Inhibition Of Function Research Articles

Investigation of the inhibitory effect and mechanism of EGCG against Streptococcus suis sortase A.

Streptococcus suis (S. suis) seriously harms people and animals, and importantly, causes great economic losses in the pig industry. Similar to most gram-positive pathogenic bacteria, sortase A (SrtA) of S. suis can mediate the anchoring of a variety of virulence factors that contain specific sorting sequences to the surface of the bacterial cell wall envelope and participate in pathogenicity. The purpose of this study is to clarify the molecular mechanism of epigallocatechin-3-gallate (EGCG) inhibiting Streptococcus suis SrtA and provide more evidence for the development of novel anti- Streptococcus suis infections drugs. Through the SrtA substrate cleavage experiment, we found that the main component of green tea, EGCG, can effectively inhibit the enzyme activity of Streptococcus suis SrtA. Further, molecular docking and molecular dynamics simulation were used to clarify the molecular mechanism of its inhibitory effect, demonstrating that EGCG mainly interacts with amino acids at 113 and 115 to exert its inhibitory function. It was previously found that EGCG can inhibit the growth of S. suis and reduce the activity of suilysin and inhibit its expression. Our research reveals a new function of EGCG in S. suis infection. Our research proves that EGCG can effectively inhibit the transpeptidase activity of SrtA. We also clarify the accompanying molecular mechanism, providing more sufficient evidence for the use of EGCG as a potential lead compound against S. suis infection.

Frameshift mutations of immunomodulatory BTN2A1, BTN2A2, and BTNL3 genes in colon cancers

The butyrophilin family genes are immunoregulatory genes with either immune stimulatory or inhibitory functions. In the present study, we analyzed three butyrophilin genes, BTN2A1 (immune-stimulatory), BTN2A2 (inhibitory), and BTNL3 (stimulatory) genes in sporadic colon cancers (CCs). By the mutation analysis, we identified the frameshift mutations of BTN2A1, BTN2A2, and BTNL3 genes in 2, 4, and 8 CCs in microsatellite instability-high (MSI-H) CCs (2.1–8.4% of MSI-H), respectively, but not the microsatellite stable (MSS) CCs. Four of 16 MSI-H CCs (25%) exhibited regional heterogeneous mutations (RHM) of BTN2A1, BTN2A2, and BTNL3 genes. In immunohistochemistry, BTNL3 expression was lost in approximately 30% of CCs, and BTN2A2 loss was minimal in CCs (around 3%) irrespective of the MSI status. Our study revered that butyrophilin family genes BTN2A1, BTN2A2, and BTNL3 harbored multiple levels of gene alterations at frameshift mutations, RHMs, and expression losses in CCs, suggesting that butyrophilin family genes could contribute to CC pathogenesis by altering immune responses.

Inhibitory to non-inhibitory evolution of the ζ subunit of the F1FO-ATPase of Paracoccus denitrificans and α-proteobacteria as related to mitochondrial endosymbiosis.

