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Summary: Chronic cough is a common refractory symptom of various respiratory diseases. However, the neural mechanisms that modulate the cough sensitivity and mediate chronic cough remain elusive. Here, we report that GABAergic neurons in the lateral/ventrolateral periaqueductal gray (l/vlPAG) suppress cough processing via a descending pathway. We found that l/vlPAG neurons are activated by coughing-like behaviors and that tussive agent-evoked coughing-like behaviors are impaired after activation of l/vlPAG neurons. In addition, we showed that l/vlPAG neurons form inhibitory synapses with the nucleus of the solitary tract (NTS) neurons. The synaptic strength of these inhibitory projections is weaker in cough hypersensitivity model mice than in naïve mice. Important, activation of l/vlPAG GABAergic neurons projecting to the NTS decreases coughing-like behaviors. In contrast, suppressing these neurons enhances cough sensitivity. These results support the notion that l/vlPAG GABAergic neurons play important roles in cough hypersensitivity and chronic cough through disinhibition of cough processing at the medullary level.

For ecological economic evaluation based on the unified biophysical matrix this research illustrates an updated emergy synthesis in terms of embodied cosmic exergy instead of embodied solar energy, which successes the foundation of systems ecological theory but changes the starting point for the estimation from simply the sun to the cosmos. According to the modified definition implicating explicit scarcity and strict additivity based on the fundamental thermodynamics laws, the updated emergy approach overcomes the confusable and intractable deficiencies of traditional one and shows firmer theoretical basis as well as better applicability. As a case study for the regional socio-economic ecosystem, a cosmic emergy based ecological economic evaluation of the Beijing urban ecosystem during the period 1978-2004 is presented. The local and external resources supporting the concerned ecosystem are accounted and analyzed in a common unit, i.e., cosmic Joule, according to which a series of indicators are applied to reveal its evolutional characteristics through five aspects as emergy structure, emergy intensity, emergy welfare, environmental impacts, and degree of exploitation and economic efficiency. During the analyzed period, the major emergy source sustaining the operation of the ecosystem had changed from the renewable resources exploited locally to the nonrenewable resources purchased from outside. Emergy intensity for the Beijing urban ecosystem kept rising owing to the continuous investment of resources, which not only improved the living standard but also intensified the environmental pressure. Moreover, the increase of exploitation degree was accompanied with the decline of economic efficiency, while the rising emergy investment ratio implicates that Beijing was at the risks of resources shortage and high dependence on external resources

Abstract Land hermit crabs are a group of shell-carrying crabs that have evolved remarkable terrestrial adaptations in behavior, morphology, physiology, and biochemistry. However, the genetic mechanisms underlying these adaptations remain unclear. In addition, usually it is very difficult to get good genome assemblies for crustaceans. In this study, we managed to assemble the first chromosome-level genome for a land hermit crab (Coenobita brevimanus) with careful manual curation. The final assembly spans 4.74 Gb, with the contig N50 of 1.75 Mb and scaffold N50 of 42.95 Mb, encompassing 117 chromosomes that account for 96.54% of the genome. The evaluations including genome BUSCO (95.26%), Merqury qv (35.88) and the mapping ratio of pair-end short reads (99.48%) showed the high-continuity of C. brevimanus genome assembly, making it the genome with the highest quality in crustaceans with genome size bigger than 3 Gb. The availability of this chromosome-scale genome of crustaceans represents a valuable resource for the land hermit crab, which represents an independent water-to-land transition evolutionary event in the animal kingdom.

Abstract Oxidative stress (OS) is believed to be a significant factor in the decline of semen quality, with mitochondrial DNA copy number (mtDNAcn) serving as a sensitive biomarker for both semen quality and mitochondrial dysfunction resulting from oxidative stress. While glutathione S-transferases (GSTs) are commonly known as ‘antioxidant’ enzymes, there is ongoing debate regarding the relationship between GST genotypes and semen quality. In a study involving 568 male volunteers from the outpatient department of Puyang Reproductive Medicine Center, sperm mtDNAcn, semen quality, and GSTM1/GSTT1 genotypes were analyzed to investigate the potential link between GSTM1/GSTT1 gene variations and semen quality, as well as the impact of GSTs gene variations on the connection between sperm mtDNAcn and semen quality. Adjusting for variables such as age, BMI, smoking, and alcohol consumption, it was found that mtDNAcn was significantly correlated with decreased sperm concentration and total sperm count (b = − 0.109, − 0.128, respectively; P = 0.002, 0.001, respectively). GSTM1 was associated with progressive motility (OR 0.390, 95% CI 0.218, 0.697), Straight line velocity (VSL) (OR = 0.606, 95% CI 0.385, 0.953), and Straightness (STR) (OR 0.604, 95% CI 0.367, 0.994), while GSTT1 was linked to progressive motility (OR 0.554, 95% CI 0.324, 0.944) and Beat crossover frequency (OR 0.624, 95% CI 0.397, 0.982). The GSTT1 was found to moderate the relationship between mtDNAcn and sperm motility parameters linearity (LIN), STR, and Wobble (WOB), with additive interaction effects observed between GSTT1 and mtDNAcn on LIN, STR, and WOB (P for interaction = 0.008, 0.034, 0.010, respectively). Overall, this study suggests that GSTT1 and GSTM1 gene variations may play a role in sperm motility, with GSTT1 potentially influencing the impact of oxidative stress on sperm motility.

Abstract Triptolide (TP), a major active component of the herb Tripterygium wilfordii Hook F, has been shown excellent pharmacological effects on rheumatoid arthritis. However, TP is prone to causing severe organ toxicity, which limits its clinical application. In recent years, microneedle technology has provided a new option for the treatment of arthritis due to its advantages of efficient local transdermal drug delivery. In this study, we constructed a microneedle platform to deliver TP locally to the joints, thereby enhancing TP penetration and reducing systemic toxicity. Additionally, we investigated whether acupoint drug delivery can produce a synergistic effect of needles and drugs. First, TP was loaded into microneedles using polyvinylpyrrolidone and hyaluronic acid as matrix materials. Next, we established a rat adjuvant-induced arthritis (AIA) model to evaluate the therapeutic effect of TP-loaded microneedles. The experiments showed that TP-loaded microneedles alleviated the AIA rats’ inflammatory response, joint swelling, and bone erosion. However, there was no significant difference in the therapeutic effect observed in the acupoint and non-acupoint administration groups. In conclusion, TP-loaded microneedles have the advantages of safety, convenience, and high efficacy over conventional administration routes, laying a foundation for the transdermal drug delivery system-based treatment of rheumatoid arthritis.

