ATG5-mediated keratinocyte ferroptosis promotes M1 polarization of macrophages to aggravate UVB-induced skin inflammation.

Autophagy participates in the regulation of ferroptosis. Among numerous autophagy-related genes (ATGs), ATG5 plays a pivotal role in ferroptosis. However, how ATG5-mediated ferroptosis functions in UVB-induced skin inflammation is still unclear. In this study, we unveil that the core ferroptosis inhibitor GPX4 is significantly decreased in human skin tissue exposed to sunlight. We report that ATG5 deletion in mouse keratinocytes strongly protects against UVB-induced keratinocyte ferroptosis and skin inflammation. Mechanistically, ATG5 promotes the autophagy-dependent degradation of GPX4 in UVB-exposed keratinocytes, which leads to UVB-induced keratinocyte ferroptosis. Furthermore, we find that IFN-γ secreted by ferroptotic keratinocytes facilitates the M1 polarization of macrophages, which results in the exacerbation of UVB-induced skin inflammation. Together, our data indicate that ATG5 exacerbates UVB-induced keratinocyte ferroptosis in the epidermis, which subsequently gives rise to the secretion of IFN-γ and M1 polarization. Our study provides novel evidence that targeting ATG5 may serve as a potential therapeutic strategy for the amelioration of UVB-caused skin damage.

Determinants of sedentary behavior in community-dwelling older adults with type 2 diabetes based on the behavioral change wheel: a path analysis.

BACKGROUND: Sedentary behavior (SB) is deeply ingrained in the daily lives of community-dwelling older adults with type 2 diabetes mellitus (T2DM). However, the specific underlying mechanisms of the determinants associated with SB remain elusive. We aimed to explore the determinants of SB based on the behavior change wheel framework as well as a literature review. METHODS: This cross-sectional study recruited 489 community-dwelling older adults with T2DM in Jinan City, Shandong Province, China. Convenience sampling was used to select participants from relevant communities. This study used the Measure of Older Adults' Sedentary Time-T2DM, the Abbreviated-Neighborhood Environment Walkability Scale, the Social Support Rating Scale, the Lubben Social Network Scale 6, the Subjective Social Norms Questionnaire for Sedentary Behavior, the Functional Activities Questionnaire, the Numerical Rating Scale, the Short Physical Performance Battery, and the Montreal Cognitive Assessment Text to assess the levels of and the determinants of SB. Descriptive statistical analysis and path analysis were conducted to analyze and interpret the data. RESULTS: Pain, cognitive function, social isolation, and social support had direct and indirect effects on SB in community-dwelling older adults with T2DM (total effects: ß = 0.426, ß = -0.171, ß = -0.209, and ß = -0.128, respectively), and physical function, walking environment, and social function had direct effects on patients' SB (total effects: ß = -0.180, ß = -0.163, and ß = 0.127, respectively). All the above pathways were statistically significant (P < 0.05). The path analysis showed that the model had acceptable fit indices: RMSEA = 0.014, χ 2/df = 1.100, GFI = 0.999, AGFI = 0.980, NFI = 0.997, RFI = 0.954, IFI = 1.000, TLI = 0.996, CFI = 1.000. CONCLUSION: Capability (physical function, pain, and cognitive function), opportunity (social isolation, walking environment, and social support), and motivation (social function) were effective predictors of SB in community-dwelling older adults with T2DM. Deeper knowledge regarding these associations may help healthcare providers design targeted intervention strategies to decrease levels of SB in this specific population.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model.

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aß plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aß clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Malignant melanotic schwannoma of the cervical spinal cord: a case report.

Spinal cord malignant melanotic schwannoma (MMNST) is a rare central nervous system tumor that originates from the spinal cord or spinal myelin sheath cells and can produce melanin. This type of tumor is usually highly aggressive and malignant, with a poor prognosis. The clinical manifestations of spinal cord MMNST are mainly pain, paresthesia, muscle weakness, muscle atrophy, etc., and symptoms of spinal cord compression, such as intestinal and bladder dysfunction, paraplegia, etc. Early detection of tumor lesions can facilitate tumor removal, improve patients' quality of life, and prolong patients' survival. In this case report, a 27-year-old young woman was diagnosed with MMNST of the cervical spinal cord due to weakness of her limbs in our hospital, and underwent surgical resection. The patient's limbs returned to normal after surgery. It is worth mentioning that the patient visited our hospital 7 months ago for "right upper limb pain for 3 days" and was diagnosed with a cervical spine space-occupying lesion at the same position this time, but the pathology report was "hemosiderosis". The patient's limbs returned to normal after surgery. It is worth mentioning that the patient visited our hospital 7 months ago for "right upper limb pain for 3 days" and was diagnosed with a cervical spine space-occupying lesion at the same position this time, but the pathology report was "hemosiderosis". This case report aims to raise awareness of the problem of spinal cord MMNST and contribute to greater knowledge of this rare tumor. This case report aims to raise awareness of the problem of spinal cord MMNST and contribute to greater knowledge of this rare tumor.

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.

Stable Near-Infrared Photoluminescence of Hexagonal-Shaped PbS Nanoparticles with 1-Dodecanethiol Ligands.

In this study, lead(II) sulphide (PbS) nanoparticles of varying particle sizes were synthesized using the hot injection method, employing 1-octadecene (ODE) as a coordinating ligand in conjunction with oleylamine (OAm). This synthesis approach was compared with the preparation of hexagonal-shaped nanoparticles through the ligand of 1-Dodecanethiol (DT), resulting in DT-capped PbS nanoparticles. The prepared nanoparticles were characterized using multiple techniques including photoluminescence (PL), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR). The condensation reaction of DT ligands led to various nanoparticles within the range of 34.87 nm to 35.87 nm across different synthesis temperatures (120 °C, 150 °C, 180 °C, 210 °C, and 240 °C). The PbS with DT ligands exhibited a highly crystalline and superhydrophilic structure. Interestingly, near-infrared (NIR)-PL analysis revealed peaks at 1100 nm, representing the lowest-energy excitonic absorption peak of PbS nanoparticles for both ligands. This suggests their potential utility in various applications, including IR photoreactors, as well as in the development of non-toxic nanoparticles for potential applications in in vivo bioimaging.

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.

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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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.

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.

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.

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.

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.

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.

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.