Cystatin SA attenuates gastric cancer cells growth and increases sensitivity to oxaliplatin via PI3K/AKT signaling pathway.

PURPOSE: Cystatin SA (CST2) belongs to the superfamily of cysteine protease inhibitors. Emerging research indicates that CST2 is often dysregulated across various cancers. Its role and molecular mechanisms in gastric cancer remain underexplored. This study aims to explore the expression and function of CST2 in gastric cancer. METHODS: CST2 expression was analyzed and validated through Western blot. CST2 overexpression was induced by lentivirus in GC cells, and the correlation between CST2 expression levels and downstream signaling pathways was assessed. In addition, multiple assays, including cell proliferation, colony formation, wound-healing, and transwell migration/invasion, were considered to ascertain the influence of CST2 overexpression on gastric cancer. The cell cycle and apoptosis were detected by flow cytometry. RESULTS: CST2 expression at the protein level was decreased to be reduced in both gastric cancer tissues and cell lines, and CST2 expression attenuate gastric cancer growth, an effect restricted to gastric cancer cells and absent in gastric epithelial GES-1 cells. Furthermore, CST2 was demonstrated to improve chemosensitivity to Oxaliplatin in gastric cancer cells through the PI3K/AKT signaling pathway. CONCLUSION: These findings indicate that CST2 is downregulated at the protein level in gastric cancer tissues and cell lines. Additionally, CST2 was found to attenuate the growth of gastric cancer cells and to enhance sensitivity to Oxaliplatin through the PI3K/AKT signaling pathway, specific to gastric cancer cell lines. CST2 may serve as a tumor suppressor gene increasing sensitivity to Oxaliplatin in gastric cancer.

Asian-European differentiation of schizophrenia-associated genes driven by admixture and natural selection.

The European-centered genome-wide association studies of schizophrenia (SCZ) may not be well applied to non-European populations. We analyzed 1,592 reported SCZ-associated genes using the public genome data and found an overall higher Asian-European differentiation on the SCZ-associated variants than at the genome-wide level. Notable examples included 15 missense variants, a regulatory variant SLC5A10-rs1624825, and a damaging variant TSPAN18-rs1001292. Independent local adaptations in recent 25,000 years, after the Asian-European divergence, could have contributed to such genetic differentiation, as were identified at a missense mutation LTN1-rs57646126-A in Asians, and a non-risk allele ZSWIM6-rs72761442-G in Europeans. Altai-Neanderthal-derived alleles may have opposite effects on SCZ susceptibility between ancestries. Furthermore, adaptive introgression was detected on the non-risk haplotype at 1q21.2 in Europeans, while in Asians it was observed on the SCZ risk haplotype at 3p21.31 which is also potentially ultra-violet protective. This study emphasizes the importance of including more representative Asian samples in future SCZ studies.

Shenqi Fuzheng injection alleviates chemotherapy-induced cachexia by restoring glucocorticoid signaling in hypothalamus.

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Linguistic correlates of societal variation: A quantitative analysis.

Traditionally, many researchers have supported a uniformitarian view whereby all languages are of roughly equal complexity, facilitated by internal trade-offs between complexity at different levels, such as morphology and syntax. The extent to which the speakers' societies influence the trade-offs has not been well studied. In this paper, we focus on morphology and syntax, and report significant correlations between specific linguistic and societal features, in particular those relating to exoteric (open) vs. esoteric (close-knit) society types, characterizable in terms of population size, mobility, communication across distances, etc. We conduct an exhaustive quantitative analysis drawing upon WALS, D-Place, Ethnologue and Glottolog, finding some support for our hypothesis that languages spoken by exoteric societies tend towards more complex syntaxes, while languages spoken by esoteric societies tend towards more complex morphologies.

M1 intestinal macrophages-derived exosomes promote colitis progression and mucosal barrier injury.