Abstract Seminal fluid is rich in sugars, but their role beyond supporting sperm motility is unknown. In this study, we found Drosophila melanogaster males transfer a substantial amount of a phospho-galactoside to females during mating, but only half as much when undernourished. This seminal substance, which we named venerose, induces an increase in germline stem cells (GSCs) and promotes sperm storage in females, especially undernourished ones. Venerose enters the hemolymph and directly activates nutrient-sensing Dh44+ neurons in the brain. Food deprivation directs the nutrient-sensing neurons to secrete more of the neuropeptide Dh44 in response to infused venerose. The secreted Dh44 then enhances the local niche signal, stimulating GSC proliferation. It also extends the retention of ejaculate by females, resulting in greater venerose absorption and increased sperm storage. In this study, we uncovered the role of a sugar-like seminal substance produced by males that coordinates reproductive responses to nutritional challenges in females.

Abstract With the advancement of 3D scanning technologies and deep learning theories, point cloud-based deep learning networks have gained considerable attention in the fields of 3D vision and computer graphics. Leveraging the rich geometric information present in 3D point clouds, these networks facilitate more accurate feature learning tasks. However, existing networks often suffer from generalization defects caused by variations in pose and inconsistent representations of training data. In this paper, we propose a novel data augmentation framework to overcome these limitations. Our approach utilizes principal component analysis (PCA) to generate four aligned copies of a point cloud. These copies are then input into a multi-channel structure, which is compatible with popular backbones of point cloud-based deep networks. Finally, the outputs of the multi-channel structure are merged to generate rotation-invariant feature learning results. Experimental evaluations demonstrate the efficacy of our framework, showcasing significant improvements in various existing point cloud-based deep learning methods. Notably, our method exhibits enhanced robustness in classification tasks, particularly when dealing with point clouds containing random pose variations and non-uniform densities. Project link: https://github.com/LAB123-tech/PCAlign .

Abstract Understanding and preserving the deep sea ecosystems is paramount for marine conservation efforts. Automated object (deep-sea biota) classification can enable the creation of detailed habitat maps that not only aid in biodiversity assessments but also provide essential data to evaluate ecosystem health and resilience. Having a significant source of labelled data helps prevent overfitting and enables training deep learning models with numerous parameters. In this paper, we contribute to the establishment of a significant deep-sea remotely operated vehicle (ROV) image classification dataset with 3994 images featuring deep-sea biota belonging to 33 classes. We manually label the images through rigorous quality control with human-in-the-loop image labelling. Leveraging data from ROV equipped with advanced imaging systems, our study provides results using novel deep-learning models for image classification. We use deep learning models including ResNet, DenseNet, Inception, and Inception-ResNet to benchmark the dataset that features class imbalance with many classes. Our results show that the Inception-ResNet model provides a mean classification accuracy of 65%, with AUC scores exceeding 0.8 for each class.

Abstract Achilles tendon reconstruction is an effective method of repairing Achilles tendon rupture defects. We introduce a new approach for Achilles tendon reconstruction using transversal calcaneal anchored autogenous semitendinosus tendon graft. The study aimed to evaluate the clinical role of this new Achilles tendon reconstruction. We retrospectively enrolled patients who underwent Achilles tendon reconstruction using transversal calcaneal anchored autogenous semitendinosus tendon graft for acute Achilles tendon rupture defects from 2016 to 2021. The clinical and radiological results were assessed at the preoperative and the final postoperative follow-up with Visual Analog Score (VAS) scores, American Orthopaedic Foot & Ankle Society (AOFAS) scores and Achilles tendon Total Rupture Scores (ATRS). Besides, at the last postoperative follow-up, the difference in ankle range of motion between the two side of the patients and the incidence of postoperative complications were recorded. Results revealed patients had significantly lower VAS and higher AOFAS and ATRS (P

To enhance the aerodynamic performance of aero engine blades, simulations and experiments regarding microtextures to reduce the flow loss on the blade surfaces were carried out. First, based on the axisymmetric characteristics of the impeller, a new simulation method was proposed to determine the aerodynamic parameters of the blade model through the comparison of flow field characteristics and simulation results. Second, the placement position and geometrical parameters (height, width, and spacing) of microtextures with lower energy loss were determined by our simulation of microtextures on the blade surface, and the drag reduction mechanism was analyzed. Triangular ribs with a height of 0.2 mm, a width of 0.3 mm, and a spacing of 0.2 mm exhibited the best drag reduction, reducing the energy loss coefficient and drag by 1.45% and 1.31% for a single blade, respectively. Finally, the blades with the optimal microtexture parameters were tested in the wind tunnel. The experimental results showed that the microtexture decreased energy loss by 3.7% for a single blade under 57° angle of attack and 136.24 m/s, which was favorable regarding the drag reduction performance of the impeller with 45 blades.

Abstract Telemedicine and video-based diagnosis have raised significant concerns regarding the protection of facial privacy. Effective de-identification methods require the preservation of diagnostic information related to normal and pathological facial movements, which play a crucial role in the diagnosis of various movement, neurological, and psychiatric disorders. In this work, we have developed FaceMotionPreserve , a deep generative model-based approach that transforms patients’ facial identities while preserving facial dynamics with a novel face dynamic similarity module to enhance facial landmark consistency. We collected test videos from patients with Parkinson’s disease recruited via telemedicine for evaluation of model performance and clinical applicability. The performance of FaceMotionPreserve was quantitatively evaluated based on neurologist diagnostic consistency, critical facial behavior fidelity, and correlation of general facial dynamics. In addition, we further validated the robustness and advancements of our model in preserving medical information with clinical examination videos from a different cohort of patients. FaceMotionPreserve is applicable to real-time integration, safeguarding facial privacy while retaining crucial medical information associated with facial movements to address concerns in telemedicine, and facilitating safer and more collaborative medical data sharing.

