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Abstract Background Neoadjuvant immune checkpoint blockade (ICB) combined with chemoradiotherapy offers high pathologic complete response (pCR) rate for patients with locally advanced esophageal squamous cell carcinomas (ESCC). But the dynamic tumor immune microenvironment modulated by such neoadjuvant therapy remains unclear. Patients and methods A total of 41 patients with locally advanced ESCC were recruited. All patients received neoadjuvant toripalimab combined with concurrent chemoradiotherapy. Matched pre- and post-treatment tissues were obtained for fluorescent multiplex immunohistochemistry (mIHC) and IHC analyses. The densities and spatial distributions of immune cells were determined by HALO modules. The differences of immune cell patterns before and after neoadjuvant treatment were investigated. Results In the pre-treatment tissues, more stromal CD3 + FoxP3 + Tregs and CD86+/CD163 + macrophages were observed in patients with residual tumor existed in the resected lymph nodes (pN1), compared with patients with pCR. The majority of macrophages were distributed in close proximity to tumor nest in pN1 patients. In the post-treatment tissues, pCR patients had less CD86 + cell infiltration, whereas higher CD86 + cell density was significantly associated with higher tumor regression grades (TRG) in non-pCR patients. When comparing the paired pre- and post-treatment samples, heterogeneous therapy-associated immune cell patterns were found. Upon to the treatment, CD3 + T lymphocytes were slightly increased in pCR patients, but markedly decreased in non-pCR patients. In contrast, a noticeable increase and a less obvious decrease of CD86 + cell infiltration were respectively depicted in non-pCR and pCR patients. Furthermore, opposite trends of the treatment-induced alterations of CD8 + and CD15 + cell infiltrations were observed between pN0 and pN1 patients. Conclusions Collectively, our data demonstrate a comprehensive picture of tumor immune landscape before and after neoadjuvant ICB combined with chemoradiotherapy in ESCC. The infiltration of CD86 + macrophage may serve as an unfavorable indicator for neoadjuvant toripalimab combined with chemoradiotherapy.

Abstract Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders.

Abstract Albuminuria is a well-known predictor of chronic kidney disease in patients with type 2 diabetes mellitus (DM). However, proteinuria is associated with chronic complications in patients without albuminuria. In this retrospective cohort study, we explored whether non-albumin proteinuria is associated with all-cause mortality and compared the effects of non-albumin proteinuria on all-cause mortality between patients with and without albuminuria. We retrospectively collected data from patients with type 2 DM for whom we had obtained measurements of both urinary albumin-to-creatinine ratio (UACR) and urinary protein-to-creatinine ratio (UPCR) from the same spot urine specimen. Urinary non-albumin protein-creatinine ratio (UNAPCR) was defined as UPCR–UACR. Of the 1809 enrolled subjects, 695 (38.4%) patients died over a median follow-up of 6.4 years. The cohort was separated into four subgroups according to UACR (30 mg/g) and UNAPCR (120 mg/g) to examine whether these indices are associated with all-cause mortality. Compared with the low UACR and low UNAPCR subgroup as the reference group, multivariable Cox regression analyses indicated no significant difference in mortality in the high UACR and low UNAPCR subgroup (hazard ratio [HR] 1.189, 95% confidence interval [CI] 0.889–1.589, P = 0.243), but mortality risks were significantly higher in the low UACR and high UNAPCR subgroup (HR 2.204, 95% CI 1.448–3.356, P

The genus Impatiens exhibits some varied floral features with a dichogamous reproductive system, in which pollination biology plays a key role in speciation and adaptive evolution. China is one of the centers of Impatiens species, including a large number of endemic and sympatric distributions, but there are few data on their pollination biology. Comparative pollination biology of two Chinese endemic and sympatric species, Impatiens corchorifolia and I. cyathiflora, were investigated, including flowering phenology, floral features, pollinators, behavior of pollinators, and as well as breeding systems. The results were as follows: (1) Morphology of spur was varied in two species, which played a key role in different floral syndromes. The spurs in I. corchorifolia and I. cyathiflora could produced a similar nectar sugar content, (45.48 ± 2.28)% and (46.12 ± 1.48)%, respectively. They could share two pollinators, Apis cerana and Vespa. However, the short spur in I. corchorifolia produced less amount of (4.57 ± 1.43) μL nectar while the long spur in I. cyathiflora yielded more nectar content of (10.15 ± 3.28) μL. And then, the latter also could be pollinated by the other insects including one species of Macroglossum and two species of Bombus. (2) The behavior of the common pollinators shared in I. corchorifolia and I. cyathiflora were obviously distinguished by their staggered flower visits and differential sizes of flower channels for visitors with inconsistent positions of pollens carried. (3) Breeding system experiments showed that species possessed obvious hybridization barriers and obvious cross-pollination. Thus, significant differences in spur morphology lead to distinct pollination syndrome differentiation and different pollinator behavior. Both species prefer cross-pollination to self-fertiliation, which greatly depend on the effective pollinators. Reproductive isolation could be maintained by different flower visiting behavior of shared pollinators, differences in floral morphology, and heterozygous discordance. It provides new evidence for a better understanding the relationships between pollination syndrome, pollinators behavior, and cross-breeding stystem in Impatiens.

