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This paper presents a novel analytical method based on improved Gaussian mixture model (GMM) to solve the probabilistic load flow problem. The proposed method accounts for the uncertainty introduced due to increasing percentages of renewable generation. First, the joint probability density function of several wind farms outputs is derived by using the improved GMM with the estimated parameters obtained by genetic algorithm (GA) in this paper, which could improve the accuracy of the probabilistic model. Next, the analytical expressions between the output power of wind farms and line power of power system are deduced by linearizing load flow equations. And, the joint probability density function and joint cumulative distribution function of line power are obtained from linear load equation and joint probability density function of wind output power. Finally, the proposed method, Monte Carlo simulation (MCS) and traditional GMM based methods are all tested on a modified IEEE 39-bus system and a modified IEEE 118-bus system with multiple wind farms, which demonstrates the feasibility of the proposed method.

Background: Coffee consumption is inversely associated with type 2 diabetes. Cafestol, a bioactive compound in coffee, has demonstrated glucose-lowering and insulin-secretory properties in cell and animal studies. The acute effects of cafestol on glucose metabolism in humans have only been briefly investigated, and longer-term effects have not been explored. This study aimed to assess the effects of purified cafestol on insulin sensitivity and other metabolic parameters in healthy individuals with increased waist circumference at risk of developing type 2 diabetes. Methods: A 12-week randomized, placebo-controlled, parallel trial was conducted with 40 participants. Insulin suppression tests, mixed meal tests, and MRI scans were performed before and after the intervention. Results: Administering 6 mg of cafestol twice daily did not alter insulin sensitivity or glucose tolerance but led to significant reductions in body weight (2%), visceral fat volume (5%), and gamma-glutamyl transferase levels (15%) compared to the placebo. Conclusions: Cafestol may hold promise for weight and visceral fat reduction. Cafestol did not improve insulin sensitivity or glucose tolerance in this study but might still contribute to the observed inverse association between coffee consumption and type 2 diabetes. Future research should explore higher dosages and longer treatment durations, particularly in individuals with impaired glucose metabolism and type 2 diabetes.

Background: Coffee consumption is inversely associated with type 2 diabetes. Cafestol, a bioactive compound in coffee, has demonstrated glucose-lowering and insulin-secretory properties in cell and animal studies. The acute effects of cafestol on glucose metabolism in humans have only been briefly investigated, and longer-term effects have not been explored. This study aimed to assess the effects of purified cafestol on insulin sensitivity and other metabolic parameters in healthy individuals with increased waist circumference at risk of developing type 2 diabetes. Methods: A 12-week randomized, placebo-controlled, parallel trial was conducted with 40 participants. Insulin suppression tests, mixed meal tests, and MRI scans were performed before and after the intervention. Results: Administering 6 mg of cafestol twice daily did not alter insulin sensitivity or glucose tolerance but led to significant reductions in body weight (2%), visceral fat volume (5%), and gamma-glutamyl transferase levels (15%) compared to the placebo. Conclusions: Cafestol may hold promise for weight and visceral fat reduction. Cafestol did not improve insulin sensitivity or glucose tolerance in this study but might still contribute to the observed inverse association between coffee consumption and type 2 diabetes. Future research should explore higher dosages and longer treatment durations, particularly in individuals with impaired glucose metabolism and type 2 diabetes. [ABSTRACT FROM AUTHOR]

In the uncertain vibration analysis of fractionally-damped beams whose damping characteristic is described using fractional derivative model, the uncertain excitation is usually modeled as a stochastic process. However, it is often difficult to obtain sufficient samples of the excitation to establish a precise probability distribution function for the stochastic process model in practical engineering problems. Hence, in this paper, a nonrandom vibration analysis method for fractionally-damped beams is proposed to obtain the dynamic displacement response bounds of the beams under the uncertain excitation. Specifically, the uncertain excitation applied to the fractionally-damped beam is treated as a spatial-time interval field, so that the dynamic displacement response of the beam is also a space-time interval field. The middle point function and the radius function of the displacement response of the fractionally-damped beam can be derived based on the modal superposition method and the Laplace transform, through which the bound functions of the dynamic displacement response can be obtained. In addition, several numerical examples are given to demonstrate the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