AIM: This work aimed to investigate the role of M1 intestinal macrophages-derived exosomes (M1-Exo) in colitis and its mechanism. METHODS: M1 polarization of intestinal macrophages was induced in vitro, and their exosomes were extracted and identified. Thereafter, the DSS-induced colitis mouse model was built. Each mouse was given intraperitoneal injection of exosomes, and then mouse weight and DAI were dynamically monitored. In addition, the levels of cytokines were detected by ELISA. After treatment with the TLR4 inhibitor Resatorvid, the effects of M1 macrophages-derived exosomes were observed. Besides, the mouse intestinal epithelial cells were cultured in vitro for observing function of M1-Exo. RESULTS: M1-exo aggravated the colitis and tissue inflammation in mice, activated the TLR4 signal, and destroyed the mucosal barrier. But M0 macrophages-derived exosomes (M0-Exo) did not have the above effects. Resatorvid treatment antagonized the roles of M1-exo. Moreover, as confirmed by cellular experiments in vitro, M1-exo destroyed mucosal barrier. CONCLUSION: M1-exo serve as the pro-inflammatory mediator, which can promote mouse colitis progression by activating TLR4 signal.

The emerging role of lactate in tumor microenvironment and its clinical relevance.

In recent years, the significant impact of lactate in the tumor microenvironment has been greatly documented. Acting not only as an energy substance in tumor metabolism, lactate is also an imperative signaling molecule. It plays key roles in metabolic remodeling, protein lactylation, immunosuppression, drug resistance, epigenetics and tumor metastasis, which has a tight relation with cancer patients' poor prognosis. This review illustrates the roles lactate plays in different aspects of tumor progression and drug resistance. From the comprehensive effects that lactate has on tumor metabolism and tumor immunity, the therapeutic targets related to it are expected to bring new hope for cancer therapy.

Gasdermin E promotes translocation of p65 and c-jun into nucleus in keratinocytes for progression of psoriatic skin inflammation.

Gasdermin E (GSDME) has recently been identified as a critical executioner to mediate pyroptosis. While epidermal keratinocytes can initiate GSDME-mediated pyroptosis, the role of keratinocyte GSDME in psoriatic dermatitis remains poorly characterized. Through analysis of GEO datasets, we found elevated GSDME levels in psoriatic lesional skin. Additionally, GSDME levels correlated with both psoriasis severity and response to biologics treatments. Single-cell RNA sequencing (scRNA-seq) from a GEO dataset revealed GSDME upregulation in keratinocytes of psoriasis patients. In the imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model, both full-length and cleaved forms of caspase-3 and GSDME were elevated in the epidermis. Abnormal proliferation and differentiation of keratinocytes and dermatitis were attenuated in Gsdme-/- mice and keratinocyte-specific Gsdme conditional knockout mice after IMQ stimulation. Exposure of keratinocytes to mixed cytokines (M5), mimicking psoriatic conditions, led to GSDME cleavage. Moreover, the interaction between GSDME-FL and p65 or c-jun was significantly increased after M5 stimulation. GSDME knockdown inhibited nuclear translocation of p65 and c-jun and decreased upregulation of psoriatic inflammatory mediators such as IL1ß, CCL20, CXCL1, CXCL8, S100A8, and S100A9 in M5-challenged keratinocytes. In conclusion, GSDME in keratinocytes contributes to the pathogenesis and progression of psoriasis, potentially in a pyroptosis-independent manner by interacting and promoting translocation of p65 and c-jun. These findings suggest that keratinocyte GSDME could serve as a potential therapeutic target for psoriasis treatment.

Mechanical and chemical itch regulated by neuropeptide Y-Y1 signaling.

Itch is a somatosensory sensation to remove potential harmful stimulation with a scratching desire, which could be divided into mechanical and chemical itch according to diverse stimuli, such as wool fiber and insect biting. It has been reported that neuropeptide Y (NPY) neurons, a population of spinal inhibitory interneurons, could gate the transmission of mechanical itch, with no effect on chemical itch. In our study, we verified that chemogenetic activation of NPY neurons could inhibit the mechanical itch as well as the chemical itch, which also attenuated the alloknesis phenomenon in the chronic dry skin model. Afterwards, intrathecal administration of NPY1R agonist, [Leu31, Pro34]-NPY (LP-NPY), showed the similar inhibition effect on mechanical itch, chemical itch and alloknesis as chemo-activation of NPY neurons. Whereas, intrathecal administration of NPY1R antagonist BIBO 3304 enhanced mechanical itch and reversed the alloknesis phenomenon inhibited by LP-NPY treatment. Moreover, selectively knocking down NPY1R by intrathecal injection of Npy1r siRNA enhanced mechanical and chemical itch behavior as well. These results indicate that NPY neurons in spinal cord regulate mechanical and chemical itch, and alloknesis in dry skin model through NPY1 receptors.