Introduction: The ζ subunit is a potent inhibitor of the F1FO-ATPase of Paracoccus denitrificans (PdF1FO-ATPase) and related α-proteobacteria different from the other two canonical inhibitors of bacterial (ε) and mitochondrial (IF1) F1FO-ATPases. ζ mimics mitochondrial IF1 in its inhibitory N-terminus, blocking the PdF1FO-ATPase activity as a unidirectional pawl-ratchet and allowing the PdF1FO-ATP synthase turnover. ζ is essential for the respiratory growth of P. denitrificans, as we showed by a Δζ knockout. Given the vital role of ζ in the physiology of P. denitrificans, here, we assessed the evolution of ζ across the α-proteobacteria class. Methods: Through bioinformatic, biochemical, molecular biology, functional, and structural analyses of several ζ subunits, we confirmed the conservation of the inhibitory N-terminus of ζ and its divergence toward its C-terminus. We reconstituted homologously or heterologously the recombinant ζ subunits from several α-proteobacteria into the respective F-ATPases, including free-living photosynthetic, facultative symbiont, and intracellular facultative or obligate parasitic α-proteobacteria. Results and discussion: The results show that ζ evolved, preserving its inhibitory function in free-living α-proteobacteria exposed to broad environmental changes that could compromise the cellular ATP pools. However, the ζ inhibitory function was diminished or lost in some symbiotic α-proteobacteria where ζ is non-essential given the possible exchange of nutrients and ATP from hosts. Accordingly, the ζ gene is absent in some strictly parasitic pathogenic Rickettsiales, which may obtain ATP from the parasitized hosts. We also resolved the NMR structure of the ζ subunit of Sinorhizobium meliloti (Sm-ζ) and compared it with its structure modeled in AlphaFold. We found a transition from a compact ordered non-inhibitory conformation into an extended α-helical inhibitory N-terminus conformation, thus explaining why the Sm-ζ cannot exert homologous inhibition. However, it is still able to inhibit the PdF1FO-ATPase heterologously. Together with the loss of the inhibitory function of α-proteobacterial ε, the data confirm that the primary inhibitory function of the α-proteobacterial F1FO-ATPase was transferred from ε to ζ and that ζ, ε, and IF1 evolved by convergent evolution. Some key evolutionary implications on the endosymbiotic origin of mitochondria, as most likely derived from α-proteobacteria, are also discussed.

Effect of pregnancy-specific β1-glycoprotein on the expression of arginase-1 and indolamine-2,3-dioxygenase by myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSC) - a population of immature cells of myeloid origin with inhibitory functions, mainly related to T lymphocytes. Normally, MDSC account for less than 1% of leukocytes in peripheral blood. The number of these cells increases during healthy pregnancy. However, MDSC have been shown to play a critical role in the maintenance of tumor growth and in autoimmune diseases.
 Because MDSC are now considered important regulators of immunity, finding ways to manipulate their functions is important for the development of therapies for malignant and autoimmune diseases, as well as for pregnancy pathologies and post-transplant complications. The immunosuppressive mechanisms of these cells are mediated by their expression of the surface molecules CD73, ADAM17, PD -L1, the enzymes arginase 1 (Arg 1), inducible nitric oxide synthase (iNOS), and indoleamine 2,3-dioxygenase (IDO), reactive oxygen species, and the production of the anti-inflammatory cytokines IL -10 and TGF-1.
 Pregnancy-specific 1-glycoprotein (PSG) is a pregnancy glycoprotein that has immunomodulatory effects on natural (dendritic cells and macrophages) and adaptive (T cells) immunity cells. At the same time, the effect of PSG on MDSC has not been investigated so far. Since this glycoprotein has promising pharmacological applications, it is necessary to study not only the native variant of PSG but also its recombinant form.
 Since the main function of MDSC is immunosuppression, the aim of our work was to evaluate one of its mechanisms, namely the intracellular expression of amino acid degradation enzymes Arg1 and IDO under the influence of native and recombinant PSG in vitro.
 MDSC differentiation was performed from CD11b+ cells isolated from peripheral blood of healthy volunteers. Cells were cultured for 7 days with stepwise addition of GM-CSF, IL -1, and LPS. Native (n) (1, 10, and 100 g/mL) and recombinant (r) (1 and 10 g/mL) PSG was added to the cultures three days before the end of incubation. The percentage of MDSCs (Lin- HLA-DR -CD11b+CD33+) intracellularly expressing Arg1 and IDO was determined by flow cytometry.
 It was found that nPSG and rPSG did not alter the amount of Arg1-expressing MDSCs at all concentrations examined. However, at a concentration of 10 g/mL, both types of proteins caused a statistically significant increase in the percentage of cells expressing IDO.
 We have already established that nPSG and rPSG affect MDSC differentiation by increasing the proportion of these cells belonging to the monocytic subpopulation. However, now we can say that PSG, in addition, enhances the suppressive function of the studied cells.
 The obtained data are novel and open perspectives for targeting myeloid suppressor cells to improve cellular technologies in science and medicine.

