276 5321 2027 2030 9197262Not checked yet

  Not checked in the free run.

• cites [39] Jarraud S Lyon G Figueiredo A Gérard L Vandenesch F Etienne J Muir T Novick R Exfoliatin-Producing Strains Define a Fourthagr Specificity Group in Staphylococcus aureus J Bacteriol 2000 182 22 6517 6522 11053400 PMC94802Not checked yet

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• cites [40] McDowell P Affas Z Reynolds C Holden MT Wood SJ Saint S Cockayne A Hill PJ Dodd CE Bycroft BW Chan WC Williams P Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus Mol Microbiol 2001 41 2 503 512 11489134Not checked yet

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May combine two claims.

The macrocycle part of the AIP signal is involved in initial receptor recognition, while the exocyclic tail region is largely involved in receptor activation.

“These groups found that the macrocycle part of the AIP signal was involved in the initial receptor recognition, while the exocyclic tail region was largely involved in receptor activation.[50, 53, 55]”

• cites [50] Wright JS Lyon GJ George EA Muir TW Novick RP Hydrophobic interactions drive ligand-receptor recognition for activation and inhibition of staphylococcal quorum sensing Proc Natl Acad Sci U S A 2004 101 46 16168 16173 15528279 PMC528941Not checked yet

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• cites [53] Tal-Gan Y Ivancic M Cornilescu G Cornilescu CC Blackwell HE Structural characterization of native autoinducing peptides and abiotic analogues reveals key features essential for activation and inhibition of an AgrC quorum sensing receptor in Staphylococcus aureus J Am Chem Soc 2013 135 49 18436 18444 24219181 PMC3887510Not checked yet

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• cites [55] Tal-Gan Y Ivancic M Cornilescu G Blackwell HE Characterization of structural elements in native autoinducing peptides and non-native analogues that permit the differential modulation of AgrC-type quorum sensing receptors in Staphylococcus aureus Org Biomol Chem 2016 14 1 113 121 26416476 PMC4681674Not checked yet

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May combine two claims.

Groups -I and -II are predominately found to cause invasive infections, Group -III is predominantly responsible for TSS, and group -IV is considered rare and is mainly involved in skin infections.

“Groups -I and -II are predominately found to cause invasive infections, Group -III is predominantly responsible for TSS, and group -IV is considered rare and is mainly involved in skin infections.[42–46]”

• cites [42] Jarraud S Mougel C Thioulouse J Lina G Meugnier H Forey F Nesme X Etienne J Vandenesch F Relationships between Staphylococcus aureus genetic background, virulence factors, agr groups (Alleles), and human disease Infect Immun 2002 70 2 631 641 11796592 PMC127674Not checked yet

  Not checked in the free run.

• cites [43] Holtfreter S Grumann D Schmudde M Nguyen HTT Eichler P Strommenger B Kopron K Kolata J Giedrys-Kalemba S Steinmetz I Witte W Broker BM Clonal distribution of superantigen genes in clinical Staphylococcus aureus isolates J Clin Microbiol 2007 45 8 2669 2680 17537946 PMC1951235Not checked yet

  Not checked in the free run.

• cites [44] Limbago B Fosheim GE Schoonover V Crane CE Nadle J Petit S Heltzel D Ray SM Harrison LH Lynfield R Dumyati G Townes JM Schaffner W Mu Y Fridkin SK Characterization of Methicillin-Resistant Staphylococcus aureus Isolates Collected in 2005 and 2006 from Patients with Invasive Disease: a Population-Based Analysis J Clin Microbiol 2009 47 5 1344 1351 19321725 PMC2681881Not checked yet

  Not checked in the free run.

• cites [45] Tal-Gan Y Stacy DM Foegen MK Koenig DW Blackwell HE Highly potent inhibitors of quorum sensing in Staphylococcus aureus revealed through a systematic synthetic study of the group-III autoinducing peptide J Am Chem Soc 2013 135 21 7869 7882 23647400Not checked yet

  Not checked in the free run.

• cites [46] Goerke C Kümmel M Dietz K Wolz C Evaluation of intraspecies interference due to agr polymorphism in Staphylococcus aureus during infection and colonization J Infect Dis 2003 188 2 250 256 12854080Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The agr QS circuitry has attracted significant attention as a potential anti-infective target for drug development.

“Thus, this QS circuitry has attracted significant attention as a potential anti-infective target for drug development.”

May combine two claims.

These specificity groups possess unique AIP signals, AgrC sensory domains and AgrB endopeptidases.

“These specific groups were found to possess unique AIP signals (Figure 2), AgrC sensory domains and AgrB endopeptidases.[30]”

• cites [30] Thoendel M Kavanaugh JS Flack CE Horswill AR Peptide signaling in the staphylococci Chem Rev 2011 111 1 117 151 21174435 PMC3086461Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

S. epidermidis, while originally believed harmless, has been identified as one of the major causative agents of nosocomial infections.

“S. epidermidis, while originally believed to be harmless, has been identified as one of the major causative agents of nosocomial infections.[59]”

• cites [59] Vuong C Otto M Staphylococcus epidermidis infections Microbes Infect 2002 4 4 481 489 11932199Not checked yet

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May combine two claims.

The ring size of GBAP can be adjusted without a loss of agonistic activity, and the carbonyl of the macrocycle linker is critical for agonistic activity.

“These experiments revealed that the ring size can be adjusted without a loss of agonistic activity, and that the carbonyl of the macrocycle linker is critical for agonistic activity.”

• cites [77] Nishiguchi K Nagata K Tanokura M Sonomoto K Nakayama J Structure-activity relationship of gelatinase biosynthesis-activating pheromone of Enterococcus faecalis J Bacteriol 2009 191 2 641 650 18996993 PMC2620804Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

In a clinical setting, enterococci are responsible for a wide range of infections including endocarditis, bacteremia, urinary tract infections, and pelvic and intra-abdominal infections.

“In a clinical setting, enterococci are responsible for a wide range of infections including endocarditis, bacteremia, urinary tract infections, and pelvic and intra-abdominal infections.[67]”

• cites [67] Sood S Malhotra M Das BK Kapil A Enterococcal infections & antimicrobial resistance Indian J Med Res 2008 128 2 111 121 19001673Not checked yet

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May combine two claims.

Val3 was critical for activation of the S. epidermidis AgrC-I receptor, and Asp1 and Ser6 could be modified to have increased agonistic activity compared to the native peptide.

“Furthermore, they found that Val3 was critical for activation of the S. epidermidis AgrC-I receptor, and that Asp1 and Ser6 could be modified to have increased agonistic activity compared to the native peptide.[64]”

• cites [64] Yang T Tal-Gan Y Paharik AE Horswill AR Blackwell HE Structure-Function Analyses of a Staphylococcus epidermidis Autoinducing Peptide Reveals Motifs Critical for AgrC-type Receptor Modulation ACS Chem Biol 2016 11 7 1982 1991 27159024 PMC4946969Not checked yet

  Not checked in the free run.