Abstract With the development of cloud computing, users are more inclined to outsource complex computing tasks to cloud servers with strong computing capacity, and the cloud returns the final calculation results. However, the cloud is not completely trustworthy, which may leak the data of user and even return incorrect calculations on purpose. Therefore, it is important to verify the results of computing tasks without revealing the privacy of the users. Among all the computing tasks, the polynomial calculation is widely used in information security, linear algebra, signal processing and other fields. Most existing polynomial-based verifiable computation schemes require that the input of the polynomial function must come from a single data source, which means that the data must be signed by a single user. However, the input of the polynomial may come from multiple users in the practical application. In order to solve this problem, the researchers have proposed some schemes for multi-source outsourced data, but these schemes have the common problem of low efficiency. To improve the efficiency, this paper proposes an efficient polynomial-based verifiable computation scheme on multi-source outsourced data. We optimize the polynomials using Horner’s method to increase the speed of verification, in which the addition gate and the multiplication gate can be interleaved to represent the polynomial function. In order to adapt to this structure, we design the corresponding homomorphic verification tag, so that the input of the polynomial can come from multiple data sources. We prove the correctness and rationality of the scheme, and carry out numerical analysis and evaluation research to verify the efficiency of the scheme. The experimental indicate that data contributors can sign 1000 new data in merely 2 s, while the verification of a delegated polynomial function with a power of 100 requires only 18 ms. These results confirm that the proposed scheme is better than the existing scheme.

Abstract Phosphorus (P) limitation of ecosystem processes is widespread in terrestrial habitats. While a few auxiliary metabolic genes (AMGs) in bacteriophages from aquatic habitats are reported to have the potential to enhance P-acquisition ability of their hosts, little is known about the diversity and potential ecological function of P-acquisition genes encoded by terrestrial bacteriophages. Here, we analyze 333 soil metagenomes from five terrestrial habitat types across China and identify 75 viral operational taxonomic units (vOTUs) that encode 105 P-acquisition AMGs. These AMGs span 17 distinct functional genes involved in four primary processes of microbial P-acquisition. Among them, over 60% (11/17) have not been reported previously. We experimentally verify in-vitro enzymatic activities of two pyrophosphatases and one alkaline phosphatase encoded by P-acquisition vOTUs. Thirty-six percent of the 75 P-acquisition vOTUs are detectable in a published global topsoil metagenome dataset. Further analyses reveal that, under certain circumstances, the identified P-acquisition AMGs have a greater influence on soil P availability and are more dominant in soil metatranscriptomes than their corresponding bacterial genes. Overall, our results reinforce the necessity of incorporating viral contributions into biogeochemical P cycling.

Abstract Background Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. Methods We selected 8115 patients with osteoporosis (T-score ≤ − 2.5) and 55,942 healthy individuals (T-score > − 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient’s cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. Results The GBA1 gene variant rs11264345 was significantly associated [P