N6-methyladenosine (m6A) methyltransferase WTAP-mediated miR-92b-5p accelerates osteoarthritis progression

The study was design to investigate the functional roles of Wilms tumor 1-associated protein (WTAP), an enzyme catalyzes m6A modification, in the pathogenesis of osteoarthritis (OA) and further elucidate its possible regulatory mechanism. Herein, we discovered that WTAP was outstandingly upregulated in chondrocyte stimulated with Lipopolysaccharide (LPS) and cartilage tissue of patients with OA. Functional studies have demonstrated that WTAP knockdown enhances proliferation ability, suppresses apoptosis, and reduces extracellular matrix (ECM) degradation in an LPS—induced OA chondrocyte injury model and ameliorates cartilage damage in a destabilizing the medial meniscus (DMM)—induced OA mice model. Conversely, overexpression of WTAP contributes to the opposite effects. Mechanistically, our data has demonstrated that m6A modification mediated by WTAP promotes the maturation of pri-miR-92b to miR-92b-5p, thereby enhancing the targeted inhibitory function of miR-92b-5p on TIMP4. Furthermore, we have discovered that WTAP can directly facilitate the degradation of TIMP4 mRNAs in a YTHDF2-dependent manner. In a nutshell, our findings suggested that WTAP knockdown alleviated OA progression by modulating the miR-92b-5p/TIMP4 axis in an m6A-dependent manner. Our study disclosed that WTAP-mediated m6A modification displayed a crucial role in OA development and suggested that targeting WTAP could be a promising preventive and therapeutic target for patients with OA.7QG3J4kX7R4LACdpcrQ_FqVideo

Effects of different food hardness on cognitive inhibitory control function.

Mastication leads to an immediate enhancement in cognitive functions, including inhibitory control. Furthermore, the hardness of the food increases sympathetic nerve activity during and immediately after mastication. Hence, the cognitive function could be enhanced by increased sympathetic nerve activity. The present study aimed to investigate the effects of food hardness on cognitive inhibitory control function in humans. The participants were 23 healthy adults (19-22 years old). Experiments were conducted with two types of gummies (soft and hard). The participants ingested 13 g of gummies and performed a stop-signal task to measure cognitive inhibitory control function after they rested for 5 min. The reaction time for the stop-signal task after gummy consumption was significantly shorter in the hard gummy condition compared to the soft gummy condition (p < .05). Furthermore, the accuracy rate of the responses was also significantly higher in the hard gummy condition compared to the soft gummy condition (p < .05). The results of the present study suggest that food hardness enhances cognitive inhibitory control function in humans.

Taste masking and stability improvement of Korean red ginseng (Panax ginseng) by nanoencapsulation using chitosan and gelatin

In this study, red ginseng extract (RGE)-loaded nanoparticles (NPs) were prepared by ionic gelation between chitosan (CS) and gelatin (Gel), and the physical characteristics of the RGE-loaded CS-Gel NPs (RGE-CS/Gel NPs), including particle size and polydispersity index (PDI), using different ratios of CS and Gel were examined. The particle size and PDI were 398.1 ± 41.3 nm and 0.433 ± 0.033, respectively for the optimal ratio of CS (0.075 mg/mL) and Gel (0.05 mg/mL). In vitro taste masking test and in vivo sensory evaluation using 10 panelists demonstrated that the CS/Gel NPs significantly reduced the bitter taste of RGE. Additionally, the CS/Gel NPs improved the thermal and acid stabilities, which were almost 6 and 8 times higher than those in the free RGE (p < 0.05), respectively. Likewise, our findings revealed that the RGE-CS/Gel NPs effectively maintain their inhibitory function against platelet aggregation (76.30 %) in an acidic environment. Therefore, the CS/Gel NPs can be used as a potential delivery system to mask the bitterness and improve the stability of RGE, which may enhance its application as a more palatable functional food ingredient with high anti-platelet activity.