This work presents a potential solution for enabling the use of multicast in the 5G New Radio Release 17, called 5G NR Mixed Mode. The proposed multicast/broadcast mode follows one of the two approaches envisaged in 3GPP, which enables a dynamic and seamless switching between unicast and multicast, both in the downlink and the uplink. This paper also provides a performance evaluation of several IMT-2020 KPIs, including available data rate and spectral efficiency, user and control plane latencies, energy efficiency, and mobility, highlighting the potential advantages of this solution over unicast in relevant scenarios. Finally, other multipoint–based KPIs such as coverage or packet loss rate are also evaluated by means of system level simulations. [ABSTRACT FROM AUTHOR]

What is known and objective Hyperthermia is an effective treatment modality that augments the anticancer effects of radiotherapy and chemotherapy. Hyperthermia-chemo-radiotherapy ( HCRT) is a combination therapy that can strengthen anticancer effects through a synergistic interaction between heat, chemotherapy and radiation. Here, we carried out a systematic review and meta-analysis to evaluate the clinical efficacy and safety of chemoradiation combined with regional hyperthermia ( HCRT) for oesophageal carcinoma. Methods We conducted computer searches of foreign databases, including Cochrane Library, PubMed, EMBASE, Web of Science and Chinese databases, including CBM, CNKI and WanFang; we also retrieved other sources as supplement. All relevant randomized controlled trials ( RCTs) were collected to compare HCRT and other therapies, including chemotherapy combined with radiotherapy ( CRT) and radiotherapy alone ( RT). After literature screening, data extraction and quality evaluation performed by appropriate criteria, the meta-analyses were conducted using RevMan 5.1 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Results and discussion Nineteen RCTs were included, comprising 1519 patients. Meta-analysis showed that the 1-, 3-, 5- and 7-year survival, complete response and total effective rates of the HCRT group were higher than those of the CRT group; the rates of gastrointestinal reaction, leucocytopenia and radiation oesophagitis in the HCRT group were lower than those of the CRT group, indicating significant differences ( P < 0·05). The 1-, 2-, 3- and 5-year survival, complete response and total effective rates of the HCRT group were higher than those of the RT group, the recurrence and distant metastasis rates of the HCRT group were lower than those of the RT group, and there were significant differences in all of the indicators ( P < 0·05). What is new and conclusions This is the first systematic review and meta-analysis to evaluate HCRT for oesophageal carcinoma. Compared with CRT or RT, HCRT can improve long-term and short-term curative effects; it is also safe and feasible. Additional high-quality and large sample size RCTs will be necessary to further demonstrate the long-term survival benefits and comprehensive safety profile of HCRT. [ABSTRACT FROM AUTHOR]

A protein-folding model is proposed at the amino acid level, in which the folding process is divided into two successive stages: the rate-determining step, dominated by the "stochastic interactions"of solvent molecules, and the rapid phase, dominated by the "order interactions"among atoms in polypeptide. The master equation approach is used to investigate the folding kinetics, and an analytical treatment of the master equation yields a simple three-parameter expression for folding time. It is found that both two-state and downhill protein-folding kinetics can be described by a unifying model. [ABSTRACT FROM AUTHOR]

In this letter, by using the properties of the entropy function and the fundamental equation of thermodynamics, we discuss the reasons that there exist different proposals for relativistic temperature transformation. Further, we illustrate this point by studying a concrete thermodynamic system-blackbody radiation. [ABSTRACT FROM AUTHOR]