Abstract Current gene therapy for Duchenne muscular dystrophy (DMD) utilizes adeno-associated virus (AAV) to deliver micro-dystrophin (µDys), which does not provide full protection for striated muscles as it lacks many important functional domains of full-length (FL) dystrophin. Here we develop a triple vector system to deliver FL-dystrophin into skeletal and cardiac muscles. We split FL-dystrophin into three fragments linked to two orthogonal pairs of split intein, allowing efficient assembly of FL-dystrophin. The three fragments packaged in myotropic AAV (MyoAAV4A) restore FL-dystrophin expression in both skeletal and cardiac muscles in male mdx 4cv mice. Dystrophin-glycoprotein complex components are also restored at the sarcolemma of dystrophic muscles. MyoAAV4A-delivered FL-dystrophin significantly improves muscle histopathology, contractility, and overall strength comparable to µDys, but unlike µDys, it also restores defective cavin 4 localization and associated signaling in mdx 4cv heart. Therefore, our data support the feasibility of a mutation-independent FL-dystrophin gene therapy for DMD, warranting further clinical development.

Abstract Efficiently fabricating a cavity that can achieve strong interactions between terahertz waves and matter would allow researchers to exploit the intrinsic properties due to the long wavelength in the terahertz waveband. Here we show a terahertz detector embedded in a Tamm cavity with a record Q value of 1017 and a bandwidth of only 469 MHz for direct detection. The Tamm-cavity detector is formed by embedding a substrate with an Nb5N6 microbolometer detector between an Si/air distributed Bragg reflector (DBR) and a metal reflector. The resonant frequency can be controlled by adjusting the thickness of the substrate layer. The detector and DBR are fabricated separately, and a large pixel-array detector can be realized by a very simple assembly process. This versatile cavity structure can be used as a platform for preparing high-performance terahertz devices and opening up the study of the strong interactions between terahertz waves and matter.

A series of 4-thio/seleno-cyanated pyrazoles was conveniently synthesized from 4-unsubstituted pyrazoles using NH4SCN/KSeCN as thio/selenocyanogen sources and PhICl2 as the hypervalent iodine oxidant. This metal-free approach was postulated to involve the in situ generation of reactive thio/selenocyanogen chloride (Cl–SCN/SeCN) from the reaction of PhICl2 and NH4SCN/KSeCN, followed by an electrophilic thio/selenocyanation of the pyrazole skeleton.

Abstract Liver cancer is one of the most common malignant tumors worldwide. Although some progress has been made in the diagnosis and treatment of Hepatocellular carcinoma (HCC), the diagnosis and treatment of HCC is still facing great challenges because of the high mortality rate and poor prognosis of HCC. The purpose of this study was to explore the relationship between adhesion-regulating molecule1 (ADRM1), and liver cancer, and the relationship between prognoses. ADRM1 is highly expressed in tumors and is closely associated with the prognosis of patients with liver cancer. In our previous study, we found that ADRM1 was highly expressed in HCC and was closely related to tumor immune and immune checkpoint levels in HCC. We validated the immune expression of ADRM1 in liver cancer cells using flow cytometry. In hepatocellular carcinoma tissues, miR-891a-5p regulates ADRM1. Upregulation of miR-891a-5p upregulates ADRM1, and downregulation of miR-891a-5p downregulates ADRM1. It is suggested that ADRM1 plays a key role in the occurrence and development of hepatocellular carcinoma. This study is expected to provide new ideas for the research and development of anti-HCC drugs targeting miR-891a-5p/ADRM1. However, further trials are needed to confirm these results and explore the actual results in patients with HCC.

Summary: Autographiviridae phage HH109 is a lytic Vibrio alginolyticus E110-specific phage, but the molecular mechanism underlying host recognition of this phage remains unknown. In this study, a transposon mutagenesis library of E110 was used to show that several capsular polysaccharide (CPS) synthesis-related genes were linked to the phage HH109 infection. Gene deletion combined with multiple functional assays demonstrated that CPS serves as the receptor for the phage HH109. Deletions of CPS genes caused reduction or loss of capsule and reduced adsorption. Comparative genome analysis revealed that phage-resistant mutants harbored loss-of-function mutations in the previously identified genes responsible for CPS biosynthesis. The tail protein gp02 of phage HH109 was identified as the receptor-binding protein (RBP) on CPS using antibody blocking assay, immunofluorescence staining, and CPS quantification. Additionally, we found that the phage HH109 could degrade approximately 88% of mature biofilms. Our research findings provide a theoretical basis against vibriosis.

Abstract Timing it right framework was used as a framework to explore the illness experiences of patients infected with COVID-19 and to analyze the patients' perceptions of the disease and their true inner feelings to provide a reference for the control of infectious diseases. This research adopted a phenomenological research approach to develop a longitudinal qualitative study. A purposive sampling method was used to select participants and 37 patients were recruited. Depending on the principle that participants should have maximum variation and sampling should cease when interviews content saturation is achieved, 16 COVID-19 patients in an isolation ward in Ningbo City, Zhejiang Province were finally included. Data were collected using semi-structured interviews, and the content of the interviews was analyzed by Colaizzi’s 7-step method. The themes of COVID-19 patients’ experiences at various phase were presented as follows: multiple emotions intertwined at the time of diagnosis (anxiety, stressful panic, facing the diagnosis calmly), multiple pressures during the hospitalization period (concerns about the disease, unable to adapt to the ward environment, worrying about future hardship), growth of positive illness experience during the isolation and observation period (sublimated outlook on life, affirmation of the government's anti-epidemic policy, more concerned about their own health), adjustment after returning to society (stigma, loss of previous living environment, problems caused by nucleic acid testing), and adaptation to social life (return to normal life, avoidance of illness experience, post-covid-19 syndrome). The illness experience of COVID-19 patients changed dynamically with time, but a sense of shame and uncertainty about recovery was present throughout the process. Interventions should be developed according to the needs of the patients at different times to inform subsequent optimization of care and management of infectious diseases.

