Effective biomarkers and therapeutic targets of nerve-immunity interaction in the treatment of depression: an integrated investigation of the miRNA-mRNA regulatory networks

May combine two claims.

FunRich analysis found 578 up-regulated target mRNAs and 635 down-regulated DE-miRNAs.

“578 up-regulated target mRNA and 635 down-regulated DE-miRNAs were found (Figure 5C)”

May combine two claims.

Five hub mRNAs were identified: KCND2, MYT1L, GJA1, CHL1, and SNAP25, all up-regulated.

“We discovered five hub genes: KCND2, MYT1L, GJA1, CHL1, and SNAP25, which were all up-regulated genes.”

• Also stated in: § PPI network construction and screening of hub mRNAs and miRNAs · plain

  “It can be pointed out that the core genes include KCND2, MYT1L, GJA1, CHL1, and SNAP25 (Table 3).”

• Also stated in: § DISCUSSION · plain

  “We discovered 5 hub DE-mRNAs: KCND2, MYT1L, GJA1, CHL1, and SNAP25, which were all up-regulated genes.”

May combine two claims. The quote only partly states this claim.

In MDD, hsa-miR-206 and hsa-miR-338-3p were both down-regulated.

“However, in MMD, the equivalent miRNAs, hsa-miR-206 and hsa-miR-338-3p, were both down-regulated.”

• Also stated in: § DISCUSSION · plain

  “Both hsa-miR-206 and hsa-miR-338-3p, which are down-regulated in MMD, are similar miRNAs.”

May combine two claims.

FunRich discovered 59 biological processes, 267 cellular components, and 116 molecular functions for DE-miRNAs.

“FunRich program discovered 59 BP, 267 CC, and 116 MF (Figure 6).”

May combine two claims.

470 BP mainly involves neutrophil, T cell and B cell activation, activation of surface receptors and immune response signal pathways, and regulation of chemical synaptic transmission.

“470 BP mainly involves neutrophil, T cell and B cell activation, activation of surface receptors and immune response signal pathways, and regulation of chemical synaptic transmission.”

• AssumptionRests on an assumption: The GEO datasets used are representative of the MMD patient population.

May combine two claims.

The B cell and T cell receptor signal pathways, the chemokine signal pathway, and the JAK-STAT signal pathway are linked to immune and neurological regulation.

“Among the signaling pathways studied in this study, the signal pathways mentioned below are linked to immune and neurological regulation. The B cell and T cell receptor signal pathways, the chemokine signal pathway, and the JAK-STAT signal pathway.”

• AssumptionRests on an assumption: The GEO datasets used are representative of the MMD patient population.

May combine two claims.

Th1 and Th2 cell differentiation, and Th17 cell differentiation are involved in immune and neurological regulation.

“Th1 and Th2 cell differentiation, and Th17 cell differentiation are all involved.”

• AssumptionRests on an assumption: The GEO datasets used are representative of the MMD patient population.

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

BDNF participates in neuroplasticity and protection throughout brain development and plays an important role in emotion-related brain activities.

“BDNF participates in neuroplasticity and protection throughout brain development, as well as playing an important role in emotion-related brain activities [33].”

• cites [33] Weinberger, 2003, The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function., Cell sourceNot checked yet

  Not checked in the free run.

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

MiRNAs directly regulate more than 30% of the genes in cells by inhibiting the degradation or translation of target mRNAs.

“MiRNAs are tiny non-coding RNAs that directly regulate more than 30% of the genes in cells by inhibiting the degradation or translation of target mRNAs [28].”

• cites [28] Rajewsky, 2007, The evolution of gene regulation by transcription factors and microRNAs., Nat Rev Genet sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

These miRNAs can activate or inhibit the T cell receptor signal pathway, JAK-STAT and other signal pathways, govern immune-inflammatory response, neuronal remodeling, and mediate the onset and development of MMD.