May combine two claims.

Upon reaching an extracellular threshold concentration, GBAP binds and activates FsrC, a transmembrane histidine kinase receptor that phosphorylates the response regulator FsrA to trigger the QS response.

“Upon reaching an extracellular threshold concentration, the GBAP binds and activates FsrC, a transmembrane histidine kinase receptor that phosphorylates the response regulator, FsrA, to trigger the QS response.[74, 76, 77]”

• cites [74] Nakayama J Cao Y Horii T Sakuda S Akkermans AD De Vos WM Nagasawa H Gelatinase biosynthesis-activating pheromone: a peptide lactone that mediates a quorum sensing in Enterococcus faecalis Mol Microbiol 2001 41 1 145 154 11454207Not checked yet

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• cites [76] Nakayama J Cao Y Horii T Sakuda S Nagasawa H Chemical synthesis and biological activity of the gelatinase biosynthesis-activating pheromone of Enterococcus faecalis and its analogs Biosci Biotechnol Biochem 2001 65 10 2322 2325 11758932Not checked yet

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• cites [77] Nishiguchi K Nagata K Tanokura M Sonomoto K Nakayama J Structure-activity relationship of gelatinase biosynthesis-activating pheromone of Enterococcus faecalis J Bacteriol 2009 191 2 641 650 18996993 PMC2620804Not checked yet

  Not checked in the free run.

May combine two claims.

Reversed-alanine scanning identified several novel peptides capable of FsrC inhibition, with the most potent analog being [Ala5,9,11]Z-GBAP.

“Using an N-terminal benzyloxycarbonyl protected receptor binding scaffold, several novel peptides capable of FsrC inhibition were identified, with the most potent analog being [Ala5,9,11]Z-GBAP.”

• cites [78] Nakayama J Yokohata R Sato M Suzuki T Matsufuji T Nishiguchi K Kawai T Yamanaka Y Nagata K Tanokura M Sonomoto K Development of a peptide antagonist against fsr quorum sensing of Enterococcus faecalis ACS Chem Biol 2013 8 4 804 811 23362999Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Enterococci are Gram-positive commensal bacteria known to inhabit soil or the alimentary canals of humans and animals.

“Enterococci are Gram-positive commensal bacteria, known to inhabit soil or the alimentary canals of humans and animals.”

• cites [65] Arias CA Murray BE The rise of the Enterococcus: beyond vancomycin resistance Nat Rev Microbiol 2012 10 4 266 278 22421879 PMC3621121Not checked yet

  Not checked in the free run.

May combine two claims.

The Trp10 side chain contributes to both receptor binding and conformational stability of the cyclic peptide in its compact form.

“In addition, the Trp10 side chain was found to contribute to both receptor binding and conformational stability of the cyclic peptide in its compact form.”

• cites [77] Nishiguchi K Nagata K Tanokura M Sonomoto K Nakayama J Structure-activity relationship of gelatinase biosynthesis-activating pheromone of Enterococcus faecalis J Bacteriol 2009 191 2 641 650 18996993 PMC2620804Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

These infections are caused by a wide range of enterococcal virulence factors, including adhesins, hemolysins, gelatinases, and biofilm formation.

“These infections are caused by a wide range of enterococcal virulence factors, including adhesins, hemolysins, gelatinases, and biofilm formation.[68]”

• cites [68] Coque TM Patterson JE Steckelberg JM Murray BE Incidence of hemolysin, gelatinase, and aggregation substance among enterococci isolated from patients with endocarditis and other infections and from feces of hospitalized and community-based persons J Infect Dis 1995 171 5 1223 1229 7751697Not checked yet

  Not checked in the free run.

May combine two claims.

This GBAP-mediated fsr QS system is responsible for regulation of many enterococcal virulence factors including gelatinase, serine protease, biofilm formation, and other extracellular proteases, making this system a key target for attenuation of E. faecalis virulence.

“This GBAP-mediated fsr QS system is responsible for the regulation of many enterococcal virulence factors including gelatinase, serine protease, biofilm formation, and other extracellular proteases, making this system a key target for the attenuation of E. faecalis virulence.[68]”

• cites [68] Coque TM Patterson JE Steckelberg JM Murray BE Incidence of hemolysin, gelatinase, and aggregation substance among enterococci isolated from patients with endocarditis and other infections and from feces of hospitalized and community-based persons J Infect Dis 1995 171 5 1223 1229 7751697Not checked yet

  Not checked in the free run.

May combine two claims.

The Phe7 side chain faces outside of the cyclic ring and is likely directly involved in binding to the FsrC receptor.

“Combined, the biological assays and structural studies revealed that the Phe7 side chain was facing outside of the cyclic ring, and that this side chain is likely directly involved in binding to the FsrC receptor.”

• cites [77] Nishiguchi K Nagata K Tanokura M Sonomoto K Nakayama J Structure-activity relationship of gelatinase biosynthesis-activating pheromone of Enterococcus faecalis J Bacteriol 2009 191 2 641 650 18996993 PMC2620804Not checked yet

  Not checked in the free run.

May combine two claims.

Two additional agr specificity groups were identified in S. epidermidis, and their AIPs were characterized as 12-amino acid peptides with a ring size equivalent to AIP-I.

“After the discovery of this first S. epidermidis AIP, two additional agr specificity groups were identified in S. epidermidis, and their AIPs were characterized.[61, 62] It was determined that both AIP-II and AIP-III were 12-amino acid peptides, with a ring size equivalent to AIP-I (Figure 2).”

• cites [61] Dufour P Jarraud S Vandenesch F Greenland T Novick RP Bes M Etienne J Lina G High genetic variability of the agr locus in Staphylococcus species J Bacteriol 2002 184 4 1180 1186 11807079 PMC134794Not checked yet

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• cites [62] Olson ME Todd DA Schaeffer CR Paharik AE Van Dyke MJ Buttner H Dunman PM Rohde H Cech NB Fey PD Horswill AR Staphylococcus epidermidis agr quorum-sensing system: signal identification, cross talk, and importance in colonization J Bacteriol 2014 196 19 3482 3493 25070736 PMC4187671Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The rising trend in vancomycin resistance among enterococci, coupled with observed transfer of these antibiotic resistance genes to MRSA, makes enterococci a rapidly increasing threat in the clinical setting.