Conservation genomic investigation of an endangered conifer, Thuja sutchuenensis, reveals low genetic diversity but also low genetic load.

Endangered species generally have small populations with low genetic diversity and a high genetic load. Thuja sutchuenensis is an endangered conifer endemic to southwestern China. It was once considered extinct in the wild, but in 1999 was rediscovered. However, little is known about its genetic load. We collected 67 individuals from five wild, isolated T. sutchuenensis populations, and used 636,151 SNPs to analyze the level of genetic diversity and genetic load in T. sutchuenensis to delineate the conservation units of T. sutchuenensis, based on whole transcriptome sequencing data, as well as target capture sequencing data. We found that populations of T. sutchuenensis could be divided into three groups. These groups had low levels genetic diversity and were moderately genetically differentiated. Our findings also indicate that T. sutchuenensis suffered two severe bottlenecks around the Last Glaciation Period and Last Glacial Maximum. Among Thuja species, T. sutchuenensis presented the lowest genetic load and hence might have purged deleterious mutations efficiently through purifying selection. However, distribution of fitness effects analysis indicated a high extinction risk for T. sutchuenensis. Multiple lines of evidence identified three management units for T. sutchuenensis. Although T. sutchuenensis possesses a low genetic load, low genetic diversity, suboptimal fitness, and anthropogenic pressures all present an extinction risk for this rare conifer. This might also hold true for many endangered plant species in the mountains all over the world.

Energy preservation for skeletal muscles: Shenqi Fuzheng injection prevents tissue wasting and restores bioenergetic profiles in a mouse model of chemotherapy-induced cachexia.

BACKGROUND: Energy deficiency is the characteristic of chemotherapy-induced cachexia (CIC) which is manifested by muscle wasting. glycolysis, tricarboxylic acid (TCA) cycle, and lipid metabolism are central to muscle bioenergy production, which is vulnerable to chemotherapy during cancer treatment. Recent investigations have spotlighted the potential of Shenqi Fuzheng injection (SQ), a Chinese proprietary medicine comprising Radix Codonopsis and Radix Astragali, in alleviating CIC. However, the specific effects of SQ on muscle energy metabolism remains less explored. PURPOSE AND METHODS: Here, we integrated transcriptomics, spatial metabolomics, gas chromatography-mass spectrometry targeted quantitative analysis, and transmission electron microscopy techniques, combined with Seahorse live-cell metabolic analysis to reveal the changes in genes and pathways related to energy metabolism in the CIC model and SQ's protective effects at molecular and functional levels. RESULTS: Our data showed that chemotherapeutic agents caused glycolysis imbalance, which further leads to metabolic derangements of TCA cycle intermediates. SQ maintained glycolysis balance by facilitating pyruvate fluxing to mitochondria for more efficient bioenergy production, which involved a dual effect on promoting functions of mitochondrial pyruvate dehydrogenase complexes and inhibiting lactate dehydrogenase for lactate production. As a result of the sustained pyruvate level achieved by SQ administration, glycolysis balance was maintained, which further led to the preservation of mitochondrial integrity and function of electron transport chain, thereby, ensuring the normal operation of the TCA cycle and the proper synthesis of adenosine triphosphate (ATP). The above results were further validated using the Seahorse live-cell assay. CONCLUSION: In conclusion, our study highlights SQ as a promising strategy for CIC management, emphasizing its ability to harmonize the homeostasis of the muscle bioenergetic profile. Beyond its therapeutic implications, this study also offers a novel perspective for the development of innovative treatments in the realm of herbal medicine.