“These miRNAs can activate or inhibit the T cell receptor signal pathway, JAK-STAT and other signal pathways, govern immune-inflammatory response, neuronal remodeling, and mediate the onset and development of MMD”

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

MiR-338-3p was first thought to be a cancer-related miRNA, but was later found to be involved in neuronal regulation, including the Parkinson's disease pathway.

“MiR-338-3p was first thought to be a cancer-related miRNA, but it was later found to be involved in neuronal regulation, including the Parkinson’s disease pathway [32].”

• cites [32] Luikart, 2017, MiR-338-3p regulates neuronal maturation and suppresses glioblastoma proliferation., PLoS One sourceNot checked yet

  Not checked in the free run.

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

MiR-206 was first thought to regulate skeletal muscle embryonic development.

“MiR-206, a member of the muscle-specific miR-1 family, was first thought to regulate skeletal muscle embryonic development [31].”

• cites [31] Fang, 2014, MiRNA-206 and BDNF genes interacted in bipolar I disorder., J Affect Disord sourceNot checked yet

  Not checked in the free run.

May combine two claims.

miR-338-3P and miR-206 might be effective biomarkers and possible therapeutic targets for the treatment of MDD via nerve-immunity interaction.

“The results of a thorough bioinformatics investigation of miRNAs and mRNAs in MDD showed that miR-338-3P and miR-206 might be effective biomarkers and possible therapeutic targets for the treatment of MDD via nerve-immunity interaction.”

• AssumptionRests on an assumption: The plasma miRNA and mRNA expression profiles from the GEO datasets reflect the nerve-immunity processes relevant to MDD in the brain.

May combine two claims.

MiR-338 can promote myelination in the nervous system, and over-expression of miR-338 can enhance oligodendrocyte differentiation while inhibiting myelin negative regulators Sox6 and Hes5, therefore promoting myelin formation.

“MiR-338 can promote myelination in the nervous system, and over-expression of miR-338 can enhance oligodendrocyte differentiation while inhibiting myelin negative regulators Sox6 and Hes5, therefore promoting myelin formation [36].”

• cites [36] Peng, 2019, Down-regulated expression of microRNA-338-5p contributes to neuropathology in Alzheimer’s disease., FASEB J sourceNot checked yet

  Not checked in the free run.

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

Changes in miRNA expression are connected to the pathogenesis of a variety of neurodegenerative diseases.

“Changes in miRNA expression are thought to be connected to the pathogenesis of a variety of neurodegenerative diseases [30].”

• cites [30] Gulyaeva, 2019, The Missing Link: How Exosomes and miRNAs can Help in Bridging Psychiatry and Molecular Biology in the Context of Depression, Bipolar Disorder and Schizophrenia., Cell Mol Neurobiol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The study validated hsa-miR-206 with GJA1 and SNAP25, and hsa-miR-338-3p with KCND2 and MYT1L via the miRDB database, and hsa-miR-338-3p via the TargetScan database.

“Although 5 pairs of regulatory relationships between miRNA and mRNA have never been reported before, this study validated hsa-miR-206 with GJA1, SNAP25, hsa-miR-338-3p with KCND2, MYT1L via the miRDB database, and hsa-miR-338-3p via the TargetScan database, and predicted the possibility of interaction between 5 pairs of miRNA-mRNA.”

May combine two claims.

Up-regulation of miR-206 has been demonstrated to impair neuron function and result in poor adaptive behavior.

“Up-regulation of miR-206 has been demonstrated to impair neuron function and result in poor adaptive behavior [35].”

• cites [35] Gean, 2020, MicroRNA-206 Regulates Stress-Provoked Aggressive Behaviors in Post-weaning Social Isolation Mice., Mol Ther Nucleic Acids sourceNot checked yet

  Not checked in the free run.

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

Both Th1 and Th2 cells can release cytokines, which boost their proliferation while inhibiting each other to maintain a relative equilibrium; when the equilibrium is disrupted (Th1/Th2 drift), it can result in the emergence and development of disorders associated with immunological escape.