“The rising trend in vancomycin resistance among enterococci, coupled with the observed transfer of these antibiotic resistance genes to MRSA, makes enterococci a rapidly increasing threat in the clinical setting.[70, 71]”

• cites [70] Weigel LM Clewell DB Gill SR Clark NC McDougal LK Flannagan SE Kolonay JF Shetty J Killgore GE Tenover FC Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus Science 2003 302 5650 1569 1571 14645850Not checked yet

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• cites [71] Cetinkaya Y Falk P Mayhall CG Vancomycin-resistant enterococci Clin Microbiol Rev 2000 13 4 686 707 11023964 PMC88957Not checked yet

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May combine two claims.

Alanine scanning analysis determined that GBAP's entire ring region is involved in agonistic activity, while the tail region side chains are not strictly recognized.

“Through the alanine scanning, it was determined that GBAP’s entire ring region is involved in agonistic activity, while the tail region side chains are not strictly recognized.”

• cites [77] Nishiguchi K Nagata K Tanokura M Sonomoto K Nakayama J Structure-activity relationship of gelatinase biosynthesis-activating pheromone of Enterococcus faecalis J Bacteriol 2009 191 2 641 650 18996993 PMC2620804Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Many species of enterococci, mainly Enterococcus faecalis and Enterococcus faecium, are opportunistic pathogens and enterococci as a genus are the third most commonly isolated nosocomial pathogen.

“Many species of enterococci, mainly Enterococcus faecalis and Enterococcus faecium, are opportunistic pathogens and enterococci as a genus are the third most commonly isolated nosocomial pathogen.[66]”

• cites [66] Hollenbeck BL Rice LB Intrinsic and acquired resistance mechanisms in enterococcus Virulence 2012 3 5 421 569 23076243 PMC3485979Not checked yet

  Not checked in the free run.

May combine two claims.

The native S. epidermidis peptide was effective at inhibiting delta-toxin expression by S. aureus subgroups -I, -II, and -III, while it showed no effect on subgroup -IV.

“The native S. epidermidis peptide was found to be effective at inhibiting delta-toxin expression by S. aureus subgroups -I, -II, and -III, while it showed no effect on subgroup –IV.[63]”

• cites [63] Otto M Echner H Voelter W Götz F Pheromone Cross-Inhibition between Staphylococcus aureus and Staphylococcus epidermidis Infect Immun 2001 69 3 1957 1960 11179383 PMC98112Not checked yet

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May combine two claims.

Initial alanine scanning analysis of GBAP identified several peptides with lessened agonistic activity, but none exhibited antagonistic activity against FsrC.

“Overall, the initial alanine scanning analysis of GBAP identified several peptides with lessened agonistic activity, however, none exhibited antagonistic activity against FsrC.”

• cites [77] Nishiguchi K Nagata K Tanokura M Sonomoto K Nakayama J Structure-activity relationship of gelatinase biosynthesis-activating pheromone of Enterococcus faecalis J Bacteriol 2009 191 2 641 650 18996993 PMC2620804Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Enterococci have high levels of intrinsic and acquired resistance to many antibiotics, including acquired resistance to vancomycin.

“One of the most notable traits of enterococci is their high level of intrinsic and acquired resistance to many antibiotics. Among these is an acquired resistance to the last resort antibiotic, vancomycin, which is generally used to treat multi-drug resistant pathogens like Clostridium difficile and MRSA.[69]”

• cites [69] Eliopoulos GM Gold H Vancomycin-resistant enterococci: mechanisms and clinical observations Clin Infect Dis 2001 33 2 210 219 11418881Not checked yet

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May combine two claims.

Biofilm formation in S. epidermidis is regulated by the agr QS circuit, presenting an opportunity to significantly attenuate S. epidermidis virulence by intercepting this circuitry.

“Biofilm formation in S. epidermidis is regulated by the agr QS circuit, presenting an opportunity to significantly attenuate S. epidermidis virulence by intercepting this circuitry.”

May combine two claims.

agr interference occurred between groups -I and -II, and -I and -III, suggesting that these groups are in competition for the same niches and resources.

“It was determined that agr interference occurred between groups –I and –II, and –I and –III, suggesting that these groups are in competition for the same niches and resources.[62]”

• cites [62] Olson ME Todd DA Schaeffer CR Paharik AE Van Dyke MJ Buttner H Dunman PM Rohde H Cech NB Fey PD Horswill AR Staphylococcus epidermidis agr quorum-sensing system: signal identification, cross talk, and importance in colonization J Bacteriol 2014 196 19 3482 3493 25070736 PMC4187671Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The mutually symbiotic role of L. plantarum in the human body provides an opportunity to improve human health by activating the lam QS circuitry and thus promoting productive processes that can benefit the human host.

“Although not much is known about the lam QS circuit in L. plantarum, the mutually symbiotic role of this bacterium in the human body provides an opportunity to improve human health by activating the lam QS circuitry and thus promoting productive processes that can benefit the human host.”

May combine two claims.

LamA-null L. plantarum strains exhibited significantly reduced adherence ability, and down regulation of sugar metabolism.

“Moreover, de Vos and co-workers reported that LamA-null L. plantarum strains exhibited significantly reduced adherence ability, and down regulation of sugar metabolism.[99]”

• cites [99] Sturme MH Nakayama J Molenaar D Murakami Y Kunugi R Fujii T Vaughan EE Kleerebezem M de Vos WM An agr-like two-component regulatory system in Lactobacillus plantarum is involved in production of a novel cyclic peptide and regulation of adherence J Bacteriol 2005 187 15 5224 5235 16030216 PMC1196011Not checked yet

  Not checked in the free run.

May combine two claims.

One of these QS-TCSs is homologous to the staphylococcal agr and enterococci fsr QS circuits and has been identified as the Lactobacillus agr-like module (lam) with four genes: LamA, LamB, LamC, and LamD that play analogous role to their agr and fsr counterparts.

“One of these QS-TCSs is homologous to the staphylococcal agr and the enterococci fsr QS circuits and has been identified as the Lactobacillus agr-like module (lam) with four genes: LamA, LamB, LamC, and LamD that play analogous role to their agr and fsr counterparts.[99]”

• cites [99] Sturme MH Nakayama J Molenaar D Murakami Y Kunugi R Fujii T Vaughan EE Kleerebezem M de Vos WM An agr-like two-component regulatory system in Lactobacillus plantarum is involved in production of a novel cyclic peptide and regulation of adherence J Bacteriol 2005 187 15 5224 5235 16030216 PMC1196011Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

These bacteria form a durable endospore to survive in oxygen-rich and high temperature environments, and are regarded among some of the most widely distributed pathogens in nature.

“These bacteria are known to form a durable endospore to survive in oxygen-rich and high temperature environments, and they are regarded among some of the most widely distributed pathogens in nature.[79, 80]”

• cites [79] Rood JI Cole ST Molecular genetics and pathogenesis of Clostridium perfringens Microbiol Rev 1991 55 4 621 648 1779929 PMC372840Not checked yet

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• cites [80] Shimizu T Ohtani K Hirakawa H Ohshima K Yamashita A Shiba T Ogasawara N Hattori M Kuhara S Hayashi H Complete genome sequence of Clostridium perfringens, an anaerobic flesh-eater Proc Natl Acad Sci U S A 2002 99 2 996 1001 11792842 PMC117419Not checked yet

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May combine two claims.