Abstract We present unprecedented datasets of current and future projected weather files for building simulations in 15 major cities distributed across 10 climate zones worldwide. The datasets include ambient air temperature, relative humidity, atmospheric pressure, direct and diffuse solar irradiance, and wind speed at hourly resolution, which are essential climate elements needed to undertake building simulations. The datasets contain typical and extreme weather years in the EnergyPlus weather file (EPW) format and multiyear projections in comma-separated value (CSV) format for three periods: historical (2001–2020), future mid-term (2041–2060), and future long-term (2081–2100). The datasets were generated from projections of one regional climate model, which were bias-corrected using multiyear observational data for each city. The methodology used makes the datasets among the first to incorporate complex changes in the future climate for the frequency, duration, and magnitude of extreme temperatures. These datasets, created within the IEA EBC Annex 80 “Resilient Cooling for Buildings”, are ready to be used for different types of building adaptation and resilience studies to climate change and heatwaves.

Abstract DNA replication in bacteria takes place on highly compacted chromosomes, where segregation, transcription, and repair must occur simultaneously. Within this dynamic environment, colocalization of sister replisomes has been observed in many bacterial species, driving the hypothesis that a physical linker may tether them together. However, replisome splitting has also been reported in many of the same species, leaving the principles behind replisome organization a long-standing puzzle. Here, by tracking the replisome β-clamp subunit in live Caulobacter crescentus, we find that rapid DNA segregation can give rise to a second focus which resembles a replisome, but does not replicate DNA. Sister replisomes can remain colocalized, or split apart to travel along DNA separately upon disruption of chromosome inter-arm alignment. Furthermore, chromosome arm-specific replication-transcription conflicts differentially modify replication speed on the two arms, facilitate the decoupling of the two replisomes. With these observations, we conclude that the dynamic chromosome organization flexibly shapes the organization of sister replisomes, and we outline principles which can help to reconcile previously conflicting models of replisome architecture.

Abstract Advanced artificial nerve conduits offer a promising alternative for nerve injury repair. Current research focuses on improving the therapeutic effectiveness of nerve conduits by optimizing scaffold materials and functional components. In this study, a novel poly(3,4‐ethylenedioxythiophene) (PEDOT)‐integrated fish swim bladder (FSB) is presented as a conductive nerve conduit with ordered topology and electrical stimulation to promote nerve regeneration. PEDOT nanomaterials and adhesive peptides (IKVAV) are successfully incorporated onto the decellularized FSB substrate through pre‐coating with polydopamine. The obtained PEDOT/IKVAV‐integrated FSB substrate exhibits outstanding mechanical properties, high electrical conductivity, stability, as well as excellent biocompatibility and bioadhesive properties. In vitro studies confirm that the PEDOT/IKVAV‐integrated FSB can effectively facilitate the growth and directional extension of pheochromocytoma 12 cells and dorsal root ganglion neurites. In addition, in vivo experiments demonstrate that the proposed PEDOT/IKVAV‐integrated FSB conduit can accelerate defective nerve repair and functional restoration. The findings indicate that the FSB‐derived conductive nerve conduits with multiple regenerative inducing signals integration provide a conducive milieu for nerve regeneration, exhibiting great potential for repairing long‐segment neural defects.

Abstract Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R‐CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species‐responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg‐Gly‐Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R‐CM@MSN@BC executed both photodynamic and glutamine‐metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time‐of‐flight mass cytometry analysis revealed that R‐CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1‐type macrophages, reducing infiltration of M2‐type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti‐programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.

Addressing the threats of climate change, pollution, and overfishing to marine ecosystems necessitates a deeper understanding of coastal and oceanic fluid dynamics. Within this context, Lagrangian Coherent Structures (LCS) emerge as essential tools for elucidating the complexities of marine fluid dynamics. Methods used to detect LCS include geometric, probabilistic, cluster-based and braid-based approaches. Advancements have been made to employ Finite-time Lyapunov Exponents (FTLE) to detect LCS due to its high efficacy, reliability and simplicity. It has been proven that the FTLE approach has provided invaluable insights into complex oceanic phenomena like shear, confluence, eddy formations, and oceanic fronts, which also enhanced the understanding of tidal-/wind-driven processes. Additionally, FTLE-based LCS were crucial in identifying barriers to contaminant dispersion and assessing pollutant distribution, aiding environmental protection and marine pollution management. FTLE-based LCS has also contributed significantly to understanding ecological interactions and biodiversity in response to environmental issues. This review identifies pressing challenges and future directions of FTLE-based LCS. Among these are the influences of external factors such as river discharges, ice formations, and human activities on ocean currents, which complicate the analysis of ocean fluid dynamics. While 2D FTLE methods have proven effective, their limitations in capturing the full scope of oceanic phenomena, especially in 3D environments, are evident. The advent of 3D LCS analysis has marked progress, yet computational demands and data quality requirements pose significant hurdles. Moreover, LCS extracted from FTLE fields involves establishing an empirical threshold that introduces considerable variability due to human judgement. Future efforts should focus on enhancing computational techniques for 3D analyses, integrating FTLE and LCS into broader environmental models, and leveraging machine learning to standardize LCS detection.

Summary: Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the intestinal absorption of diverse compounds. Despite a rich literature on the dietary and pharmaceutical compounds that impact P-gp activity, its sensitivity to gut microbial metabolites remains an open question. Surprisingly, we found that the cardiac drug-metabolizing gut Actinobacterium Eggerthella lenta increases drug absorption in mice. Experiments in cell culture revealed that E. lenta produces a soluble factor that post-translationally inhibits P-gp ATPase efflux activity. P-gp inhibition is conserved in the Eggerthellaceae family but absent in other Actinobacteria. Comparative genomics identified genes associated with P-gp inhibition. Finally, activity-guided biochemical fractionation coupled to metabolomics implicated a group of small polar metabolites with P-gp inhibitory activity. These results highlight the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism.