“Both Th1 and Th2 cells can release cytokines, which can boost their proliferation while inhibiting each other to maintain a relative equilibrium. When the equilibrium is disrupted, also known as”

• cites [56] Gurgel, 2018, Flavonoids as Th1/Th2 cytokines immunomodulators: A systematic review of studies on animal models., Phytomedicine sourceNot checked yet

  Not checked in the free run.

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

JAK/STAT is one of the most important transmembrane signal transduction routes and the most important signal pathway activated by inflammatory cytokines.

“This is not only one of the most important transmembrane signal transduction routes, but also the most important signal pathway activated by inflammatory cytokines [59].”

• cites [59] Attia, 2015, Regulation of TNF-α and NF-κB activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation., Immunobiology sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Th17 is elevated in the brains of MMD model mice, but RORt defective mice demonstrate resistance to learning helplessness; an increase in Th17 can cause MMD, whereas suppressing Th17 production or function can lessen the risk of MMD in mice.

“Th17 had been proven to be elevated in the brains of MMD model mice, but RORt defective mice demonstrated resistance to learning helplessness. As a result, an increase in Th17 can cause MMD, whereas suppressing Th17 production or function can lessen the risk of MMD in mice [55].”

• cites [55] Jope, 2013, Inflammatory T helper 17 cells promote depression-like behavior in mice., Biol Psychiatry sourceNot checked yet

  Not checked in the free run.

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

MiR-338-5p safeguards the cognitive function of transgenic APP/PS1 mice by lowering neuronal death.

“MiR-338-5p has been found to safeguard the cognitive function of transgenic APP/PS1 mice by lowering neuronal death [37].”

• cites [37] Zhi, 2020, MicroRNA-338-5p alleviates neuronal apoptosis via directly targeting BCL2L11 in APP/PS1 mice., Aging (Albany NY) sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Microglia shows excessive activation in pathological conditions such as chronic stress or infection, resulting in increased levels of inflammatory chemicals in the brain and neuronal damage and death.

“Microglia shows excessive activation in pathological condition such as chronic stress or infection, resulting increased not only in levels of inflammatory chemicals in the brain, but also neuronal damage and death [10].”

• cites [10] Zhen, 2018, miRNA-3473b contributes to neuroinflammation following cerebral ischemia., Cell Death Dis sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The multi-chip data were rectified by batch normalization using Sva and Limma.

“The R4.1.0 Sva and Limma were used to multi-chips for data rectification (batch Normalize).”

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

JAK and STAT are key components of many signaling pathways that regulate cell growth, differentiation, survival, and pathogen resistance, including those involving the IL-6 (gp130) receptor family, which aids in the regulation of B cell differentiation, plasma cell production, and acute phase response.

“Furthermore, JAK and STAT are key components of many signaling pathways that regulate cell growth, differentiation, survival, and pathogen resistance, including those involving the IL-6 (gp130) receptor family, which aids in the regulation of B cell differentiation, plasma cell production, and acute phase response [60].”

• cites [60] Tang, 2018, Activation of the IL-6/JAK2/STAT3 pathway induces plasma cell mastitis in mice., Cytokine sourceNot checked yet

  Not checked in the free run.

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

Because the current data is derived from the GEO database, it is challenging to determine the dependability and quality of the statistical data.

“Because the current data is derived from the GEO database, it is challenging to determine the dependability and quality of the statistical data.”

May combine two claims.

Acupuncture can increase serum 5-HT, up-regulate anti-inflammatory cytokine IL-10, and reduce proinflammatory cytokine IL-6 and TNF-α.

“Acupuncture can increase the content of serum 5-HT, up-regulate the content of anti-inflammatory cytokine IL-10, and reduce the content of proinflammatory cytokine IL-6 and TNF-α [26].”

• cites [26] Hsieh, 2019, Signal Transduction Pathways of Acupuncture for Treating Some Nervous System Diseases., Evid Based Complement Alternat Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Chronic moderate stress, neuroinflammation, and immune response changes have all been connected to the genesis of MDD.