The transcriptional repressor B cell lymphoma 6 (BCL6) plays a critical role in driving tumorigenesis of diffuse large B-cell lymphoma (DLBCL). However, the therapeutic potential of inhibiting or degrading BCL6 for DLBCL has not been thoroughly understood. Herein, we reported the discovery of a series of novel BCL6-targeting PROTACs based on our previously reported N-phenyl-4-pyrimidinamine BCL6 inhibitors. The optimal compound DZ-837 degraded BCL6 with DC 50 values around 600 nM and effectively inhibited the proliferation of several DLBCL cell lines. Further study indicated that DZ-837 induced significant G1 phase arrest and exhibited sustained reactivation of BCL6 downstream genes. In the SU-DHL-4 xenograft model, DZ-837 significantly inhibited tumor growth with TGI of 71.8 % at 40 mg/kg once daily. Furthermore, the combination of DZ-837 with BTK inhibitor Ibrutinib showed synergistic effects and overcame acquired resistance against DLBCL cells. Overall, our findings demonstrate that DZ-837 is an effective BCL6 degrader for DLBCL treatment as a monotherapy or in combination with Ibrutinib., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Multilayer dense myelin tissue provides insulating space and nutritional support for axons in healthy spinal cord tissue. Oligodendrocyte precursor cells (OPCs) are the main glial cells that complement myelin loss in the central nervous system and play an important role in the repair of spinal cord injury (SCI). However, the regulation of axonal remyelination after SCI is still insufficient. In this study, we focused on the changes in genes related to myelin repair after rat hemisection SCI by gene set enrichment analysis (GSEA). Key genes proteolipid protein 1 (Plp1), hexosaminidase subunit alpha (Hexa), and hexosaminidase subunit beta (Hexb) during remyelination after SCI were found. Through quantitative real-time polymerase chain reaction (qPCR) experiments, we confirmed that within 28 days after rat hemisection SCI, the mRNA expression of gene Plp1 gradually decreased, while the expressions of gene Hexa and Hexb gradually increased, which was consistent with RNA sequencing results. In vitro, we performed EdU proliferation assays on OPC cell line OLN-93 and primary rat OPCs. We found that interference of Plp1 promoted OPC proliferation, while interference of Hexa and Hexb inhibited OPC proliferation. In addition, we performed in vitro differentiation experiments on primary rat OPCs. By measuring myelin sheath branch outgrowth and the fluorescence intensity of the mature myelin sheath marker myelin basic protein (MBP), we found that interference of Hexa or Hexb promoted OPC differentiation and maturation, but interference of Plp1 inhibited this process. Finally, we injected Hexb siRNA in vivo and found that interfering Hexb could improve motor movements and myelin regeneration after SCI in rats. Our results provide new target genes that can selectively regulate the proliferation and differentiation of endogenous OPCs, providing new ideas for promoting remyelination and functional recovery after SCI., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Triplostegia glandulifera Wall (T. glandulifera) is an ethnomedicine commonly used by ethnic minorities in Yunnan, China, to treat kidney disease. However, there are few reports on the renoprotective effects of this substance, and the active ingredients remain unclear. In this study, we extracted the polysaccharide fractions TGB and TGC using the water extraction-alcohol precipitation method and determined their molecular weight (Mw) and monosaccharide composition. The study investigated the protective effects of TGB and TGC fractions against diabetic nephropathy (DN) using an in vitro high glucose-induced HRMCs model and an in vivo STZ-induced diabetic mouse model. HPLC analysis revealed that TGB contained D-galacturonic acid, D-glucose, D-galactose, and D-arabinose, and had a lower Mw than TGC. In vitro, TGB showed concentration-dependent antioxidant activity and effectively reduced abnormal proliferation and while attenuating oxidative stress in HRMCs. In mice with diabetes, TGB corrected the dysregulation of glucose-lipid metabolism and alleviated oxidative stress in the kidneys. Additionally, it improved renal function and reduced renal tissue damage. The study suggests that the low Mw polysaccharides (TGB) have better activity against DN through the antioxidative stress mechanism., (© 2024. The Author(s).)