LamC is the histidine kinase receptor and LamA acts as the cognate response regulator of this QS circuit.

“LamC is the histidine kinase receptor and LamA acts as the cognate response regulator of this QS circuit.”

Probably not a substantial claim: may not pass S3 (load-bearing).

It has been suggested that clostridium species like C. perfringens that lack the AgrC and AgrA components have the VirS/VirR two-component regulatory system, which has an analogous role to the AgrC/AgrA two-component system found within most agr-based QS circuits.

“It has been suggested that clostridium species like C. perfringens that lack the AgrC and AgrA components have the VirS/VirR two-component regulatory system, which has an analogous role to the AgrC/AgrA two-component system found within most agr-based QS circuits.[85, 90, 91]”

• cites [85] Vidal JE Ma M Saputo J Garcia J Uzal FA McClane BA Evidence that the Agr-like quorum sensing system regulates the toxin production, cytotoxicity and pathogenicity of Clostridium perfringens type C isolate CN3685 Mol Microbiol 2012 83 1 179 194 22150719 PMC3285497Not checked yet

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• cites [90] Vidal JE Chen J Li J McClane BA Use of an EZ-Tn 5-based random mutagenesis system to identify a novel toxin regulatory locus in Clostridium perfringens strain 13 PLoS One 2009 4 7 e6232 19597556 PMC2706048Not checked yet

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• cites [91] Ohtani K Hirakawa H Tashiro K Yoshizawa S Kuhara S Shimizu T Identification of a two-component VirR/VirS regulon in Clostridium perfringens Anaerobe 2010 16 3 258 264 19835966Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

In human infections, clostridium species are responsible for a wide range of diseases including gas gangrene, necrotizing enterocolitis, severe pseudomembranous colitis, and botulism.

“In human infections, clostridium species are responsible for a wide range of diseases including gas gangrene, necrotizing enterocolitis, severe pseudomembranous colitis, and botulism.[79, 81–83]”

• cites [79] Rood JI Cole ST Molecular genetics and pathogenesis of Clostridium perfringens Microbiol Rev 1991 55 4 621 648 1779929 PMC372840Not checked yet

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• cites [81] Hambleton P Clostridium botulinum toxins: a general review of involvement in disease, structure, mode of action and preparation for clinical use J Neurol 1992 239 1 16 20 1311751Not checked yet

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• cites [82] Kelly CP LaMont JT Clostridium difficile infection Annu Rev Med 1998 49 375 390 9509270Not checked yet

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• cites [83] Leffler DA Lamont JT Clostridium difficile infection N Engl J Med 2015 372 16 1539 1548 25875259Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Clostridium species are Gram-positive anaerobes commonly found in soil and sewage, but also known to inhabit the human gastrointestinal tract.

“Clostridium species are Gram-positive anaerobes that are commonly found in soil and sewage, but are also known to inhabit the human gastrointestinal tract.[79]”

• cites [79] Rood JI Cole ST Molecular genetics and pathogenesis of Clostridium perfringens Microbiol Rev 1991 55 4 621 648 1779929 PMC372840Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Recently, several different regulators of toxin production and endospore formation have been discovered in clostridium species.

“Recently, several different regulators of toxin production and endospore formation have been discovered in clostridium species.[84]”

• cites [84] Chen J McClane BA Role of the Agr-like quorum-sensing system in regulating toxin production by Clostridium perfringens type B strains CN1793 and CN1795 Infect Immun 2012 80 9 3008 3017 22689820 PMC3418738Not checked yet

  Not checked in the free run.

May combine two claims.

The ability to modulate many facets of clostridium pathogenesis using QS interference highlights the potential of cyclic peptide analogs that target non-essential pathways in clostridium species as therapeutic agents that are not likely to pressure the bacteria to develop resistance.

“The ability to modulate many facets of clostridium pathogenesis using QS interference highlights the potential of cyclic peptide analogs that target non-essential pathways in clostridium species as therapeutic agents that are not likely to pressure the bacteria to develop resistance.”

• AssumptionRests on an assumption: Prokaryotic cyclic peptide signaling pathways, such as quorum sensing, are non-essential.
• AssumptionRests on an assumption: Therapeutic modulation of quorum sensing pathways is not likely to pressure bacteria to develop resistance.

May combine two claims.

Lactobacillus plantarum naturally colonizes the human gastrointestinal tract and was found to possess multiple QS two-component regulatory systems that include a transmembrane histidine kinase and response regulator.

“One such species is Lactobacillus plantarum, a bacterium that naturally colonizes the human gastrointestinal tract, which was found to possess multiple QS two-component regulatory systems (QS-TCSs) that include a transmembrane histidine kinase and response regulator.[96–99]”

• cites [96] Kleerebezem M Boekhorst J van Kranenburg R Molenaar D Kuipers OP Leer R Tarchini R Peters SA Sandbrink HM Fiers MW Stiekema W Lankhorst RM Bron PA Hoffer SM Groot MN Kerkhoven R de Vries M Ursing B de Vos WM Siezen RJ Complete genome sequence of Lactobacillus plantarum WCFS1 Proc Natl Acad Sci U S A 2003 100 4 1990 1995 12566566 PMC149946Not checked yet

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• cites [97] Sturme MH Francke C Siezen RJ de Vos WM Kleerebezem M Making sense of quorum sensing in lactobacilli: a special focus on Lactobacillus plantarum WCFS1 Microbiology 2007 153 12 3939 3947 18048908Not checked yet

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• cites [98] Kleerebezem M Quadri LE Kuipers OP De Vos WM Quorum sensing by peptide pheromones and two-component signal-transduction systems in Gram-positive bacteria Mol Microbiol 1997 24 5 895 904 9219998Not checked yet

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• cites [99] Sturme MH Nakayama J Molenaar D Murakami Y Kunugi R Fujii T Vaughan EE Kleerebezem M de Vos WM An agr-like two-component regulatory system in Lactobacillus plantarum is involved in production of a novel cyclic peptide and regulation of adherence J Bacteriol 2005 187 15 5224 5235 16030216 PMC1196011Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Targeting the agr-based QS circuit, likely using cyclic peptide inhibitors derived from the native signaling peptide, could be utilized as a therapeutic pathway for treatment and prevention of clostridium-based infections.

“As sporulation and toxin production are important not only for clostridium pathogenesis, but also for their survival, targeting the agr-based QS circuit, likely using cyclic peptide inhibitors derived from the native signaling peptide, could be utilized as a therapeutic pathway for the treatment and prevention of clostridium-based infections.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Lactic acid bacteria are part of the genus Lactobacillus and are essential to the human gastrointestinal microflora, providing major health benefits by breaking down food and synthesizing essential vitamins.