“Chronic moderate stress, neuroinflammation, and immune response changes have all been connected to the genesis of MDD [7].”

• cites [7] Georgiev, 2019, Immunoregulatory natural compounds in stress-induced depression: An alternative or an adjunct to conventional antidepressant therapy?, Food Chem Toxicol sourceNot checked yet

  Not checked in the free run.

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

Combining microRNA and mRNA expression analysis in pediatric multiple sclerosis is an integrated approach to uncovering novel disease pathogenic mechanisms.

“Liguori discovered that combining microRNA and mRNA expression analysis in pediatric multiple sclerosis is an integrated approach to uncovering novel disease pathogenic mechanisms [12].”

• cites [12] Trojano, 2018, Combined microRNA and mRNA expression analysis in pediatric multiple sclerosis: an integrated approach to uncover novel pathogenic mechanisms of the disease., Hum Mol Genet sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In MMD patients, immunological function is compromised, with increased T cell apoptosis, increased neutrophils, and decreased total lymphocytes.

“In MMD patients, the immunological function was compromised, for T cell apoptosis increased, neutrophils rose, and total lymphocytes decreased.”

• cites [57] Bogerts, 2020, Increased densities of T and B lymphocytes indicate neuroinflammation in subgroups of schizophrenia and mood disorder patients., Brain Behav Immun sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Changes in miRNA expression are linked to the pathogenesis of numerous neurodegenerative diseases and hold significant therapeutic promise in the treatment of mood disorders, including clinical MDD.

“Changes in miRNA expression are well known to be linked to the pathogenesis of numerous neurodegenerative diseases and hold significant therapeutic promise in the treatment of mood disorders, including clinical MDD [15].”

• cites [15] Turecki, 2021, miR-323a regulates ERBB4 and is involved in depression., Mol Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

MMD occurs and progresses as a result of multi-target, multi-pathway, multi-signal pathway, and multi-mechanism interactions, and the regulatory process is synergistic and bi-directional.

“To summarize, MMD occurs and progresses as a result of multi-target, multi-pathway, multi-signal pathway, and multi-mechanism interactions, and the regulatory process is synergistic and bi-directional.”

• AssumptionRests on an assumption: The neuro-endocrine-immune network is a valid framework for understanding MMD.

May combine two claims.

Over-expression of miR-338-3p blocks the ERK/p38MAPK signaling pathway and reduces the expression of pro-inflammatory genes VCAM-1 and ICAM-1RNA.

“Over-expression of miR-338-3p has been shown to block the ERK/p38MAPK signaling pathway and reduce the expression of pro-inflammatory genes VCAM-1 and ICAM-1RNA [43].”

• cites [43] Deng, 2020, miR-135a Alleviates Silica-Induced Pulmonary Fibrosis by Targeting NF-B/Inflammatory Signaling Pathway., Mediators Inflamm sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Medications and other treatment interventions can suppress neuronal death and promote nerve reorganization by altering the JAK/STAT signal pathway's associated molecules.

“As a consequence, medications and other treatment interventions can suppress neuronal death and promote nerve reorganization by altering the JAK/STAT signal pathway’s associated molecules.”

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

B cells mediate humoral immunity via antibodies, and as the number of B cells falls, the rate of transformation falls.

“B cells mediate humoral immunity via antibodies; as the number of B cells falls, so does the rate of transformation [57].”

• cites [57] Bogerts, 2020, Increased densities of T and B lymphocytes indicate neuroinflammation in subgroups of schizophrenia and mood disorder patients., Brain Behav Immun sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Silencing miR-338-5p can result in neuronal polarity loss and a considerable decrease in the number of neurons.

“Other researches have shown that silencing miR-338-5p can result in neuronal polarity loss and a considerable decrease in the number of neurons.”

• cites [38] Li, 2017, MiR-338-3p inhibits TNF-α-induced lipogenesis in human sebocytes., Biotechnol Lett sourceNot checked yet

  Not checked in the free run.