Microgravity, as a unique hazardous factor encountered in space, can induce a series of harmful effects on living organisms. The impact of microgravity on the pivotal functional gene modules stemming from gene enrichment analysis via the regulation of miRNAs is not fully illustrated. To explore the microgravity-induced alterations in critical functional gene modules via the regulation of miRNAs, in the present study, we proposed a novel bioinformatics algorithm for the integrated analysis of miRNAome and transcriptome from short-term space-flown C. elegans. The samples of C. elegans were exposed to two space conditions, namely spaceflight (SF) and spaceflight control (SC) onboard the International Space Station for 4 days. Additionally, the samples of ground control (GC) were included for comparative analysis. Using the present algorithm, we constructed regulatory networks of functional gene modules annotated from differentially expressed genes (DEGs) and their associated regulatory differentially expressed miRNAs (DEmiRNAs). The results showed that functional gene modules of molting cycle, defense response, fatty acid metabolism, lysosome, and longevity regulating pathway were facilitated by 25 down-regulated DEmiRNAs (e.g., cel-miR-792, cel-miR-65, cel-miR-70, cel-lsy-6, cel-miR-796, etc.) in the SC vs. GC groups, whereas these modules were inhibited by 13 up-regulated DEmiRNAs (e.g., cel-miR-74, cel-miR-229, cel-miR-70, cel-miR-249, cel-miR-85, etc.) in the SF vs. GC groups. These findings indicated that microgravity could significantly alter gene expression patterns and their associated functional gene modules in short-term space-flown C. elegans. Additionally, we identified 34 miRNAs as post-transcriptional regulators that modulated these functional gene modules under microgravity conditions. Through the experimental verification, our results demonstrated that microgravity could induce the down-regulation of five critical functional gene modules (i.e., molting cycle, defense response, fatty acid metabolism, lysosome, and longevity regulating pathways) via the regulation of miRNAs in short-term space-flown C. elegans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)

Background: Hyperglycemia is associated with worse stroke outcomes, but it is uncertain whether tight glycemic control during the acute stroke period is associated with a better outcome. We conducted a meta-analysis to compare the effect of tight glycemic control versus loose glycemic control in the acute phase of stroke patients., Methods: A literature search was performed to identify randomized controlled trials comparing the safety and efficacy of tight glycemic control with a relatively loose control of blood glucose of acute stroke (ischemic or hemorrhagic) patients within 24 h after stroke onset. We required that the blood glucose level of the patients should not be lower than 6.11 mmol/L at the time of enrollment, and for the intensive blood glucose control range, we defined the blood glucose level as lower than that of the control group. The primary efficacy outcome measure was deaths from any cause at 90 days. Secondary efficacy outcomes comprised the number of participants with modified Rankin score (mRS). We define mRS scores 0-2 as favorable scores, recurrent stroke, and the National Institute of Health Stroke Scale or the European Stroke Scale scores. We defined the number of participants with hypoglycemia as our primary safety outcome. Subgroup analysis was performed according to age, the variety of interventions, maintained glucose level, and status of hypoglycemia on National Institute of Health Stroke Scale (NIHSS) scores or European Stroke Scale (ESS) scores., Results: Fifteen randomized controlled trials (RCTs) with 2957 participants meeting the including criteria were identified and included in this meta-analysis, although not all included data on every outcome measure. Data on the primary efficacy endpoint, mortality at 90 days, was available in 11 RCTs, a total of 2575 participants. There was no significant difference between the intervention and control groups (odds ratio (OR): 1.00; 95% confidence interval (CI): 0.81-1.23; P = 0.99). For secondary endpoints, there was no difference between intervention and control groups for a mRS from 0 to 2 (OR: 0.96; 95% CI: 0.80-1.15; P = 0.69; data from 9 RCTs available), or recurrent stroke (OR: 1.34; 95% CI: 0.92-1.96; P = 0.13; data from 3 RCTs available). For NIHSS scores or ESS scores, there was a small difference in favor of intensive controls (standardized mean difference: -0.29; 95% CI: -0.54 to -0.04; P = 0.02). There was a marked increase in hypoglycemia with tight control: (OR of 9.46 (95% CI: 4.59-19.50; P < 0.00001; data from 9 RCTs available)., Conclusion: There was no difference between tight and loose glycemic control on mortality, independence, or recurrent stroke outcome in acute stroke, but an increase in hypoglycemia. There was a small effect improvement on neurological scales, but the relevance of this needs to be confirmed in future adequately powered studies., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