LOXL1-AS1 promotes cell proliferation in hepatocellular carcinomathrough miR-1224-5p/ITPRIPL2/AKT axis.

LncRNA has been validated to be related to different cancers, whereas its regulation mechanism in hepatocellular carcinoma (HCC) is poorly known. In this study, LOXL1-AS1 was overexpressed in HCC cell lines, and LOXL1-AS1 knockdown repressed cell proliferation and stimulated apoptosis in HCC. Besides, the activating role of LOXL1-AS1 in the AKT pathway was also confirmed. Further, miR-1224-5p was sponged by LOXL1-AS1, and overexpression exerted inhibitory function in HCC. Moreover, ITPRIPL2 as amiR-1224-5ptarget gene. Meanwhile, ITPRIPL2 deficiency suppressed HCC cell proliferation. Finally, miR-1224-5p inhibitor reversed the hindering role of LOXL1-AS1 depletion in HCC cell proliferation and AKT pathway, and this rescuing effect was offset by ITPRIPL2 silencing. In summary, LOXL1-AS1 induced cell proliferation and suppresses cell apoptosis in primary HCCvia activating AKT pathway, sponging miR-1224-5p and upregulating ITPRIPL2, which may provide some fresh thoughts for researches about the molecular regulation mechanism of lncRNA in HCC.

Role of sestrins in metabolic and aging-related diseases.

Sestrins are a type of highly conserved stress-inducing protein that has antioxidant and mTORC1 inhibitory functions. Metabolic dysfunction and aging are the main risk factors for development of human diseases, such as diabetes, neurodegenerative diseases, and cancer. Sestrins have important roles in regulating glucose and lipid metabolism, anti-tumor functions, and aging by inhibiting the reactive oxygen species and mechanistic target of rapamycin complex 1 pathways. In this review, the structure and biological functions of sestrins are summarized, and how sestrins are activated and contribute to regulation of the downstream signal pathways of metabolic and aging-related diseases are discussed in detail with the goal of providing new ideas and therapeutic targets for the treatment of related diseases.

Extracellular matrix proteoglycans support aged hippocampus networks: a potential cellular-level mechanism of brain reserve

One hallmark of normative brain aging is vast heterogeneity in whether older people succumb to or resist cognitive decline. Resilience describes a brain’s capacity to maintain cognition in the face of aging and disease. One factor influencing resilience is brain reserve—the status of neurobiological resources available to support neuronal circuits as dysfunction accumulates. This study uses a cohort of behaviorally characterized adult, middle-aged, and aged rats to test whether neurobiological factors that protect inhibitory neurotransmission and synapse function represent key components of brain reserve. Histochemical analysis of extracellular matrix proteoglycans, which play critical roles in stabilizing synapses and modulating inhibitory neuron excitability, was conducted alongside analyses of lipofuscin-associated autofluorescence. The findings indicate that aging results in lower proteoglycan density and more lipofuscin in CA3. Aged rats with higher proteoglycan density exhibited better performance on the Morris watermaze, whereas lipofuscin abundance was not related to spatial memory. These data suggest that the local environment around neurons may protect against synapse dysfunction or hyperexcitability and could contribute to brain reserve mechanisms.

Influence of glutamatergic and GABAergic neurotransmission on obstructive sleep apnea.