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

Screening by PPI networks to identify hub genes had no influence on the results.

“Despite the fact that PPI networks are less closely associated to mRNA expressions, our goal after differential analysis was to screen by PPI networks to identify hub genes, which had no influence on our results.”

May combine two claims.

Common antidepressants such as escitalopram and fluoxetine improve central function by increasing central serotonergic nerve activity and can regulate levels of brain-derived neurotrophic factors and inflammatory factors in patients' blood.

“Common antidepressants, such as escitalopram and fluoxetine, have been shown to improve central function by increasing central serotonergic nerve activity. It can also successfully regulate the levels of brain-derived neurotrophic factors and inflammatory factors in patients’ blood [25].”

• cites [25] Filip, 2021, Escitalopram Targets Oxidative Stress, Caspase-3, BDNF and MeCP2 in the Hippocampus and Frontal Cortex of a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress., Int J Mol Sci sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Th17 and Treg are connected in differentiation and function and are frequently in a state of dynamic equilibrium; if their proportion is no longer balanced, it results in aberrant immunological responses such as inflammatory, tumor and autoimmune reactions.

“Furthermore, Th17 and Treg are connected in differentiation and function, and they are frequently in a state of dynamic equilibrium. If the proportion of them is no longer balanced, it will result in aberrant immunological responses such as inflammatory, tumor and autoimmune reactions [54].”

• cites [54] Fessler, 2017, Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders., Molecules sourceNot checked yet

  Not checked in the free run.

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

The major purpose of chemokines is to control leukocyte migration (homing) to their proper regions during inflammation and homeostasis; some control immune cell chemotaxis during immune surveillance, while others attract neutrophils to the site of infection or tissue injury for anti-infection, acting as a directing role in innate and adaptive immune systems; chemokines have an important role inthe

“the major purpose of chemokines is to control leukocyte migration (homing) to their proper regions during inflammation and homeostasis. Some control immune cell chemotaxis during the immune surveillance process, while others attract neutrophils to the site of infection or tissue injury for anti-infection, which acts as a directing role in the innate and adaptive immune systems. Furthermore, chemo”

• cites [58] Pavón, 2020, Serum levels of chemokines in adolescents with major depression treated with fluoxetine., World J Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Nerve-immunity network dysfunction generates excessive production of inflammatory components and stimulates glucocorticoid release, both of which contribute to the initiation of MMD.

“According to researches, nerve-immunity network dysfunction generates excessive production of inflammatory components and stimulates glucocorticoid release, both of which contribute to the initiation of MMD [23].”

• cites [23] Liu, 2017, Effects of the chronic restraint stress induced depression on reward-related learning in rats., Behav Brain Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

GJA-1 expression is down-regulated in MDD patients, as is the Cx43 mRNA that encodes it.

“Gap junction alpha-1 protein (GJA-1) expression had proven to be down-regulated in MDD patients, as was the Cx43 mRNA that encoded It [49].”

• cites [49] Turecki, 2015, Astrocytic abnormalities and global DNA methylation patterns in depression and suicide., Mol Psychiatry sourceNot checked yet

  Not checked in the free run.

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

The study was unable to acquire sufficient external data from other publicly available sources to evaluate the model's dependability.

“First, we were unable to acquire sufficient external data from other publicly available sources to evaluate model’s dependability.”

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

Performing TF analysis using FunRich and GO and KEGG analyses allowed the results to be verified against each other to increase the feasibility of the results.

“Third, we not only performed TF analysis (including BP, CC, (MF)) using FunRich, but also GO and KEGG analyses, which allowed the results to be verified against each other to increase the feasibility of the results.”

Classified as probably not a substantial claim. May combine two claims.

MiRNAs may govern cell proliferation, division, apoptosis, and metabolism as regulators of numerous biological processes by promoting degradation of mRNAs and inhibiting their translation, so that targeted mRNAs play a negative feedback regulatory function.