JOURNAL/nrgr/04.03/01300535-202408000-00035/figure1/v/2023-12-16T180322Z/r/image-tiff Exosomes exhibit complex biological functions and mediate a variety of biological processes, such as promoting axonal regeneration and functional recovery after injury. Long non-coding RNAs (lncRNAs) have been reported to play a crucial role in axonal regeneration. However, the role of the lncRNA-microRNA-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network in exosome-mediated axonal regeneration remains unclear. In this study, we performed RNA transcriptome sequencing analysis to assess mRNA expression patterns in exosomes produced by cultured fibroblasts (FC-EXOs) and Schwann cells (SC-EXOs). Differential gene expression analysis, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interaction network analysis were used to explore the functions and related pathways of RNAs isolated from FC-EXOs and SC-EXOs. We found that the ribosome-related central gene Rps5 was enriched in FC-EXOs and SC-EXOs, which suggests that it may promote axonal regeneration. In addition, using the miRWalk and Starbase prediction databases, we constructed a regulatory network of ceRNAs targeting Rps5, including 27 microRNAs and five lncRNAs. The ceRNA regulatory network, which included Ftx and Miat, revealed that exsosome-derived Rps5 inhibits scar formation and promotes axonal regeneration and functional recovery after nerve injury. Our findings suggest that exosomes derived from fibroblast and Schwann cells could be used to treat injuries of peripheral nervous system., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Fused Deposition Modeling (FDM), a widely-utilized additive manufacturing (AM) technology, has found significant favor among automotive manufacturers. Polypropylene (PP) compound is extensively employed in the production of automotive parts due to its superior mechanical properties and formability. However, aiming at the problem of poor dimensional accuracy of pure PP parts, the quality of products can be enhanced by optimizing the combination of processing parameters. In this paper, the dimensional accuracy of 3D-printed components made from pure PP material is investigated. Key influencing factors such as infill percentage, infill pattern, layer thickness, and extrusion temperature are considered. To gain a deeper understanding, fluid simulation is conducted, and mathematical models are established to correlate processing parameters with dimensional accuracy. Furthermore, the Taguchi's experiments are designed and the experimental data are subjected to rigorous Signal-to-Noise ratio and ANOVA analyses. Within the experimental range, the lower extrusion temperature, infill percentage and layer thickness yield the best dimensional accuracy. Considering the influence factors of X, Y and Z directions, the optimal processing parameters for PP prints using screw extrusion 3D printers are determined as follows: an extrusion temperature of 210 °C, an infill percentage of 40 %, a layer thickness of 0.3 mm, and a concentric circle infill pattern. This study provides reference value for the subsequent improvement of the dimensional accuracy of the printed parts., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures remains unclear. We previously detected rare variants in GABRG2, which encodes the γ 2 subunit of γ-aminobutyric acid type A receptor (GABA A R), in patients with SHE and demonstrated that these variants impaired GABA A R function in vitro. However, the mechanisms by which GABRG2 variants contribute to seizure attacks during sleep remain unclear., Methods: In this study, we designed a knock-in (KI) mouse expressing the mouse Gabrg2 T316N variant, corresponding to human GABRG2 T317N variant, using CRISPR/Cas9. Continuous video-electroencephalogram monitoring and in vivo multichannel electrophysiological recordings were performed to explore seizure susceptibility to pentylenetetrazol (PTZ), alterations in the sleep-wake cycle, spontaneous seizure patterns, and synchronized activity in the motor thalamic nuclei (MoTN) and secondary motor cortex (M2). Circadian variations in the expression of total, membrane-bound, and synaptic GABA A R subunits were also investigated., Results: No obvious changes in gross morphology were detected in Gabrg2 T316N/+ mice compared to their wild-type (Gabrg2 +/+ ) littermates. Gabrg2 T316N/+ mice share key phenotypes with patients, including sleep fragmentation and spontaneous seizures during sleep. Gabrg2 T316N/+ mice showed increased susceptibility to PTZ-induced seizures and higher mortality after seizures. Synchronization of the local field potentials between the MoTN and M2 was abnormally enhanced in Gabrg2 T316N/+ mice during light phase, when sleep dominates, accompanied by increased local activities in the MoTN and M2. Interestingly, in Gabrg2 +/+ mice, GABA A R γ2 subunits showed a circadian increase on the neuronal membrane and synaptosomes in the transition from dark phase to light phase, which was absent in Gabrg2 T316N/+ mice., Conclusion: We generated a new SHE mouse model and provided in vivo evidence that rare variants of GABRG2 contribute to seizure attacks during sleep in SHE., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