Abstract We examined the effects of climatic factors and Demodex infestations on meibomian gland dysfunction (MGD)-associated dry eye disease (DED) in a cross-sectional study. This study included 123 patients from Tianjin and Chengdu regions, and climate factors and the Air Quality Index (AQI) were recorded for one year. Ocular surface parameters and Demodex infestations were evaluated using various tests. Significant differences in all climatic factors and AQI were observed between Tianjin and Chengdu (P

Abstract Non‐fullerene acceptors (NFAs) have recently emerged as pivotal materials for enhancing the efficiency of organic solar cells (OSCs). To further advance OSC efficiency, precise control over the energy levels of NFAs is imperative, necessitating the development of a robust computational method for accurate energy level predictions. Unfortunately, conventional computational techniques often yield relatively large errors, typically ranging from 0.2 to 0.5 electronvolts (eV), when predicting energy levels. In this study, the authors present a novel method that not only expedites energy level predictions but also significantly improves accuracy , reducing the error margin to 0.06 eV. The method comprises two essential components. The first component involves data cleansing, which systematically eliminates problematic experimental data and thereby minimizes input data errors. The second component introduces a molecular description method based on the electronic properties of the sub‐units comprising NFAs. The approach simplifies the intricacies of molecular computation and demonstrates markedly enhanced prediction performance compared to the conventional density functional theory (DFT) method. Our methodology will expedite research in the field of NFAs, serving as a catalyst for the development of similar computational approaches to address challenges in other areas of material science and molecular research.

The decomposition of maize residues has a vital influence on soil aggregate buildup–breakdown (turnover) processes, but the following remain unclear: i) which size aggregates of Mollisols are primarily affected by the decomposition of maize residues and ii) the turnover proportions of these aggregates. In the study, rare earth oxides (REOs) were used to trace and quantify the buildup–breakdown paths of soil aggregate fractions during the whole incubation time. The two treatments were designed as follows: i) REO-labelled soil with maize residues addition (maize residue treatment) and ii) REO-labelled soil without maize residues addition (control, CK). The soil respiration, aggregate size distribution, REO concentrations, SOC and pH were measured during 84 days of incubation. The results showed that on days 0–14, the incorporation of maize residues significantly increased soil respiration and promoted the formation of 2–5 mm and 0.25–2 mm aggregate fractions at the expense of

Synapse is the fundamental structure for neurons to transmit information between cells. The proper synapse formation is crucial for developing neural circuits and cognitive functions of the brain. The aberrant synapse formation has been proved to cause many neurological disorders, including autism spectrum disorders and intellectual disability. Synaptic cell adhesion molecules (CAMs) are thought to play a major role in achieving mechanistic cell-cell recognition and initiating synapse formation via trans-synaptic interactions. Due to the diversity of synapses in different brain areas, circuits and neurons, although many synaptic CAMs, such as Neurexins (NRXNs), Neuroligins (NLGNs), Synaptic cell adhesion molecules (SynCAMs), Leucine-rich-repeat transmembrane neuronal proteins (LRRTMs), and SLIT and NTRK-like protein (SLITRKs) have been identified as synaptogenic molecules, how these molecules determine specific synapse formation and whether other molecules driving synapse formation remain undiscovered are unclear. Here, to provide a tool for synapse labeling and synaptic CAMs screening by artificial synapse formation (ASF) assay, we generated synaptotagmin-1-tdTomato (Syt1-tdTomato) transgenic mice by inserting the tdTomato-fused synaptotagmin-1 coding sequence into the genome of C57BL/6J mice. In the brain of Syt1-tdTomato transgenic mice, the tdTomato-fused synaptotagmin-1 (SYT1-tdTomato) signals were widely observed in different areas and overlapped with synapsin-1, a widely-used synaptic marker. In the olfactory bulb, the SYT1-tdTomato signals are highly enriched in the glomerulus. In the cultured hippocampal neurons, the SYT1-tdTomato signals showed colocalization with several synaptic markers. Compared to the wild-type (WT) mouse neurons, cultured hippocampal neurons from Syt1-tdTomato transgenic mice presented normal synaptic neurotransmission. In ASF assays, neurons from Syt1-tdTomato transgenic mice could form synaptic connections with HEK293T cells expressing NLGN2, LRRTM2, and SLITRK2 without immunostaining. Therefore, our work suggested that the Syt1-tdTomato transgenic mice with the ability to label synapses by tdTomato, and it will be a convenient tool for screening synaptogenic molecules.

Abstract Previous studies have speculated that brain activity directly controls immune responses in lymphoid organs. However, the upstream brain regions that control lymphoid organs and how they interface with lymphoid organs to produce stress-induced anxiety-like behavior remain elusive. Using stressed human participants and rat models, we show that CCL5 levels are increased in stressed individuals compared to controls. Stress-inducible CCL5 is mainly produced from cervical lymph nodes (CLN). Retrograde tracing from CLN identifies glutamatergic neurons in the red nucleus (RN), the activities of which are tightly correlated with CCL5 levels and anxiety-like behavior in male rats. Ablation or chemogenetic inhibition of RN glutamatergic neurons increases anxiety levels and CCL5 expression in the serum and CLNs, whereas pharmacogenetic activation of these neurons reduces anxiety levels and CCL5 synthesis after restraint stress exposure. Chemogenetic inhibition of the projection from primary motor cortex to RN elicits anxiety-like behavior and CCL5 synthesis. This brain-lymph node axis provides insights into lymph node tissue as a stress-responsive endocrine organ.

Abstract Flexible pressure sensors are indispensable components in various applications such as intelligent robots and wearable devices, whereas developing flexible pressure sensors with both high sensitivity and wide linear range remains a great challenge. Here, we present an elegant strategy to address this challenge by taking advantage of a pyramidal carbon foam array as the sensing layer and an elastomer spacer as the stiffness regulator, realizing an unprecedentedly high sensitivity of 24.6 kPa−1 and an ultra-wide linear range of 1.4 MPa together. Such a wide range of linearity is attributed to the synergy between the nonlinear piezoresistivity of the sensing layer and the nonlinear elasticity of the stiffness regulator. The great application potential of our sensor in robotic manipulation, healthcare monitoring, and human-machine interface is demonstrated. Our design strategy can be extended to the other types of flexible sensors calling for both high sensitivity and wide-range linearity, facilitating the development of high-performance flexible pressure sensors for intelligent robotics and wearable devices.