“Lactic acid bacteria are part of the genus Lactobacillus and are essential to the human gastrointestinal microflora, providing major health benefits by breaking down food and synthesizing essential vitamins.[93–95]”

• cites [93] Vaughan EE de Vries MC Zoetendal EG Ben-Amor K Akkermans AD de Vos WM In Lactic Acid Bacteria: Genetics, Metabolism and Applications Springer 2002 341 352Not checked yet

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• cites [94] Ouwehand AC Salminen S Isolauri E Probiotics: an overview of beneficial effects Antonie Van Leeuwenhoek 2002 82 1–4 279 289 12369194Not checked yet

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• cites [95] Ahrné S Nobaek S Jeppsson B Adlerberth I Wold AE Molin G The normal Lactobacillus flora of healthy human rectal and oral mucosa J Appl Microbiol 1998 85 1 88 94 9721659Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

There are three structural groups of hormones: fat or phospholipid derived hormones (eicosanoids and steroids), amino acid derived hormones (monoamine derivatives), and polypeptide derived hormones (peptides and protein).

“There are three structural groups of hormones: fat or phospholipid derived hormones (eicosanoids and steroids), amino acid derived hormones (monoamine derivatives), and polypeptide derived hormones (peptides and protein).[101]”

• cites [101] Nussey SS Whitehead SA Endocrinology: an integrated approach CRC Press 2013 20821847Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Lanreotide is administered once every 7-14 days and is used to treat acromegaly in addition to helping ease symptoms of neuroendocrine tumors.

“A similar long-lasting FDA approved synthetic analog, Lanreotide, is administered once every 7–14 days and is used to treat acromegaly in addition to helping ease symptoms of neuroendocrine tumors.”

Probably not a substantial claim: may not pass S3 (load-bearing).

According to the signal hypothesis, polypeptides contain a signal sequence at the N-terminus that aids in transporting the protein or peptide to the rough endoplasmic reticulum through the translocon.

“According to the signal hypothesis proposed by Blobel and Sabatini, polypeptides contain a signal sequence at the N-terminus that aids in transporting the protein/peptide to the rough endoplasmic reticulum (ER) through the translocon.[104, 105]”

• cites [104] Johnson AE van Waes MA The translocon: a dynamic gateway at the ER membrane Annu Rev Cell Dev Biol 1999 15 1 799 842 10611978Not checked yet

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• cites [105] Blobel G Sabatini DD Biomembranes Springer 1971 193 195Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The stability of different cyclic peptides can vary dramatically; oxytocin, vasopressin, and somatostatin have relatively short half-lives compared to insulin.

“That being said, the stability of different cyclic peptides can vary dramatically, for example oxytocin, vasopressin, and somatostatin have relatively short half-lives compared to insulin (Figure 9).”

May combine two claims.

These findings led to the development of the first FDA approved synthetic analog, Octreotide, which is used to treat acromegaly, various pituitary tumors, and pancreatic tumors by inhibiting the release of growth hormone, glucagon, and insulin.

“These findings led to the development of the first FDA approved synthetic analog, Octreotide, which is used to treat acromegaly, various pituitary tumors, and pancreatic tumors by inhibiting the release of growth hormone, glucagon, and insulin.[125]”

• cites [125] Lamberts SWJ Van der Lely A-J de Herder WW Hofland LJ Octreotide N Engl J Med 1996 334 4 246 254 8532003Not checked yet

  Not checked in the free run.

May combine two claims.

The signal peptide is cleaved by proteases in a co-translational step to transport the resulting prohormone to the ER, where it undergoes further processing including folding and cyclization.

“This signal peptide gets cleaved by proteases in a co-translational step to transport the resulting polypeptide (prohormone) to the ER, where it undergoes further processing, including proper folding and cyclization (Figure 8).[106, 107]”

• cites [106] Xu H Shields D Prohormone processing in the trans-Golgi network: endoproteolytic cleavage of prosomatostatin and formation of nascent secretory vesicles in permeabilized cells J Cell Biol 1993 122 6 1169 1184 8104189 PMC2119863Not checked yet

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• cites [107] Perone M Castro M Prohormone and proneuropeptide synthesis and secretion Histol Histopathol 1997 12 4 1179 1188 9302577Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Peptide hormones are translated as nascent polypeptides called preprohormones that contain a signal peptide sequence.

“Peptide hormones are translated as nascent polypeptides called preprohormones that contain a signal peptide sequence.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Hormones are the chemical messengers that mediate various signal transduction pathways and regulate the overall functions of multicellular organisms.

“Hormones are the chemical messengers that mediate various signal transduction pathways and regulate the overall functions of multicellular organisms.”

• cites [100] Berg JM Tymoczko JL Stryer L Biochemistry W.H. Freeman New York 2012Not checked yet

  Not checked in the free run.

May combine two claims.

Lys6 and Trp7 in SST-14 (20 and 21 in SST-28) are essential for bioactivity and incorporation of D-amino acids in these positions further stabilizes the beta turn.

“It was later determined that Lys6 and Trp7 in SST-14 (20 and 21 in SST-28) are essential for bioactivity and that the incorporation of D-amino acids in these positions further stabilizes the beta turn.”

May combine two claims.

Somatostatin produced in the hypothalamus travels to the anterior pituitary gland where it inhibits release of growth hormone, prolactin, and thyroid stimulating hormone, while somatostatin from the gastrointestinal tract and pancreas inhibits secretion of calcitonin, gastrin, insulin, glucagon and vasoactive intestinal peptide.

“Somatostatin produced in the hypothalamus travels to the anterior pituitary gland where it inhibits the release of growth hormone, prolactin, and thyroid stimulating hormone, while somatostatin produced by the gastrointestinal tract and pancreas inhibits the secretion of various gastrointestinal hormones such as calcitonin, gastrin, insulin, glucagon and vasoactive intestinal peptide.[116, 117]”

• cites [116] Kumar U Grant M Cellular Peptide Hormone Synthesis and Secretory Pathways Rehfeld FJ Bundgaard RJ Springer Berlin Heidelberg Berlin, Heidelberg 2010 97 120Not checked yet

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• cites [117] Ten Bokum A Hofland L van Hagen PM Somatostatin and somatostatin receptors in the immune system: a review Eur Cytokine Netw 2000 11 2 161 176 10903795Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

These glands secrete various hormones into the bloodstream so that the hormones can reach their target tissues or organs in a timely manner.

“These glands secrete various hormones into the bloodstream so that the hormones can reach their target tissues or organs in a timely manner.”