Glutamate and γ-aminobutyric acid (GABA) are the two main neurotransmitters in the human brain. The balance between their excitatory and inhibitory functions is crucial for maintaining the brain's physiological functions. Disturbance of glutamatergic or GABAergic neurotransmission leads to serious health problems including neurodegeneration, affective and sleep disorders. Both GABA and glutamate are involved in the control of the sleep-wake cycle. The disturbances in their function may cause sleep and sleep-related disorders. Obstructive sleep apnea (OSA) is the most common sleep respiratory disorder and is characterized by repetitive collapse of the upper airway resulting in intermittent hypoxia and sleep fragmentation. The complex pathophysiology of OSA is the basis of the development of numerous comorbid diseases. There is emerging evidence that GABA and glutamate disturbances may be involved in the pathogenesis of OSA, as well as its comorbidities. Additionally, the GABA/glutamate targeted pharmacotherapy may also influence the course of OSA, which is important in the implementation of wildly used drugs including benzodiazepines, anesthetics, and gabapentinoids. In this review, we summarize current knowledge on the influence of disturbances in glutamatergic and GABAergic neurotransmission on obstructive sleep apnea.

Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors

This study investigates the role of integrin β4 (ITGB4) and stemness-associated factor SOX2 in platinum resistance in lung squamous cell carcinoma (LUSC). The expression of SOX2 and ITGB4 is found to be high in all LUSC subtypes, but the impact of ITGB4 expression on overall patient survival varies by subtype. Cancer stem cells (CSCs) isolated from LUSC patients were found to be resistant to cisplatin, but knocking down ITGB4 or SOX2 sensitized them to cisplatin. Carfilzomib (CFZ) synergized with cisplatin and suppressed CSC growth by inhibiting ITGB4 and SOX2 expression. Additionally, CFZ was found to inhibit SOX2 expression epigenetically by inhibiting histone acetylation at the SOX2 promoter site. CFZ also suppressed the growth of SOX2-dependent small cell lung cancer cells invitro and invivo. The study highlights the unique function of CFZ as a transcriptional suppressor of SOX2, independent of its proteasome inhibitory function.

Aerobic Exercise Improves Cortical Inhibitory Function After Stroke: A Preliminary Investigation.

Aerobic exercise can elicit positive effects on neuroplasticity and cognitive executive function but is poorly understood after stroke. We tested the effect of 4 weeks of aerobic exercise training on inhibitory and facilitatory elements of cognitive executive function and electroencephalography markers of cortical inhibition and facilitation. We investigated relationships between stimulus-evoked cortical responses, blood lactate levels during training, and aerobic fitness postintervention. Twelve individuals with chronic (>6 months) stroke completed an aerobic exercise intervention (40 minutes, 3×/wk). Electroencephalography and motor response times were assessed during congruent (response facilitation) and incongruent (response inhibition) stimuli of a Flanker task. Aerobic fitness capacity was assessed as o2peak during a treadmill test pre- and postintervention. Blood lactate was assessed acutely (<1 minute) after exercise each week. Cortical inhibition (N2) and facilitation (frontal P3) were quantified as peak amplitudes and latencies of stimulus-evoked electroencephalographic activity over the frontal cortical region. Following exercise training, the response inhibition speed increased while response facilitation remained unchanged. A relationship between earlier cortical N2 response and faster response inhibition emerged postintervention. Individuals who produced higher lactate during exercise training achieved faster response inhibition and tended to show earlier cortical N2 responses postintervention. There were no associations between o2peak and metrics of behavioral or neurophysiologic function. These preliminary findings provide novel evidence for selective benefits of aerobic exercise on inhibitory control during the initial 4-week period after initiation of exercise training and implicate a potential therapeutic effect of lactate on poststroke inhibitory control.

Spatial attention modulates auditory dominance in audiovisual order judgment.

Auditory dominance in audiovisual temporal order judgment is shown here to be modulated by exogenous orienting of attention to a spatial cue independent of the cue modality. The visual stimulus has to lead the auditory one further in advance for cued relative to uncued locations in order for the two to be perceived simultaneously, possibly suggesting an inhibitory function of spatial attention on temporal processing.