Precipitation- rather than temperature-driven pattern in belowground biomass and root:shoot ratio across the Qinghai-Tibet Plateau.

The Qinghai-Tibet Plateau faces dramatic global change, which can greatly affect its plant growth, biomass accumulation, and carbon cycling. However, it is still unclear how belowground plant biomass, which is the major part of vegetation biomass on the plateau, changes with different environmental factors, impeding accurate prediction of ecosystem carbon cycling under future global change scenarios. To reveal the patterns of belowground biomass and root:shoot ratio with environmental factors in different vegetation types on the Qinghai-Tibet Plateau, we synthesized data for 158 sites from 167 publications, including 585 and 379 observations for above- and below-ground biomass, respectively. Data on temperature, precipitation, soil nitrogen content, evapotranspiration and solar radiation were collected from open databases. The results showed that precipitation, rather than temperature, was closely associated with other environmental factors including soil N and solar radiation. Also, both above- and below-ground biomass significantly increased with annual precipitation and its related environmental factors, while elevation-related coldness only slightly decreased aboveground biomass. In addition, the positive effect of precipitation on belowground biomass is more obvious in higher elevations (colder areas). As a result, root:shoot ratio significantly increased with precipitation in colder areas but not in warmer areas. Finally, the positive relationship between biomass and precipitation was stronger for dryer steppes than for wetter meadows and shrublands. Our findings indicate that precipitation, as well as the associated nitrogen availability and solar radiation, together are more important drivers than temperature for ecosystem productivity and biomass allocation on the Qinghai-Tibet Plateau. Given the heterogeneous trend of precipitation change on the plateau, productivity response to global change can be highly variable across different regions and vegetation types, which can consequently impact soil carbon dynamics and regional carbon cycling.

A meta-analysis comparing phenol treatment with surgical excision for pilonidal sinus.

Pilonidal sinus is a chronic condition characterized by inflammation, swelling, and pain in the sacrococcygeal region. In recent years, the rate of recurrence and wound complications in PSD remains high, and no treatment is universally accepted. This study aimed to compare the efficacy of phenol treatment with surgical excision treatment for PSD through a meta-analysis of controlled clinical trials. We searched three electronic databases, PubMed, Embase, and Cochrane library, to comprehensively search the literature comparing phenol treatment and surgical treatment of pilonidal sinus. Fourteen publications were included, including five RCTs and nine non-RCTs. The phenol group had a slightly higher rate of disease recurrence than the surgical group (RR = 1.12, 95% CI [0.77,1.63]), but the difference was not statistically significant (P = 0.55 > 0.05). As compared to the surgical group, wound complications were considerably less common (RR = 0.40, 95% CI [0.27,0.59]). Phenol treatment resulted in a significantly shorter operating time than surgery treatment (weighted mean difference -22.76, 95% CI [-31.13,-14.39]). The time to return to daily work was considerably shorter than in the surgical group (weighted mean difference -10.11, 95% CI [-14.58,-5.65]). Postoperative complete healing time was significantly shorter than surgical healing time (weighted mean difference -17.11, 95% CI [-32.18,-2.03]). Phenol treatment is effective for pilonidal sinus disease, and its recurrence rate is not significantly different from surgical treatment. The greatest advantage of phenol treatment is the low incidence of wound complications. Moreover, the time required for treatment and recovery are significantly lower than for surgical treatment.

Programmable photochemical deoxygenation for 2.5D grayscale printing.

Homomolecular photon upconversion-induced radical polymerization in an aerated DMSO solution occurs where molecular oxygen is depleted by sensitized photochemical deoxygenation and this photoreaction could be programmed into 2.5D grayscale printings by digital light processing.

Rational Sentence Interpretation in Mandarin Chinese.