“It may govern cell proliferation, division, apoptosis, and metabolism as regulators of numerous biological processes by promoting the degradation of mRNAs and inhibiting their translation, so that its targeted mRNAs play a negative feedback regulatory function [11].”

• cites [11] Zhang, 2014, MicroRNA expression profile and functional analysis reveal that miR-206 is a critical novel gene for the expression of BDNF induced by ketamine., Neuromolecular Med sourceNot checked yet

  Not checked in the free run.

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

No MDD studies were conducted to validate the relationship between prognostic genes and miRNA.

“Finally, no MDD studies were conducted to validate the relationship between prognostic genes and miRNA.”

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

The JAK/STAT signaling pathway is widely implicated in the proliferation and differentiation of neural stem cells (NSC) throughout central nervous system development, and it is important in controlling hippocampal nerve reorganization.

“The JAK/STAT signaling pathway is widely implicated in the proliferation and differentiation of neural stem cells (NSC) throughout central nervous system development, and it is important in controlling hippocampal nerve reorganization [61].”

• cites [61] Lue, 2011, Three important components in the regeneration of the cavernous nerve: brain-derived neurotrophic factor, vascular endothelial growth factor and the JAK/STAT signaling pathway., Asian J Androl sourceNot checked yet

  Not checked in the free run.

May combine two claims.

JAK-STAT and other signaling pathways control immune-inflammatory responses, neuron remodeling, and other processes, as well as affecting the onset and course of MMD.

“JAK-STAT and other signaling pathways control immune-inflammatory responses, neuron remodeling, and other processes, as well as affecting the onset and course of MMD.”

May combine two claims.

MiRNA affects the production of KCND2, Myt1L, GJA-1, CHL1, and SNAP-25, which can activate or inhibit the B cell receptor signal pathway, T cell receptor signal pathway, and chemokine signal pathway.

“MiRNA affects the production of KCND2, Myt1L, GJA-1, CHL1, and SNAP-25, which can activate or inhibit the B cell receptor signal pathway, T cell receptor signal pathway, and chemokine signal pathway.”

• AssumptionRests on an assumption: The miRNA-mRNA regulatory network constructed from the GEO datasets accurately represents the neuro-endocrine-immune interactions in MMD.

May combine two claims.

The realization of bi-directional regulation of the HPA axis can normalize nerve conduction, minimize immuno-inflammatory responses, and restore normal neural, endocrine, and immunological function, and plays a therapeutic role in MMD.

“The realization of bi-directional regulation of the HPA axis, which can normalize nerve conduction, minimize immuno-inflammatory responses, and restore normal neural, endocrine, and immunological function, plays a therapeutic role in MMD.”

• AssumptionRests on an assumption: The neuro-endocrine-immune network is a valid framework for understanding MMD.

May combine two claims.

The study focused more on miRNAs linked with neuroimmunity in early expression analyses but did not undertake any functional or mechanistic research.

“Second, we focused more on miRNAs linked with neuroimmunity in our early expression analyses, but did not undertake any functional or mechanistic research.”

May combine two claims.

Both the hub miRNA and the mRNA created by constructing a miRNA-mRNA network may have a role in the incidence and progression of MMD via nerve-immunity interaction.

“Both the hub miRNA and the mRNA created by constructing a miRNA-mRNA network may have a role in the incidence and progression of MMD via nerve-immunity interaction.”

• AssumptionRests on an assumption: The miRNA-mRNA regulatory network constructed from the GEO datasets accurately represents the neuro-endocrine-immune interactions in MMD.

May combine two claims.

In MMD, miRNAs are associated with depression caused by various illnesses and with response to specific treatments such as isoliquiritin, oligonucleotides, or purinergic receptor.

“In MMD, it has been reported that miRNAs are not only involved in the pathogenesis of the disease [17], but are also associated with depression caused by various illnesses [18, 19], as well as the response to specific treatments such as isoliquiritin [20], oligonucleotides [21], or purinergic receptor [22], confirming their potential as disease monitoring biomarkers.”