• cites [101] Nussey SS Whitehead SA Endocrinology: an integrated approach CRC Press 2013 20821847Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Polypeptide derived hormones are the most abundant class of hormones, consisting of short to long polypeptide chains.

“Polypeptide derived hormones are the most abundant class of hormones consisting of short to long polypeptide chains.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Some hormones, such as oxytocin, can operate under a positive feedback system where secretion increases in response to the hormone's presence.

“On the other hand, some hormones, such as oxytocin, can operate under a positive feedback system where the secretion of the hormone increases in response to the hormone’s presence.[102]”

• cites [102] Russell JA Leng G Douglas AJ The magnocellular oxytocin system, the fount of maternity: adaptations in pregnancy Front Neuroendocrinol 2003 24 1 27 61 12609499Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

SST-28 makes up about 20-30% of somatostatin in the brain and is mainly found in the gastrointestinal tract.

“SST-28 makes up about 20–30% of somatostatin in the brain and is mainly found in the gastrointestinal tract.[115]”

• cites [115] Patel YC Somatostatin and Its Receptor Family Front Neuroendocrinol 1999 20 3 157 198 10433861Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Somatostatin production starts as a 116-amino acid preprohormone, preprosomatostatin, that has its signal peptide cleaved prior to entering the ER to form the 92-amino acid prohormone, prosomatostatin.

“Somatostatin production starts as a 116-amino acid preprohormone, preprosomatostain, that has its signal peptide cleaved prior to entering the ER to form the 92-amino acid prohormone, prosomatostatin.[116, 117]”

• cites [116] Kumar U Grant M Cellular Peptide Hormone Synthesis and Secretory Pathways Rehfeld FJ Bundgaard RJ Springer Berlin Heidelberg Berlin, Heidelberg 2010 97 120Not checked yet

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• cites [117] Ten Bokum A Hofland L van Hagen PM Somatostatin and somatostatin receptors in the immune system: a review Eur Cytokine Netw 2000 11 2 161 176 10903795Not checked yet

  Not checked in the free run.

May combine two claims.

Water soluble peptide hormones act as primary messengers because they cannot cross the cell membrane, signaling target cells to initiate signal transduction cascades through intracellular secondary messengers.

“Water soluble peptide hormones act as primary messengers because they cannot cross the cell membrane, thus they signal the target cells to initiate signal transduction cascades through the production or absorption of intracellular secondary messengers.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All hormones have relatively short half-lives because they have a dynamic role of activating and deactivating various signal transduction pathways.

“In general, all hormones have relatively short half-lives since they have a dynamic role of activating and deactivating various signal transduction pathways.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Certain hormones, such as estrogen, can induce a positive feedback system on other hormones.

“In some cases, certain hormones, such as estrogen, can induce a positive feedback system on other hormones.[103]”

• cites [103] Wintermantel TM Campbell RE Porteous R Bock D Gröne H-J Todman MG Korach KS Greiner E Pérez CA Schütz G Herbison AE Definition of Estrogen Receptor Pathway Critical for Estrogen Positive Feedback to Gonadotropin-Releasing Hormone Neurons and Fertility Neuron 2006 52 2 271 280 17046690 PMC6116893Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Eicosanoid, polypeptide, and amino acid derived hormones have relatively short half-lives of seconds to minutes, while steroid hormones have moderately short half-lives of minutes to hours.

“Eicosanoids, polypeptide, and amino acid derived hormones have relatively short half-lives (seconds to minutes), while steroid hormones have moderately short half-lives (minutes to hours).”

May combine two claims.

The use of somatostatin therapeutically is limited by its short half-life and has led to the development of analogs that are longer lasting.

“The use of somatostatin therapeutically is limited by its short half-life and has led to the development of analogs that are longer lasting.”

May combine two claims.

Somatostatin is highly susceptible to endopeptidase degradation and thus has a short half-life of approximately 2-3 minutes.

“Somatostatin is highly susceptible to endopeptidase degradation and thus has a short half-life of approximately 2–3 minutes.[118, 124]”

• cites [118] Patel YC S Galanopoulou A Rabbani SN Liu J-L Ravazzola M Amherdt M Somatostatin-14, somatostatin-28, and prosomatostatin[1–10] are independently and efficiently processed from prosomatostatin in the constitutive secretory pathway in islet somatostatin tumor cells (1027B2)1 Mol Cell Endocrinol 1997 131 2 183 194 9296377Not checked yet

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• cites [124] Mentlein R Dahms P Endopeptidases 24.16 and 24.15 are responsible for the degradation of somatostatin, neurotensin, and other neuropeptides by cultivated rat cortical astrocytes J Neurochem 1994 62 1 27 36 7903352Not checked yet

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May combine two claims.

Structure-function relationship studies of somatostatin revealed that a beta turn formed by residues 7-10 in SST-14 (21-24 in SST-28) is required for receptor binding and that the disulfide bond creates a conformational constraint that stabilizes this conformation.

“Structure-function relationship studies of somatostatin revealed that a beta turn formed by residues 7–10 in SST-14 (21–24 in SST-28) is required for receptor binding and that the disulfide bond creates a conformational constraint that stabilizes this conformation.[123]”

• cites [123] Sun L Coy DH Somatostatin and its Analogs Curr Drug Targets 2016 17 5 529 537 26951062Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Octreotide has a longer half-life of 2 hours intravenously and also exists in a long-acting release form administered once every 28 days.

“Octreotide has a longer half-life of 2 hours intravenously and also exists in a long-acting release form administered once every 28 days.[125, 126]”

• cites [125] Lamberts SWJ Van der Lely A-J de Herder WW Hofland LJ Octreotide N Engl J Med 1996 334 4 246 254 8532003Not checked yet

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• cites [126] McKeage K Cheer S Wagstaff AJ Octreotide Long-Acting Release (LAR) Drugs 2003 63 22 2473 2499 14609359Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

In eukaryotic systems cyclic peptide scaffolds have a more essential role, regulating the overall function of multicellular organisms.

“In eukaryotic systems these cyclic peptide scaffolds have a more essential role, regulating the overall function of multicellular organisms.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Hormones must have high affinity and specificity to their particular receptors because they are secreted in low concentrations and should only activate their desired pathway.

“Hormones must have high affinity and specificity to their particular receptors because they are secreted in low concentrations and should only activate their desired pathway.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The dynamic functions and processes occurring in multicellular organisms require constant activation and deactivation of many signal transduction pathways.

“The dynamic functions and processes occurring in multicellular organisms require constant activation and deactivation of many signal transduction pathways.[100]”

• cites [100] Berg JM Tymoczko JL Stryer L Biochemistry W.H. Freeman New York 2012Not checked yet

  Not checked in the free run.

May combine two claims.

Somatostatin regulates, directly or indirectly, many functions in the body including cell growth, cell regeneration, and stomach acid production by binding five different somatostatin receptor subtypes (SSTR1-5).