The enhanced permeability and retention (EPR) effect has become the guiding principle for nanomedicine against cancer for a long time. However, several biological barriers severely resist therapeutic agents' penetration and retention into the deep tumor tissues, resulting in poor EPR effect and high tumor mortality. Inspired by lava, we proposed a proteolytic enzyme therapy to improve the tumor distribution and penetration of nanomedicine. A trypsin-crosslinked hydrogel (Trypsin@PSA Gel) was developed to maintain trypsin's activity. The hydrogel postponed trypsin's self-degradation and sustained the release. Trypsin promoted the cellular uptake of nanoformulations in breast cancer cells, enhanced the penetration through endothelial cells, and degraded total and membrane proteins. Proteomic analysis reveals that trypsin affected ECM components and down-regulated multiple pathways associated with cancer progression. Intratumoral injection of Trypsin@PSA Gel significantly increased the distribution of liposomes in tumors and reduced tumor vasculature. Combination treatment with intravenous injection of gambogic acid-loaded liposomes and intratumoral injection of Trypsin@PSA Gel inhibited tumor growth. The current study provides one of the first investigations into the enhanced tumor distribution of liposomes induced by a novel proteolytic enzyme therapy., (© 2024. The Author(s).)

During space exploration, space radiation is widely recognized as an inescapable perilous stressor, owing to its capacity to induce genomic DNA damage and escalate the likelihood of detrimental health outcomes. Rapid and reliable estimation of space radiation dose holds paramount significance in accurately assessing the health risks associated with spaceflight. However, the identification of space radiation-responsive genes, with their potential to serve as early indicators for diagnosing radiation dose associated with spaceflight, continues to pose a significant challenge. In this study, based on the evolutionarily conserved mechanism of radiation response, an in silico analysis method of homologous comparison was performed to identify the Caenorhabditis elegans orthologues of human radiation-responsive genes with possible roles in the major processes of response to radiation, and thereby to explore the potential C. elegans radiation-responsive genes for evaluating the levels of space radiation exposure. The results showed that there were 60 known C. elegans radiation-responsive genes and 211 C. elegans orthologues of human radiation-responsive genes implicated in the major processes of response to radiation. Through an investigation of all available transcriptomic datasets obtained from space-flown C. elegans, it was observed that the expression levels of the majority of these putative C. elegans radiation-responsive genes identified in this study were notably changed across various spaceflight conditions. Furthermore, this study indicated that within the identified genes, 19 known C. elegans radiation-responsive genes and 40 newly identified C. elegans orthologues of human radiation-responsive genes exhibited a remarkable positive correlation with the duration of spaceflight. Moreover, a noteworthy presence of substantial multi-collinearity among the majority of these identified genes was observed. This observation lends support to the possibility of treating each identified gene as an independent indicator of radiation dose in space. Ultimately, a subset of 15 potential radiation-responsive genes was identified, presenting the most promising indicators for estimation of radiation dose associated with spaceflight in C. elegans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here, we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S- transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC-MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Although direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.