Gene regulation of MMPs and TIMPs by somatostatin in human fibroblasts

Introduction:SST is a widespread neuropeptide with generally inhibitory function. The aim of this study is to evaluatethe effect of somatostatin in different concentrations on mRNA expression of MMPs and TIMPsin cultured, human, gingival fibroblasts. Methodology and resources: Human gingival fibroblasts were stimulated with 10-4, 10-9 or 10-12 M somatostatin DMEM without fetal calf serum; untreated fibroblasts served as controls. After incubation period, the RNA was extracted, and the first-strand cDNA was synthesized. Alterations in the expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-11, TIMP-1 and TIMP-2 mRNA were evaluated using real-time polymerase chain reaction (PCR). b-actin mRNA expression was used to normalize the data. Results: In 24 h treatment, SST, at the highest concentration induced a down-regulation on MMP-1, -2, -3 and -7 expression, and up-regulation on MMP-11 expression; while at the lowest concentration induced an up-regulation on MMP-1, -2, -3, TIMP-1 and -2 expression. At 72 hours treatment, similar effects were observed, except for the up-regulation on TIMP-2 at the higher SST concentration, an up-regulation on MMP-7 and -11 expression and a down-regulation on MMP-2 and TIMP-2 expression, at the lower SST concentration. Discussion:The modulation of inflammation by SST is still unclear. The findings of this work,suggests that it can modulate the gene expression of MMPs and TIMPs by cultured fibroblasts and its effects depend on the concentration. This may represent one of the mechanisms of inflammation suppression by SST.

RNA sequencing reveals the mechanism of FTO in inhibiting inflammation and excessive proliferation of lipopolysaccharide-induced human glomerular mesangial cells.

Chronic glomerulonephritis (CGN) is a leading cause of end-stage renal disease in China; thus, there is an urgent need for effective therapeutic targets and strategies for CGN treatment. However, studies on CGN pathogenesis are limited. In this study, we found that the fat mass and obesity-associated protein (FTO) was significantly decreased in the lipopolysaccharide (LPS)-induced human glomerular mesangial cells (HGMCs) (P < 0.01) and kidney tissues of CGN patients (P < 0.05). Moreover, double-labeling immunofluorescence and flow cytometry assays demonstrated that the overexpression of FTO could inhibit inflammation and excessive proliferation of HGMCs. Furthermore, RNA-sequencing (RNA-seq) and real-time quantitative polymerase chain reaction (RT-qPCR) analyses revealed that FTO overexpression induced differential expression of 269 genes (absolute fold change ≥ 2 and P-value < 0.05), including 143 upregulated and 126 downregulated genes. Further functional analysis of these differentially expressed genes by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses suggested that FTO possibly mediates its inhibitory function by regulating the mammalian target of rapamycin (mTOR) signaling pathway and substance metabolism. Lastly, analysis of the PPI network and further identification of the top 10 hub genes (RPS15, RPS18, RPL18A, GNB2L1, RPL19, EEF1A1, RPS25, FAU, UBA52, and RPS6) indicated that FTO mediates its function by affecting the ribosomal proteins. Therefore, in this study, we elucidated the important role of FTO in the regulation of inflammation and excessive proliferation of HGMCs, suggesting FTO administration as a suitable therapeutic intervention for CGN.

Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy.

The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on https://clinicaltrials.gov. Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients.

Cognitive Performance changes during a 20-day Winter Military Training Course and the Following 10-day Recovery Period

ABSTRACT Introduction: The purpose of the present study was to investigate the effects of a winter military field training course consisting of strenuous physical stressors (e.g. physical activity, sleep deprivation and cold weather) on cognitive performance among Finnish soldiers. Methods: Fifty-eight (age 19 ± 1 years, height 182 ± 6 cm, body mass 78.5 ± 7.2 kg) male soldiers took part in a 20-day military field training course in northern Finland. Cognitive performance was assessed before, during, and after the course four times on a tablet computer. Sustained Attention to Response Task (SART) was used to assess soldier’s executive and inhibitory function. Baddeley’s 3-min reasoning task (BRT) was used to assess grammatical reasoning, and Change Blindness (CB) task was used to assess visual perception. Results: Strenuous winter field training had detrimental effects in all performance tests compared to baseline. SART response rate decreased 27.3% (p < 0.001), and BRT and CB task scores decreased 20.6% (p < 0.01) and 14.1% (p < .05), respectively. Conclusion: The present study showed a decline in soldier’s cognitive performance after 20-days of physically demanding winter military field training. To be able to optimise field training, it is important to be aware of how cognitive performance changes during military exercises and missions.