Abstract Simulating the carbon-water fluxes at more widely distributed meteorological stations based on the sparsely and unevenly distributed eddy covariance flux stations is needed to accurately understand the carbon-water cycle of terrestrial ecosystems. We established a new framework consisting of machine learning, determination coefficient (R2), Euclidean distance, and remote sensing (RS), to simulate the daily net ecosystem carbon dioxide exchange (NEE) and water flux (WF) of the Eurasian meteorological stations using a random forest model or/and RS. The daily NEE and WF datasets with RS-based information (NEE-RS and WF-RS) for 3774 and 4427 meteorological stations during 2002–2020 were produced, respectively. And the daily NEE and WF datasets without RS-based information (NEE-WRS and WF-WRS) for 4667 and 6763 meteorological stations during 1983–2018 were generated, respectively. For each meteorological station, the carbon-water fluxes meet accuracy requirements and have quasi-observational properties. These four carbon-water flux datasets have great potential to improve the assessments of the ecosystem carbon-water dynamics.

Bacterial infection treatment for chronic wounds has posed a major medical threat and challenge. Bacteria at the wounded sites can compete with the immune system and subsequently invade live tissues, leading to more severe tissue damage. Therefore, there is an urgent demand for wound dressings with antibacterial and anti-inflammatory properties. Considering the concept of moist healing, hydrogels with a three-dimensional (3D) network structure are widely used as wound dressings due to their excellent hydrophilicity, water retention properties, and biocompatibility. Developing antibacterial hydrogels for the treatment of infected wounds has been receiving extensive attention recently. This article categorizes antibacterial hydrogels according to their materials and antibacterial modes, and introduces the recent findings and progress regarding their status. More importantly, with the development of emerging technologies, new therapies are utilized to prepare antibacterial hydrogels such as nanoenzymes, photothermal therapy (PTT), photodynamic therapy (PDT), metal–organic frameworks (MOFs), and other external stimuli-responsive methods. Therefore, this review also examines their progress, challenges, and future trends as wound dressings. In the following studies, there will still be a focus on antibacterial hydrogels that have a high performance, multi-functions, and intelligence, especially biocompatibility, a high and long-lasting antibacterial property, responsiveness, and on-demand therapeutic ability.

As the genome is organized into a three-dimensional structure in intracellular space, epigenomic information also has a complex spatial arrangement. However, most epigenetic studies describe locations of methylation marks, chromatin accessibility regions, and histone modifications in the horizontal dimension. Proper spatial epigenomic information has rarely been obtained. In this study, we designed spatial chromatin accessibility sequencing (SCA-seq) to resolve the genome conformation by capturing the epigenetic information in single-molecular resolution while simultaneously resolving the genome conformation. Using SCA-seq, we are able to examine the spatial interaction of chromatin accessibility (e.g. enhancer–promoter contacts), CpG island methylation, and spatial insulating functions of the CCCTC-binding factor. We demonstrate that SCA-seq paves the way to explore the mechanism of epigenetic interactions and extends our knowledge in 3D packaging of DNA in the nucleus.

The structural complexity of glycans seriously challenges the currently available analytical methods. Here, the authors report the identification of glycan isomers, glycans with varying chain lengths, and distinct branched glycans, via a glycan derivatization strategy and nanopore sensing.

cAMP is an important second messenger involved in many aspects of biological processes. Here, Li et al. shows that blood vessel epicardial substance (BVES) is a negative regulator of cAMP signaling required for maintaining muscle mass and function.

Abstract The repressor element 1 silencing transcription factor (REST) has been proposed to function as a transcription factor to silence gene transcription by binding to repressor element 1 (RE1), a highly conserved DNA motif. The functions of REST in various tumors have been studied, but its role and correlation with immune cell infiltration remains uncertain in gliomas. REST expression was analyzed in datasets of The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) and validated by the Gene Expression Omnibus and Human Protein Atlas databases. The clinical prognosis of REST was evaluated by clinical survival data of TCGA cohort and validated by Chinese Glioma Genome Atlas cohort. MicroRNAs (miRNAs) contributing to REST overexpression in glioma were identified by a combination of a series of in silico analyses, including expression analysis, correlation analysis, and survival analysis. The correlations between immune cell infiltration level and REST expression were analyzed by TIMER2 and GEPIA2 tools. Enrichment analysis of REST was performed using STRING and Metascape tools. The expression and function of predicted upstream miRNAs at REST and their association with glioma malignancy and migration were also confirmed in glioma cell lines. REST was highly expressed and associated with poorer overall survival and disease-specific survival in glioma and some other tumors. MiR-105-5p and miR-9-5p were identified as the most potential upstream miRNAs of REST in glioma patient cohort and experiments in vitro. REST expression was positively correlated with infiltration of immune cells and the expression of immune checkpoints such as PD1/PD-L1 and CTLA-4 in glioma. Furthermore, histone deacetylase 1 (HDAC1) was a potential REST-related gene in glioma. Enrichment analysis of REST found chromatin organization and histone modification were the most significant enriched terms, and Hedgehog-Gli pathway might be involved in the effect of REST on the pathogenesis of glioma. Our study suggests REST to be an oncogenic gene and the biomarker of poor prognosis in glioma. High REST expression might affect the tumor microenvironment of glioma. More basic experiments and large clinical trials aimed at the carcinogenetic study of REST in glioma will be needed in the future.

Manipulating electrical and magnetic anisotropies will stimulate multi-terminal device applications. Here, the authors discover axis dependence of current rectifications, magnetic properties and magnon modes in van der Waals multiferroic CuCrP2S6.

GluN2A and GluN2B, two predominant Glu2N subunits of NMDARs in hippocampus and cortex, display distinct organization and mobility in the neuronal surface. Here, authors show Rph3A, a GluN2A-specific binding protein, undergoes liquid-liquid phase separation, which regulate mobility, synaptic and extrasynaptic surface clustering, synaptic localization and synaptic response of GluN2A.