• cites [18] Wang, 2021, The role of miRNA-624-5p in congenital hypothyroidism and its molecular mechanism by targeting SIRT1., Genes Genomics sourceNot checked yet

  Not checked in the free run.

• cites [19] Shao, 2018, Identifying miRNA-mRNA regulation network of major depressive disorder in ovarian cancer patients., Oncol Lett sourceNot checked yet

  Not checked in the free run.

• cites [20] Wang, 2021, Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis., J Neuroinflammation sourceNot checked yet

  Not checked in the free run.

• cites [21] Artigas, 2021, Oligonucleotides as therapeutic tools for brain disorders: Focus on major depressive disorder and Parkinson’s disease., Pharmacol Ther sourceNot 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.

Although various GEO datasets were batch normalized before analysis, it had little effect on the results, and there may still be bias when compared to analysis from the same dataset.

“What’s more, although we batched Normalize various GEO datasets before analysis, it has little effect on the results, and there may still be bias when compared to analysis from the same dataset.”

May combine two claims.

Batch normalization of multiple GEO datasets before statistics improved the stability and confidence of the results and reduced the small sample bias caused by the reduced sample size.

“Secondly, we used a joint analysis of multiple GEO data, although there were individual differences, we performed a batch Normalize data correction before the statistics to improve the stability and confidence of the results. It also reduced the small sample bias caused by the reduced sample size.”

May combine two claims.

TNF may induce inflammation by stimulating the NF-κB/MAPK signaling pathway and decreasing miR-338-3p levels.

“TNF may induce inflammation by stimulating the NF-κB/MAPK signaling pathway and decreasing miR-338-3p levels [42].”

• cites [42] Fang, 2021, miRNA-338-3p/CAMK IIα signaling pathway prevents acetaminophen-induced acute liver inflammation in vivo., Ann Hepatol sourceNot checked yet

  Not checked in the free run.

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

Chemokines, which include Th17, Th1, and Th2, are key chemicals in the immunological and neurological systems; they can coordinate the migration of T and B cells to inflammatory areas, promote T cell activity and help B cell activation, and play a role in regulating immunity-inflammation in the immune system.

“Chemokines, which include Th17, Th1, and Th2, are key chemicals in the immunological and neurological systems. They can coordinate this migration of T and B cells to inflammatory areas, promote T cell activity and help B cell activation, and play a role in regulating immunity-inflammation in the immune system [66].”

• cites [66] Guo, 2021, Regulation of Th1/Th2 and Th17/Treg by pDC/mDC imbalance in primary immune thrombocytopenia., Exp Biol Med (Maywood) sourceNot checked yet

  Not checked in the free run.

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

The JAK2/STAT3 signal pathway is involved in neuronal death and nervous reorganization in ischemic encephalopathy.

“A member of its family, the JAK2/STAT3 signal pathway, is involved in neuronal death and nervous reorganization in ischemic encephalopathy [62].”

• cites [62] Sun, 2020, The role of JAK/STAT signaling pathway and its inhibitors in diseases., Int Immunopharmacol sourceNot checked yet

  Not checked in the free run.

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

Mutations in Myt1L in chromosomal band 2p25.3 have been linked to intellectual disability, while Myt1L repetition has been linked to schizophrenia and MMD.

“Mutations in Myt1L in chromosomal band 2p25.3 have been linked to intellectual disability, while Myt1L repetition has been linked to schizophrenia and MMD [48].”

• cites [48] Cao, 2018, Myt1L Promotes Differentiation of Oligodendrocyte Precursor Cells and is Necessary for Remyelination After Lysolecithin-Induced Demyelination., Neurosci Bull sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Following psychological stress, activated T cells can enter the central nervous system in a variety of ways, reduce inflammation, and support neuronal integrity via cellular immunity, thus modifying depressed behavior.

“Following psychological stress, activated T cells can enter the central nervous system in a variety of ways, reduce inflammation, and support neuronal integrity via cellular immunity, thus modifying depressed behavior [67].”