Previous work has shown that English native speakers interpret sentences as predicted by a noisy-channel model: They integrate both the real-world plausibility of the meaning-the prior-and the likelihood that the intended sentence may be corrupted into the perceived sentence. In this study, we test the noisy-channel model in Mandarin Chinese, a language taxonomically different from English. We present native Mandarin speakers sentences in a written modality (Experiment 1) and an auditory modality (Experiment 2) in three pairs of syntactic alternations. The critical materials are literally implausible but require differing numbers and types of edits in order to form more plausible sentences. Each sentence is followed by a comprehension question that allows us to infer whether the speakers interpreted the item literally, or made an inference toward a more likely meaning. Similar to previous research on related English constructions, Mandarin participants made the most inferences for implausible materials that could be inferred as plausible by deleting a single morpheme or inserting a single morpheme. Participants were less likely to infer a plausible meaning for materials that could be inferred as plausible by making an exchange across a preposition. And participants were least likely to infer a plausible meaning for materials that could be inferred as plausible by making an exchange across a main verb. Moreover, we found more inferences in written materials than spoken materials, possibly a result of a lack of word boundaries in written Chinese. Overall, the fact that the results were so similar to those found in related constructions in English suggests that the noisy-channel proposal is robust.

Retrosynthetic Analysis of the Synthetic Pathway for Antineocyclocitrinol A.

With the discovery and exploration of deep-sea fungal metabolites, researchers have found that these abundant metabolites have a wide range of therapeutic effects on human diseases. Mutagenesis, purification and structural analysis of diverse deep-sea fungal metabolites have led to a new molecule named Antineocyclocitrinol A. This molecule is difficult to synthesize because it contains a complex structure such as the unusual bicyclo [4.4.1] A/B ring system with a bridgehead double bond. This paper explains an analytical strategy for retrosynthesis concretely and provides a theoretically feasible new synthetic pathway for synthesizing Antineocyclocitrinol A. This pathway fills a gap in the specific retrosynthetic analysis of Antineocyclocitrinol A and also serves as an application idea for a more detailed synthesis of cyclocitrinols analogs. Furthermore, this pathway promotes the development of the biopharmaceutical field by using deep-sea fungal metabolites.

Motor-free contractility of active biopolymer networks.

Contractility in animal cells is often generated by molecular motors such as myosin, which require polar substrates for their function. Motivated by recent experimental evidence of motor-independent contractility, we propose a robust motor-free mechanism that can generate contraction in biopolymer networks without the need for substrate polarity. We show that contractility is a natural consequence of active binding-unbinding of crosslinkers that breaks the principle of detailed balance, together with the asymmetric force-extension response of semiflexible biopolymers. We have extended our earlier work to discuss the motor-free contraction of viscoelastic biopolymer networks. We calculate the resulting contractile velocity using a microscopic model and show that it can be reduced to a simple coarse-grained model under certain limits. Our model may provide an explanation of recent reports of motor-independent contractility in cells. Our results also suggest a mechanism for generating contractile forces in synthetic active materials.

Effective medium theory for mechanical phase transitions of fiber networks.

Networks of stiff fibers govern the elasticity of biological structures such as the extracellular matrix of collagen. These networks are known to stiffen nonlinearly under shear or extensional strain. Recently, it has been shown that such stiffening is governed by a strain-controlled athermal but critical phase transition, from a floppy phase below the critical strain to a rigid phase above the critical strain. While this phase transition has been extensively studied numerically and experimentally, a complete analytical theory for this transition remains elusive. Here, we present an effective medium theory (EMT) for this mechanical phase transition of fiber networks. We extend a previous EMT appropriate for linear elasticity to incorporate nonlinear effects via an anharmonic Hamiltonian. The mean-field predictions of this theory, including the critical exponents, scaling relations and non-affine fluctuations qualitatively agree with previous experimental and numerical results.

BTN3A3 inhibits clear cell renal cell carcinoma progression by regulating the ROS/MAPK pathway via interacting with RPS3A.