Pyroelectricity promises viable heat harvesting and sensing. Here, the authors identify transverse polarization ripple in pyroelectrics via heat localization and propagation decoupling and offer competitive power output to solar thermoelectrics.

Abstract The overhead-cable hybrid transmission lines are alternately connected by two types of lines, with a more complex structure and higher difficulty in fault location. This paper presents an ac-curate fault location method for overhead-cable hybrid lines based on traveling wave energy. Firstly, the basic concept of traveling wave energy is defined. Based on the attenuation charac-teristics of the traveling wave, the mapping relationship between traveling wave energy and fault location is analyzed. Secondly, considering the influence of S-transform error on the traveling wave energy propagation law, the traveling wave energy attenuation characteristics of common A-type and B-type hybrid lines are analyzed. Then, for the overhead-cable hybrid lines with different structures, the mapping relationship between the traveling wave energy at both ends of the line and the fault distance is quantitatively derived, and an accurate fault location method based on the initial traveling wave energy ratio at the same frequency at both ends of the line is proposed. Finally, a 110 kV hybrid transmission line fault simulation model is built in PSCAD/EMTDC, and the faults under different conditions are simulated in different line sections. The effectiveness and robustness of the proposed method are verified through the simulation.

High-voltage non-aqueous lithium metal batteries suffer from poor cycling stability due to the presence of impurities in the electrolyte solution. Here, the authors report lithium hexamethyldisilazide to scavenge HF and H2O, prevent the Ni dissolution and suppress side reactions during cycling.

Abstract Immune checkpoint inhibitor (ICI) therapy is an emerging and effective approach to the treatment of gastric cancer (GC). However, the low response rate of GC patients to ICI therapy is a major limitation of ICI therapy. We investigated the transcriptomic signature of immune genes in GC could provide a comprehensive understanding of the tumor microenvironment (TME) and identify a valuable biomarker to predict the response of GC patients receiving immunotherapy. We performed the weighted gene co-expression network analysis (WGCNA) to determine immune-related hub genes that differentially expressed in the GC dataset based on The Cancer Genome Atlas (TCGA). After that, univariate and multivariate Cox regression was performed to recognize prognostic genes associated with overall survival and to develop an immune-related gene prognostic index (IRGPI). Furthermore, we explored the possible correlation between IRGPI and immune cell infiltration and immunotherapy efficacy. Notably, IRGPI can predict the prognosis of GC patients, as well as the response to immunotherapy. IRGPI as an immune-related prognostic biomarker might bring some potential implications for immunotherapy strategies in GC.

Abstract Focal spot (light spot) at single-photon level have important applications in many fields. This report demonstrates a method for measuring focal spot size at the single-photon level indirectly. This method utilizes Silicon Photomultiplier (SiPM) as the single-photon sensitive detectors, combined with a nano-positioning stage. The approach involves one- or two-dimensional space scanning and a deconvolution operation, which enable evaluations of the size and spatial distribution of the focal spot formed by a single-photon-level pulsed laser. The results indicate that the average full width at half maximum of the focal spot is about 0.657 μm, which is close to the nominal resolution of the objective lens of the microscope (i.e. 0.42 μm). The proposed method has two key advantages: (1) it can measure focal spot at the single-photon level, and (2) the focal spot can easily be aligned with the detector because the array area of the Geiger mode avalanche photodiode (Gm-APD) cells in SiPM is usually on the order of square millimeter, and there is no need to put an optical slit, knife edge, or pinhole in front of the detector. The method described herein is applicable in weak focal spot detection related fields.

Abstract Adverse remodeling after myocardial infarction (MI) result in heart failure and sudden cardiac death. Fibulin7 (FBLN7) is an adhesion protein excreted into the extracellular matrix that functions in multiple biological processes. However, whether and how FBLN7 affects post‐MI cardiac remodeling remains unclear. Here, the authors identify FBLN7 as a critical profibrotic regulator of adverse cardiac remodeling. They observe significantly upregulated serum FBLN7 levels in MI patients with left ventricular remodeling compared to those without MI. Microarray dataset analysis reveal FBLN7 is upregulated in human heart samples from patients with dilated and hypertrophic cardiomyopathy compared with non‐failing hearts. The authors demonstrate that FBLN7 deletion attenuated post‐MI cardiac remodeling, leading to better cardiac function and reduced myocardial fibrosis, whereas overexpression of FBLN7 results in the opposite effects. Mechanistically, FBLN7 binds to the epidermal growth factor receptor (EGFR) through its EGF‐like domain, together with the EGF‐like calcium‐binding domain, and induces EGFR autophosphorylation at tyrosine (Y) 1068 and Y1173, which activates downstream focal adhesion kinase/AKT signaling, thereby leading to fibroblast‐to‐myofibroblast transdifferentiation. In addition, FBLN7‐EGFR mediates this signal transduction, and the fibrotic response is effectively suppressed by the inhibition of EGFR activity. Taken together, FBLN7 plays an important role in cardiac remodeling and fibrosis after MI.

Abstract Multifunctional nanoaggregates are widely used in cancer phototheranostics. However, it is challenging to construct their multifunctionality with a single component, and deliver them rapidly and efficiently without complex modifications. Herein, a NIR‐absorbing small molecule named TBT‐2(TP‐DPA) is designed and certify its theranostic potentials. Then, their nanoaggregates, which are simply encapsulated by DSPE‐PEG, demonstrate a photothermal efficiency of 51% while keeping a high photoluminescence quantum yield in the NIR region. Moreover, the nanoaggregates can be excited and delivered by an 808 nm pulse laser to solid tumors within only 40 min. The delivery efficiency and theranostic efficacy are better than that of the traditional enhanced permeability and retention (EPR) effect (generally longer than 24 hours). This platform is first termed as the photoinduced thermoacoustic (PTA) process, and confirm its application requires both NIR‐responsive materials and pulse laser irradiation. This study not only inspires the design of multifunctional nanoaggregates, but also offers a feasible approach to their fast delivery. The platform reported here provides a promising prospect to boost the development of multifunctional theranostic drugs and maximize the efficacy of used medicines for their clinical applications.