• cites [67] Elzinga, 2014, Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484)., Mol Psychiatry sourceNot 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 JAK/STAT signaling system influences brain remodeling by activating inflammatory cytokines and altering the metabolism of the neuro-endocrine-immune network.

“Furthermore, the JAK/STAT signaling system influences brain remodeling by activating inflammatory cytokines and altering the metabolism of the neuro-endocrine-immune network.”

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

KCND2 is a potassium voltage-gated channel subfamily D protein-coding gene that encodes a type A potassium channel protein, important during the repolarization stage of an action potential.

“KCND2 is a potassium voltage-gated channel subfamily D protein-coding gene that can encode a type A potassium channel protein, which is important during the repolarization stage of an action potential [44].”

• cites [44] Pongs, 1999, Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current., Recept ChannelsNot checked yet

  Not checked in the free run.

May combine two claims.

TNF-α activates the JAK/STAT signal pathway via the protein-gp130 on the cell membrane's surface, and so contributes to the control of central nervous system degenerative alterations.

“Numerous studies have revealed that TNF-α activates JAK/STAT signal pathway via the protein-gp130 on the cell membrane’s surface, and so contributes to the control of central nervous system degenerative alterations [63].”

• cites [63] Sun, 2021, TNFα activates MAPK and Jak-Stat pathways to promote mouse Müller cell proliferation., Exp Eye Res sourceNot checked yet

  Not checked in the free run.

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

Myt1L is important to neural differentiation, and mutations in it have been linked to autism spectrum disorder and an autosomal dominant form of cognitive dysfunction.

“This gene is important to neural differentiation, and mutations in it have been linked to autism spectrum disorder and an autosomal dominant form of cognitive dysfunction [47].”

• cites [47] Lancet, 2021, GeneCaRNA: A Comprehensive Gene-centric Database of Human Non-coding RNAs in the GeneCards Suite., J Mol Biol sourceNot checked yet

  Not checked in the free run.

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

Myt1L is a member of the Myt/NZF family, encodes a neuronal transcription factor with 6 zinc fingers, and its expression has only been found in brain tissue thus far.

“Myt1L is a member of the Myt/NZF family, which encodes a neuronal transcription factor with 6 zinc fingers. Its expression has only been found in brain tissue thus far [46].”

• cites [46] Baldridge, 2020, MYT1L: A systematic review of genetic variation encompassing schizophrenia and autism., Am J Med Genet B Neuropsychiatr Genet sourceNot checked yet

  Not checked in the free run.

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

CHL1 is a cell adhesion molecule from the L1 family; deletion and repetition of this gene have been linked to a number of neurological disorders, including autism, Parkinson's disease, and mental disability.

“CHL1 is a cell adhesion molecule from the L1 family. The deletion and repetition of this gene have been linked to a number of neurological disorders, including autism, Parkinson’s disease, and mental disability [50].”

• cites [50] Fan, 2011, CHL1 negatively regulates the proliferation and neuronal differentiation of neural progenitor cells through activation of the ERK1/2 MAPK pathway., Mol Cell Neurosci sourceNot checked yet

  Not checked in the free run.

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

Voltage-gated potassium channels regulate dendritic A-type current I (SA) in brain neurons by controlling potassium transport across the excitatory membrane in the brain.

“By controlling potassium transport across the excitatory membrane in the brain, voltage-gated potassium channels regulate dendritic A-type current I (SA) in brain neurons [45].”

• cites [45] Pongs, 2000, Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(TO) and I(SA)., Genomics sourceNot checked yet

  Not checked in the free run.

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

The central nervous system is usually regarded as an immune zone due to the blood-brain barrier, but this idea is increasingly changing.

“Existing knowledge holds that the central nervous system is usually regarded as an immune zone due to the blood-brain barrier. However, as more researches are conducted, this idea is increasingly changing [65].”

• cites [65] Kelley, 2008, From inflammation to sickness and depression: when the immune system subjugates the brain., Nat Rev Neurosci sourceNot checked yet

  Not checked in the free run.