“Therefore, somatostatin regulates, directly or indirectly, many functions in the body including cell growth, cell regeneration, and stomach acid production by binding five different somatostatin receptor subtypes (SSTR1-5).[115, 120–122]”

• cites [115] Patel YC Somatostatin and Its Receptor Family Front Neuroendocrinol 1999 20 3 157 198 10433861Not checked yet

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• cites [120] Harris AG Somatostatin and somatostatin analogues: pharmacokinetics and pharmacodynamic effects Gut 1994 35 3 Suppl S1 S4 PMC1374387 7911441Not checked yet

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• cites [121] Larsson L-I Goltermann N de Magistris L Rehfeld JF Schwartz TW Somatostatin Cell Processes as Pathways for Paracrine Secretion Science 1979 205 4413 1393 1395 382360Not checked yet

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• cites [122] Rai U Thrimawithana TR Valery C Young SA Therapeutic uses of somatostatin and its analogues: Current view and potential applications Pharmacol Therapeut 2015 152 98 110 25956467Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Within eukaryotic systems, modifications of these peptides have been explored in order to increase their stability and potential therapeutic utility.

“Within eukaryotic systems, modifications of these peptides have been explored in order to increase their stability and potential therapeutic utility.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Most hormones are under a negative feedback system to maintain homeostasis, where secretion decreases in response to activation of the hormone's signal transduction pathway.

“Most hormones are under a negative feedback system to maintain homeostasis where the secretion of hormones is decreased in response to activation of the hormone’s signal transduction pathway.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The majority of hormones produced in multicellular organisms are released into the bloodstream and are part of the endocrine system, which consists of the following hormone-producing glands: liver, pineal, pituitary, hypothalamus, parathyroid, testes, ovaries, adrenal and thymus.

“The majority of hormones produced in multicellular organisms are released into the bloodstream and are part of the endocrine system, which consists of the following hormone-producing glands: liver, pineal, pituitary, hypothalamus, parathyroid, testes, ovaries, adrenal and thymus.[101]”

• cites [101] Nussey SS Whitehead SA Endocrinology: an integrated approach CRC Press 2013 20821847Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Three insulin dimers combine to form a hexamer by coordinating two zinc atoms with the imidazole groups of three His residues located at position B10, which gets packaged with other hexamers into insulin granules.

“Three dimers will combine to form a hexamer by coordinating two zinc atoms with the imidazole groups of three His residues located at position B10 that gets packaged with other hexamers into insulin granules.[131]”

• cites [131] Fu Z Gilbert ER Liu D Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes Curr Diabetes Rev 2013 9 1 25 53 22974359 PMC3934755Not checked yet

  Not checked in the free run.

May combine two claims.

Degludec is a new FDA approved ultrastable analog very similar to Detemir, having the same ThrB30 deletion but possessing a different fatty acid, hexadecanedioic acid, attached to the epsilon-amino group of LysB29 by a γ-L-glutamic acid linker.

“Recently, a new FDA approved ultrastable analog was released to the market: Degludec (Figure 11), which is very similar to Determir, having the same ThrB30 deletion but possessing a different fatty acid, hexadecanedioic acid, attached to the epsilon-amino group of LysB29 by a γ-L-glutamic acid linker.[143]”

• cites [143] Jonassen I Havelund S Hoeg-Jensen T Steensgaard DB Wahlund P-O Ribel U Design of the Novel Protraction Mechanism of Insulin Degludec, an Ultra-long-Acting Basal Insulin Pharmaceut Res 2012 29 8 2104 2114 PMC3399081 22485010Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Current research regarding insulin analogs focuses on prolonging the bioactivity of the analogs, which would benefit diabetics by having them inject insulin less frequently.

“Current research regarding insulin analogs focuses on prolonging the bioactivity of the analogs, which would benefit diabetics by having them inject insulin less frequently.[135, 141, 142]”

• cites [135] Weiss M Design of ultra-stable insulin analogues for the developing world J Health Spec 2013 1 2 59 70Not checked yet

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• cites [141] Atkin S Javed Z Fulcher G Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus Ther Adv Chronic Dis 2015 6 6 375 388 26568812 PMC4622316Not checked yet

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• cites [142] Zinman B Newer insulin analogs: advances in basal insulin replacement Diabetes Obes Metab 2013 15 s1 6 10 23448197Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The social behaviors influenced by oxytocin include social bonding, depression, suppression of anxiety, and well-being, but it can also enhance fear and anxiety during negative or stressful experiences.

“The social behaviors influenced by oxytocin include social bonding, depression, suppression of anxiety, and well-being, but it can also enhance fear and anxiety during negative or stressful experiences.[151, 152]”

• cites [151] Churchland PS Winkielman P Modulating social behavior with oxytocin: How does it work? What does it mean? Horm Behav 2012 61 3 392 399 22197271 PMC3312973Not checked yet

  Not checked in the free run.

• cites [152] Guzman YF Tronson NC Jovasevic V Sato K Guedea AL Mizukami H Nishimori K Radulovic J Fear-enhancing effects of septal oxytocin receptors Nat Neurosci 2013 16 9 1185 1187 23872596 PMC3758455Not checked yet

  Not checked in the free run.

May combine two claims.

Seglitide selectively binds to SSTR2 and led to the development of various cyclohexapeptide analogs.

“This synthetic analog was found to selectively bind to SSTR2 and led to the development of various cyclohexapeptide analogs.[129]”

• cites [129] Robertson CR Flynn SP White HS Bulaj G Anticonvulsant neuropeptides as drug leads for neurological diseases Nat Prod Rep 2011 28 4 741 762 21340067Not checked yet

  Not checked in the free run.

May combine two claims.

Proinsulin folds into a cyclic prohormone containing three disulfide bridges and is then cleaved by prohormone convertases and a carboxypeptidase, forming a monomeric cyclic peptide hormone.

“Proinsulin folds into a cyclic prohormone containing three disulfide bridges and is then cleaved by prohormone convertases and a carboxypeptidase, forming a monomeric cyclic peptide hormone.”

• cites [131] Fu Z Gilbert ER Liu D Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes Curr Diabetes Rev 2013 9 1 25 53 22974359 PMC3934755Not checked yet

  Not checked in the free run.

May combine two claims.

Aspart is an FDA approved insulin analog where ProB28 was changed to Asp, creating a charge repulsion at the dimer interface, leading again to a rapid-acting insulin analog.