Abstract Cancer starvation therapy have received continuous attention as an efficient method to fight against wide‐spectrum cancer. However, during cancer starvation therapy, the protective autophagy promotes cancer cells survival, compromising the therapeutic effect. Herein, a novel strategy by combination of autophagy‐activated fluorescent photosensitizers (PSs) and cancer starvation therapy to realize the controllable and efficient ablation of tumor is conceived. Two dual‐emissive self‐reporting aggregation‐induced emission luminogens (AIEgens), TPAQ and TPAP, with autophagy‐activated reactive oxygen species (ROS) generation are prepared to fight against the protective autophagy in cancer starvation therapy. When protective autophagy occurs, a portion of TPAQ and TPAP will translocate from lipid droplets to acidic lysosomes with significant redshift in fluorescence emission and enhanced ROS generation ability. The accumulation of ROS induced by TPAQ‐H and TPAP‐H causes lysosomal membrane permeabilization (LMP), which further results in cell apoptosis and promotes cell death. In addition, TPAQ and TPAP can enable the real‐time self‐reporting to cell autophagy and cell death process by observing the change of red‐emissive fluorescence signals. Particularly, the efficient ablation of tumor via the combination of cancer starvation therapy and photodynamic therapy (PDT) induced by TPAQ has been successfully confirmed in 3D tumor spheroid chip, suggesting the validation of this strategy.

Natural fractures act as critical flow channels and reservoir space in the Lucaogou Formation tight reservoir of the Jimsar Sag. It is essential to identify the main controlling factors of natural fractures in order to achieve efficient development of tight oil in this area. There are mainly three types of natural fractures, including tectonic fractures, diagenetic fractures, and abnormal overpressure-induced fractures. Diagenetic fractures are predominantly bedding seams. The fracture development is affected by multiple factors including brittle minerals, lithology, tectonic stress, bed thickness, and total organic carbon (TOC). Large tectonic stress, smaller bed thickness, and higher total organic carbon are all favorable for the development of tectonic fractures and bedding seams. The controls of brittle minerals and lithology on fracture development are different for tectonic fractures and bedding seams. Specifically, carbonate minerals stimulate the tectonic fracture development, while brittle minerals have no control over the bedding seam development; tectonic fractures are most developed in the dolomitic rocks, while bedding seams are most developed in the argillaceous rocks. The calculated fracture density variation coefficients reveal that tectonic stress and brittle minerals are the main controlling factors of tectonic fracture development; total organic carbon and lithology are the main control factors of bedding seam development.

Measurement(s) vegetation index Technology Type(s) remote sensing

Abstract This study develops a general method to evaluate the contributions of localized urbanization and global climate change to long-term urban land surface temperature (ULST) change. The method is based on the understanding that long-term annual ULST is controlled by three factors: (1) localized urbanization, (2) global climate change, and (3) interannual climate variation. Then the method removes the interannual climate fluctuations on long-term observed LST time series via linear regression and separates the contributions of urbanization and climate change to the impacts on long-term ULST via urban–rural comparison. The method is applied to Lagos, a fast-growing metropolis in the tropical West Africa, as an example for reference. Combined time-series daily daytime and nighttime MODIS Land Surface Temperature (LST) data over the years of 2003–2021 are used as the representation of land surface temperature. To avoid the potentioal interannual data biase due to uneven availability of data in the rainy seasons over years, only MODIS LST data from dry seasons are used in the study. The results are summarized as follows for Lagos: (1) long-term annual ULST is confirmed to be controlled by the three factors; (2) the proposed method can separate the contribution of the three factors to the ULST; (2) both localized urbanization and global warming are verified to contribute to the ULST increase with positive trends; (3) daytime ULST increased the most in the afternoon time at a mean rate of 1.429 °C per decade, with 0.985 °C (10 year)−1 contributed by urbanization and 0.444 °C (10 year)−1 contributed by climate warming; (4) nighttime ULST in Lagos increased the most after midnight at a rate of 0.563 °C (10 year)−1, with 0.56 °C (10 year)−1 contributed by urbanization and 0.003 °C (10 year)−1 contributed by climate warming; and (5) urbanization is generally responsible for around 60.97% of the urban warming in Lagos. Therefore, the increasing urbaniztion-induced urban heat island effect is the major cause for more heat-related health risks and climate extremes that many urban residents are suffering. The results of this study are of useful reference for both urbanization and climate change related issues in the geo-science field.

High sensitivity in quantum sensing comes often at the expense of other figures of merit, usually resulting in distortion. Here, the authors propose a protocol with good sensitivity, readout linearity and high frequency resolution, and benchmark it through signal measurements at audio bands with NV centers.

Proinflammatory agonists provoke the expression of cell surface adhesion molecules on endothelium in order to facilitate leukocyte infiltration into tissues. Rigorous control over this process is important to prevent unwanted inflammation and organ damage. Protein L-isoaspartyl O-methyltransferase (PIMT) converts isoaspartyl residues to conventional methylated forms in cells undergoing stress-induced protein damage. The purpose of this study was to determine the role of PIMT in vascular homeostasis. PIMT is abundantly expressed in mouse lung endothelium and PIMT deficiency in mice exacerbated pulmonary inflammation and vascular leakage to LPS(lipopolysaccharide). Furthermore, we found that PIMT inhibited LPS-induced toll-like receptor signaling through its interaction with TNF receptor-associated factor 6 (TRAF6) and its ability to methylate asparagine residues in the coiled-coil domain. This interaction was found to inhibit TRAF6 oligomerization and autoubiquitination, which prevented NF-κB transactivation and subsequent expression of endothelial adhesion molecules. Separately, PIMT also suppressed ICAM-1 expression by inhibiting its N-glycosylation, causing effects on protein stability that ultimately translated into reduced EC(endothelial cell)-leukocyte interactions. Our study has identified PIMT as a novel and potent suppressor of endothelial activation. Taken together, these findings suggest that therapeutic targeting of PIMT may be effective in limiting organ injury in inflammatory vascular diseases.