Human cerebellum encompasses numerous neurons, exhibiting a distinct developmental paradigm from cerebrum. Here we conducted scRNA-seq, scATAC-seq and spatial transcriptomic analyses of fetal samples from gestational week (GW) 13 to 18 to explore the emergence of cellular diversity and developmental programs in the developing human cerebellum. We identified transitory granule cell progenitors that are conserved across species. Special patterns in both granule cells and Purkinje cells were dissected multidimensionally. Species-specific gene expression patterns of cerebellar lobes were characterized and we found that PARM1 exhibited inconsistent distribution in human and mouse granule cells. A novel cluster of potential neuroepithelium at the rhombic lip was identified. We also resolved various subtypes of Purkinje cells and unipolar brush cells and revealed gene regulatory networks controlling their diversification. Therefore, our study offers a valuable multi-omics landscape of human fetal cerebellum and advances our understanding of development and spatial organization of human cerebellum., (© 2024. The Author(s).)

Bird sex chromosomes play a unique role in sex-determination, and affect the sexual morphology and behavior of bird species. Core waterbirds, a major clade of birds, share the common characteristics of being sexually monomorphic and having lower levels of inter-sexual conflict, yet their sex chromosome evolution remains poorly understood. Here, by we analyse of a chromosome-level assembly of a female crested ibis (Nipponia nippon), a typical core waterbird. We identify neo-sex chromosomes resulting from fusion of microchromosomes with ancient sex chromosomes. These fusion events likely occurred following the divergence of Threskiornithidae and Ardeidae. The neo-W chromosome of the crested ibis exhibits the characteristics of slow degradation, which is reflected in its retention of abundant gametologous genes. Neo-W chromosome genes display an apparent ovary-biased gene expression, which is largely driven by genes that are retained on the crested ibis W chromosome but lost in other bird species. These results provide new insights into the evolutionary history and expression patterns for the sex chromosomes of bird species., (© 2024. The Author(s).)

The mammalian cerebral cortex contains an extraordinary diversity of cell types that emerge by implementing different developmental programs. Delineating when and how cellular diversification occurs is particularly challenging for cortical inhibitory neurons because they represent a small proportion of all cortical cells and have a protracted development. Here, we combine single-cell RNA sequencing and spatial transcriptomics to characterize the emergence of neuronal diversity among somatostatin-expressing (SST+) cells in mice. We found that SST+ inhibitory neurons segregate during embryonic stages into long-range projection (LRP) neurons and two types of interneurons, Martinotti cells and non-Martinotti cells, following distinct developmental trajectories. Two main subtypes of LRP neurons and several subtypes of interneurons are readily distinguishable in the embryo, although interneuron diversity is likely refined during early postnatal life. Our results suggest that the timing for cellular diversification is unique for different subtypes of SST+ neurons and particularly divergent for LRP neurons and interneurons., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Peripheral nerve injuries, especially those involving long-distance deficits, pose significant challenges in clinical repair. This study explores the potential of continuous microcurrent electrical nerve stimulation (cMENS) as an adjunctive strategy to promote regeneration and repair in such cases., Methods: The study initially optimized cMENS parameters and assessed its impact on Schwann cell activity, neurotrophic factor secretion, and the nerve regeneration microenvironment. Subsequently, a rat sciatic nerve defect-bridge repair model was employed to evaluate the reparative effects of cMENS as an adjuvant treatment. Functional recovery was assessed through gait analysis, motor function tests, and nerve conduction assessments. Additionally, nerve regeneration and denervated muscle atrophy were observed through histological examination., Results: The study identified a 10-day regimen of 100uA microcurrent stimulation as optimal. Evaluation focused on Schwann cell activity and the microenvironment, revealing the positive impact of cMENS on maintaining denervated Schwann cell proliferation and enhancing neurotrophic factor secretion. In the rat model of sciatic nerve defect-bridge repair, cMENS demonstrated superior effects compared to control groups, promoting motor function recovery, nerve conduction, and sensory and motor neuron regeneration. Histological examinations revealed enhanced maturation of regenerated nerve fibers and reduced denervated muscle atrophy., Discussion: While cMENS shows promise as an adjuvant treatment for long-distance nerve defects, future research should explore extended stimulation durations and potential synergies with tissue engineering grafts to improve outcomes. This study contributes comprehensive evidence supporting the efficacy of cMENS in enhancing peripheral nerve regeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kong, Teng, Liu, Wang, Zhou, Zong, Wan, Qin, Yu, Mi and Wang.)