“For example, Aspart, another FDA approved insulin analog (Figure 11), is an insulin analog where ProB28 was changed to Asp creating a charge repulsion at the dimer interface, leading again to a rapid-acting insulin analog.[134, 135]”

• cites [134] Homko C Deluzio A Jimenez C Kolaczynski JW Boden G Comparison of Insulin Aspart and Lispro Diabetes Care 2003 26 7 2027 2031 12832307Not checked yet

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• cites [135] Weiss M Design of ultra-stable insulin analogues for the developing world J Health Spec 2013 1 2 59 70Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Oxytocin regulates many social and nonsocial functions in the body by binding to the oxytocin receptor located in the uterus and central nervous system.

“Oxytocin regulates many social and nonsocial functions in the body by binding to the oxytocin receptor located in the uterus and central nervous system.[146, 149]”

• cites [146] Gimpl G Fahrenholz F The Oxytocin Receptor System: Structure, Function, and Regulation Physiol Rev 2001 81 2 629 683 11274341Not checked yet

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• cites [149] Yang H-P Wang L Han L Wang SC Nonsocial functions of hypothalamic oxytocin ISRN Neurosci 2013 2013 PMC4045544 24967304Not checked yet

  Not checked in the free run.

May combine two claims.

The active monomeric form of insulin binds to the insulin receptor located on the surface of cells and initiates a signal transduction cascade intracellularly that allows the entry of glucose into the cell.

“The active monomeric form binds to the insulin receptor located on the surface of cells and initiates a signal transduction cascade intracellularly that allows the entry of glucose into the cell.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Oxytocin has only one disulfide bridge while neurophysin I has seven.

“Oxytocin has only one disulfide-bridge while neurophysin I has seven.”

May combine two claims.

These oligomers prolong the dissociation of Degludec to the monomeric form, giving it a duration of action of more than 42 hours and allowing diabetic patients to inject it once every couple of days to help maintain basal insulin levels.

“These oligomers prolong the dissociation of the analogs to the monomeric form, giving it duration of action of more than 42 hours and allowing diabetic patients to inject it once every couple of days to help maintain basal insulin levels.[144]”

• cites [144] Haahr H Heise T A Review of the Pharmacological Properties of Insulin Degludec and Their Clinical Relevance Clin Pharmacokinet 2014 53 9 787 800 25179915 PMC4156782Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Afrezza is the first FDA approved ultra-rapid-acting insulin preparation, consisting of powdered recombinant human insulin containing fumaryl diketopiperazine as an inert excipient.

“Researchers have also found an alternative method of delivering insulin in the form of inhalation, creating the first FDA approved ultra-rapid-acting insulin preparation, Afrezza.[145] Afrezza consists of powdered recombinant human insulin containing fumaryl diketopiperazine as an inert excipient.”

• cites [145] Klonoff DC Afrezza Inhaled Insulin: The Fastest-Acting FDA-Approved Insulin on the Market Has Favorable Properties J Diabetes Sci Technol 2014 8 6 1071 1073 25355710 PMC4455463Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Therapeutic insulin and its analogs are mass produced using recombinant DNA technology for the treatment of diabetes mellitus.

“Therapeutic insulin and its analogs are mass produced using recombinant DNA technology for the treatment of diabetes mellitus.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Beta cells located in the islet of Langerhans of the pancreas produce a 110-amino acid pre-prohormone, preproinsulin, that is cleaved by signal peptidases into an 86-amino acid prohormone peptide, proinsulin.

“Beta cells located in the islet of Langerhans of the pancreas produce a 110-amino acid pre-prohormone, preproinsulin, that is cleaved by signal peptidases into an 86-amino acid prohormone peptide, proinsulin.[131]”

• cites [131] Fu Z Gilbert ER Liu D Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes Curr Diabetes Rev 2013 9 1 25 53 22974359 PMC3934755Not checked yet

  Not checked in the free run.

May combine two claims.

The addition of the two Arg residues shifted the pI of Glargine from 5.4 to 6.7, making it more soluble in acidic conditions and less soluble at physiological pH.

“The addition of the two Arg residues shifted the pI of the molecule from 5.4 to 6.7 making it more soluble in acidic conditions and less soluble at physiological pH.[137]”

• cites [137] Bolli BG Di Marchi DR Park DG Pramming S Koivisto AV Insulin analogues and their potential in the management of diabetes mellitus Diabetologia 1999 42 10 1151 1167 10525654Not checked yet

  Not checked in the free run.

May combine two claims.

Lispro is the first FDA approved insulin analog, almost identical to native insulin with amino acids ProB28 and LysB29 reversed; this modification decreases the dimerization rate resulting in a rapid-acting insulin analog.

“The first FDA approved insulin analog, Lispro (Figure 11), is almost identical to native insulin with amino acids ProB28 and LysB29 reversed. This modification decreases the dimerization rate resulting in a rapid-acting insulin analog.[133]”

• cites [133] Holleman F Hoekstra JBL Insulin Lispro N Engl J Med 1997 337 3 176 183 9219705Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Research is currently pursuing thermostable insulin analogs, which would make insulin more available to third-world countries that do not have access to electricity and refrigeration.

“Another area of research that is currently being pursued involves creating thermostable analogs, which would make insulin more available to third-world countries that do not have access to electricity and refrigeration, a requirement for most insulin preparations currently used.[135]”

• cites [135] Weiss M Design of ultra-stable insulin analogues for the developing world J Health Spec 2013 1 2 59 70Not checked yet

  Not checked in the free run.

May combine two claims.

Glargine is an insulin analog where AsnA21 was replaced with Gly and two Arg residues were added to the C-terminus of the B chain.

“Glargine is an insulin analog where the AsnA21 was replaced with Gly and two Arg residues were added to the C-terminus of the B chain.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Pasireotide binds all SSTR subtypes except SSTR-4 and was FDA approved in 2012 to treat Cushing disease.

“Pasireotide binds all SSTR subtypes except SSTR-4 and was FDA approved in 2012 to treat Cushing disease.[123]”

• cites [123] Sun L Coy DH Somatostatin and its Analogs Curr Drug Targets 2016 17 5 529 537 26951062Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Prooxytocin has a 93-amino acid carrier protein, neurophysin I, that gets cleaved from the prohormone and helps transport the mature oxytocin to the posterior pituitary gland where it gets secreted into the blood.

“Prooxytocin has a 93-amino acid carrier protein, neurophysin I, that gets cleaved from the prohormone and helps transport the mature oxytocin to the posterior pituitary gland where it gets secreted into the blood.”

• cites [148] Richter D Molecular events in expression of vasopressin and oxytocin and their cognate receptors Am J Physiol 1988 255 2 Pt 2 F207 219 2841868Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Mature insulin consists of two chains, the A chain (21 amino acids) and the B chain (30 amino acids), linked by two intermolecular disulfide bridges with an additional intramolecular disulfide bridge on the A chain.

“The mature insulin hormone consists of two chains: the A chain (21 amino acids) and the B chain (30 amino acids), which are linked by two intermolecular disulfide bridges with an additional intramolecular disulfide bridge present on the A chain.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.