Butyrophilin subfamily 3 member A3 (BTN3A3) is a member of the immunoglobulin superfamily and functions as a tumor suppressor in multiple cancer types. Our study has revealed that in clear cell renal cell carcinoma (ccRCC), patients who express high levels of BTN3A3 experience longer survival times than those with lower expression. Further, we have observed that BTN3A3 inhibits the proliferation, migration, and invasion of ccRCC cells. Through the utilization of an immunoprecipitation assay followed by mass spectrometry, we have discovered that BTN3A3 binds directly to RPS3A. Knockdown of BTN3A3 led to increased cell proliferation, migration, and invasion. However, this effect was significantly reduced when RPS3A was simultaneously overexpressed. Previous reports have demonstrated that RPS3A positively regulates mitochondrial function and reactive oxygen species (ROS) levels. Our study has shown that overexpression of both BTN3A3 and RPS3A can increase cellular oxygen consumption rate (OCR) and ROS levels. Furthermore, we have observed that the addition of H2O2 can reverse the effects of BTN3A3 knockdown on cell proliferation and migration by increasing the cellular ROS level. ROS play a crucial role in regulating the MAPK pathway and tumor cell growth. To further explore this relationship, we examined RNA-Seq and immunoblotting data and found that BTN3A3 can negatively regulate the degree of activation of the MAPK signaling pathway. This finding suggests that the BTN3A3/RPS3A complex may regulate ccRCC progression by modulating MAPK pathways. Therefore, BTN3A3 could serve as both a prognostic marker and a potential therapeutic target for ccRCC patients.

Efficient CsPbBr3 Quantum-Dot Light-Emitting Diodes Using Sputtered NiO Films as Hole Injection Layers.

Perovskite quantum dots (QDs) have showed excellent optoelectronic properties to extend the application range of novel solid-state lighting, such as perovskite QD based LEDs (QD-LEDs). However, the traditional device structure of perovskite QD-LEDs employed PEDOT:PSS as a hole inject layer (HIL), which impairs stability due to acidic surface characteristics. This study proposes the sputtered NiO films as an HIL to replace acidic PEDOT:PSS. The NiO films with significantly different characteristics were prepared by controlling the sputtering parameters to investigate the devices' performance of NiO-based CsPbBr3 QD-LEDs. The optimized device showed an excellent performance with maxima luminescence of 20,118 cd/m2 and an external quantum efficiency (EQE) up to 3.63%.

Gasdermin D-mediated keratinocyte pyroptosis as a key step in psoriasis pathogenesis.

Gasdermin D (GSDMD)-mediated pyroptosis has a significant pro-inflammation characteristic due to dramatic secretion of pro-inflammatory substances. However, its role remains unclear in psoriasis as one chronic inflammatory skin disorder with high prevalence. We found that N-terminal GSDMD (N-GSDMD) was aberrantly expressed in epidermis of skin lesion in psoriasis patients and imiquimod-induced psoriasis-like dermatitis (IIPLD) mice. In epidermis of IIPLD mice and M5 (simulating psoriatic inflammatory challenge)-treated keratinocytes cultured in vitro, cleavage products of caspase-1, GSDMD and IL-1ß were increased. M5-stimulated keratinocyte presented typical pyroptosis morphology accompanied with PI-staining. Gsdmd-/- keratinocytes could not present pyroptosis morphology while stimulated with M5. Electroporation of recombinant N-GSDMD could make the pyroptosis morphology reappear. In Gsdmd-/- mice or keratinocyte-specific Gsdmd conditional knockout mice, we observed the alleviation of psoriatic inflammation and epidermal aberrant expression of Ki-67 and differentiation markers (loricrin and keratin 5) after imiquimod stimulation. Transplanting skin tissue from control mice to Gsdmd-/- mice can evoke the response to imiquimod stimulation in the background of Gsdmd-/- mice (not limited in transplanting area). In M5-stimulated keratinocytes, disulfiram or GSDMD siRNA transfection can inhibit pyroptosis and eliminate disproportionate increases of Ki-67 and PI. We further validated that topically application of disulfiram (pyroptosis inhibitor) also alleviated IIPLD in mice. These findings indicate a novel mechanism that GSDMD-mediated keratinocyte pyroptosis facilitates hyperproliferation and aberrant differentiation induced by immune microenvironment in psoriatic skin inflammation, which contributes to pathogenesis of psoriasis. Our study provides an innovative insight that targeting pyroptosis can be considered as a therapeutic strategy against psoriasis.