Island endemic birds account for the majority of extinct vertebrates in the past few centuries. To date, the evolutionary characteristics of island endemic bird's is poorly known. In this research, we de novo assembled a high-quality chromosome-level reference genome for the Swinhoe's pheasant, which is a typical endemic island bird. Results of collinearity tests suggest rapid ancient chromosome rearrangement that may have contributed to the initial species radiation within Phasianidae, and a role for the insertions of CR1 transposable elements in rearranging chromosomes in Phasianidae. During the evolution of the Swinhoe's pheasant, natural selection positively selected genes involved in fecundity and body size functions, at both the species and population levels, which reflect genetic variation associated with island adaptation. We further tested for variation in population genomic traits between the Swinhoe's pheasant and its phylogenetically closely related mainland relative the silver pheasant, and found higher levels of genetic drift and inbreeding in the Swinhoe's pheasant genome. Divergent demographic histories of insular and mainland bird species during the last glacial period may reflect the differing impact of insular and continental climates on the evolution of species. Our research interprets the natural history and population genetic characteristics of the insular endemic bird the Swinhoe's pheasant, at a genome-wide scale, provides a broader perspective on insular speciation, and adaptive evolution and contributes to the genetic conservation of island endemic birds., (© 2023 John Wiley & Sons Ltd.)

Background: Gorals Naemorhedus resemble both goats and antelopes, which prompts much debate about the intragenus species delimitation and phylogenetic status of the genus Naemorhedus within the subfamily Caprinae. Their evolution is believed to be linked to the uplift of the Qinghai-Tibet Plateau (QTP). To better understand its phylogenetics, the genetic information is worth being resolved., Results: Based on a sample from the eastern margin of QTP, we constructed the first reference genome for Himalayan goral Naemorhedus goral, using PacBio long-read sequencing and Hi-C technology. The 2.59 Gb assembled genome had a contig N50 of 3.70 Mb and scaffold N50 of 106.66 Mb, which anchored onto 28 pseudo chromosomes. A total of 20,145 protein-coding genes were predicted in the assembled genome, of which 99.93% were functionally annotated. Phylogenetically, the goral was closely related to muskox on the mitochondrial genome level and nested into the takin-muskox clade on the genome tree, rather than other so-called goat-antelopes. The cladogenetic event among muskox, takin and goral occurred sequentially during the late Miocene (~ 11 - 5 Mya), when the QTP experienced a third dramatic uplift with consequent profound changes in climate and environment. Several chromosome fusions and translocations were observed between goral and takin/muskox. The expanded gene families in the goral genome were mainly related to the metabolism of drugs and diseases, so as the positive selected genes. The Ne of goral continued to decrease since ~ 1 Mya during the Pleistocene with active glaciations., Conclusion: The high-quality goral genome provides insights into the evolution and valuable information for the conservation of this threatened group., (© 2024. The Author(s).)