Marine alkaloid rigidin analogues as potential selective inhibitors of SHP1, a new strategy for cancer immunotherapeutics

SHP1 is a protein tyrosine phosphatase playing a central role in immunity, cell growth, development, and survival. The inhibition of SHP1 can help in better prognosis in various disorders like breast and ovarian cancer, melanoma, atherosclerosis, hypoxia, hypoactive immune response, and familial dysautonomia. The currently available inhibitors of SHP1 have the side effect of inhibiting the activity of SHP2, which shares >60% sequence similarity with SHP1 but has distinct biological functions. Thus, there is a need to search for novel specific inhibitors of SHP1. The current study uses a combination of virtual screening and molecular dynamic simulations, followed by PCA and MM-GBSA analysis, to screen about 35000 compounds; to predict that two rigidin analogues can potentially selectively inhibit SHP1 but not SHP2. Our studies demonstrate that these rigidin analogues are more potent at inhibiting SHP1 than the commercially available inhibitor NSC-87877. Further, cross-binding studies with SHP2 exhibited poor binding efficiency and lower stability of the complex, thus indicating a specificity of the rigidin analogues for SHP1, which is crucial in preventing side effects due to the diverse physiological functions of SHP2 in cellular signaling, proliferation, and hematopoiesis. Additionally, SHP1 is essential in mediating the inhibitory signaling in antitumor immune cells like NK and T cells. Hence, the rigidin analogues that inhibit SHP1 will potentiate the anti-tumor immune response by the release of inhibitory function of NK cells, thus driving NK activating response, in addition to their intrinsic anti-tumor function. Thus, SHP1 inhibition is a novel double-blade approach towards anti-cancer immunotherapeutics. Communicated by Ramaswamy H. Sarma

ITRAQ proteome analysis of insight into TLR20.2 functions through IFN1 signaling exerts regulatory effects on GCRV replication

Maternal immunization is an efficacious way to protect offspring from pathogen infections. To clarify the immune-enhancing mechanism of maternal immunization in grass carp, the iTRAQ assay was applied to screen differentially expressed proteins (DEPs) among eggs produced from maternal-immunized and non-immunized female grass carp. A total of 138 DEPs were obtained and TLR20.2 was the sole identified consensus DEP among the maternal-immunized and non-immunized groups. In general, the gene and protein expressions of TLR20.2 in the egg cell and early developmental stage embryos could be enhanced by maternal-immunized treatment. The mRNA levels of tlr20.2 were up-regulated in the liver, head kidney, and spleen in response to grass carp reovirus (GCRV) infection. Mechanistically, TLR20.2 functions through the IFN1 signaling and displayed inhibitory functions on GCRV replication by remarkably down-regulation of vp2 and vp7 expressions. The HSP90 was identified to be one of the proteins that interacted with TLR20.2, which coexpressed with TLR20.2 and mainly concentrated around the central veins. HSP90 promotes GCRV replication by inhibiting the irf3, irf7, and ifn1 expressions, which resulted in remarkably increased vp2 and vp7 gene expressions. The HMGB1a and HMGB1b could bind to the TLR20–2 promoter, and showed positive effects on tlr20.2 expression by significantly promoting its promoter activity (P < 0.01). Moreover, HMGB1a and HMGB1b exerted negative effects on HSP90 expression and thus the GCRV replication. Overall, this study provided molecular evidence that maternal immunization treatment protect against GCRV infection through the enhancement of TLR20.2 expression, and the HMGB1-TLR20.2-HSP90-IFN axis confers regulatory effects on GCRV replication. The results are novel findings to help elucidate the resistance-enhancing mechanism in fish species.