[Purpose/Significance] In the context of the digital age, knowledge collaboration platforms such as online Q&A communities, academic forums, and various professional networking platforms have become important venues for knowledge sharing and collective wisdom. These platforms bring together users from different fields, with diverse professional backgrounds and levels of expertise. They actively engage in problem solving, exchange views, and form complex and dynamic social networks. Online knowledge collaboration platforms not only enhance the accessibility of knowledge but also serve as incubators for interdisciplinary communication, problem solving, and innovative thinking by harnessing the collective wisdom and expertise of individuals. This article explores how to optimize the network structure of online knowledge collaboration platforms and balance the internal knowledge and expertise within teams. The goal is to promote cross-domain information flow, prevent the formation of information silos, and promote the creation, dissemination, and application of knowledge through collective knowledge collaboration. [Methods/Process] Due to the diversity of participants' backgrounds, experiences, and viewpoints, effectively managing and coordinating this heterogeneity becomes a critical issue. Additionally, the quality and efficiency of knowledge collaboration is also influenced by the characteristics of the network structure, such as the flow of information paths, the role of key nodes, and the interaction patterns of small groups. This study is based on actual data from Stack Overflow, the world's largest programming Q&A website. It focuses specifically on the following aspects of influence: clustering coefficient, node centrality, edge span, user knowledge heterogeneity, and user experience heterogeneity. By constructing a negative binomial regression model, the study investigates how network structure characteristics and team user heterogeneity affect the quality and efficiency of knowledge collaboration. [Results/Conclusions] The results show that, with respect to network structural characteristics, node centrality significantly improves the quality and efficiency of collaboration, and higher aggregation coefficients and larger span of connecting edges restrict information flow and are detrimental to the efficiency of knowledge collaboration. In terms of user heterogeneity, high heterogeneity in knowledge background and registration duration usually hinders collaboration, heterogeneity in experience heterogeneity in registration duration negatively affects collaboration effectiveness in both cases, heterogeneity in response acceptance rate only negatively affects collaboration quality, while heterogeneity in activity intensity positively affects it. In addition, this study still has shortcomings that deserve further exploration. First, future research could consider expanding the sample to include more questions on different topics and domains to increase the reliability and generalizability of the findings. Second, future research could focus on the dynamic changes of network structure and heterogeneity in order to better understand the impact of network structure on knowledge collaboration and to improve the prediction ability of collaboration effects; it could explore more deeply how different types of heterogeneity affect collaboration dynamics over time.

Abstract Topological materials with boundary (surface/edge/hinge) states have attracted tremendous research interest. Additionally, unconventional (obstructed atomic) materials have recently drawn lots of attention owing to their obstructed boundary states. Experimentally, Josephson junctions (JJs) constructed on materials with boundary states produce the peculiar boundary supercurrent, which was utilized as a powerful diagnostic approach. Here, we report the observations of boundary supercurrent in NiTe2-based JJs. Particularly, applying an in-plane magnetic field along the Josephson current can rapidly suppress the bulk supercurrent and retain the nearly pure boundary supercurrent, namely the magnetic field filtering of supercurrent. Further systematic comparative analysis and theoretical calculations demonstrate the existence of unconventional nature and obstructed hinge states in NiTe2, which could produce hinge supercurrent that accounts for the observation. Our results reveal the probable hinge states in unconventional metal NiTe2, and demonstrate in-plane magnetic field as an efficient method to filter out the bulk contributions and thereby to highlight the hinge states hidden in topological/unconventional materials.

This study aimed to evaluate the seroprevalence of Bordetella pertussis and persistence of antibodies following vaccination. We recruited 6060 healthy subjects from five provinces of China during 2017–2018. Serum IgG antibodies against pertussis toxin (anti-PT IgG) and filamentous hemagglutinin (anti-FHA IgG), and serum IgA antibodies against pertussis toxin (anti-PT IgA) were measured by ELISA. Geometric mean concentration (GMC), seropositivity rate, and recent infection rate were calculated. Among 0–6 years-olds, the anti-PT IgG, anti-PT IgA, and anti-FHA IgG GMCs were 6.4 IU/ml (95% CI 6.1–6.8), 2.8 IU/ml (95% CI 2.7–2.8), and 13.3 IU/ml (95% CI 12.4–14.2), respectively. The anti-PT IgG GMC increased in accordance with the primary vaccination series (4–6 months) and the toddler booster (18–24 months), but declined thereafter through to age 5 years [4.7 IU/ml (95% CI 4.2–5.4)]. The seropositivity rate of pertussis in >6 year-olds was 9.0% (95% CI 8.1–9.9) and the recent infection rate was 3.3% (95% CI, 2.7–3.8). Recent infection rate began to increase from 6 years of age, with peaks at 9, 20, 40, and ≥60 years of age. The anti-PT IgG GMCs of children aged 0–6 years who were vaccinated with DTaP, DTaP-IPV//PRP～T, and DTaP-Hib were 5.9 IU/ml (95% CI 5.6–6.3), 20.7 IU/ml (95% CI 15.6–27.8), and 11.7 IU/ml (95% CI 7.5–18.1) (p

The abundance and activity of estrogen receptor alpha (ERα) are tightly regulated by ubiquitin-specific peptidase 22 (USP22) during the progression of breast cancer (BCa). However, the post-transcriptional modifications on the USP22-ERα axis remain elusive. N6-methyladenosine (m6A) is critical to modulate RNA status in eukaryotic cells. Here, we find that METTL14 positively regulates the mRNA expression of USP22 and ERα. Mechanistically, METTL14 potently binds to the USP22 and ERα mRNA, and thereby enhancing their stability through m6A modification. YTHDC1 and YTHDF1 function as readers for m6A-modified USP22 and ERα, respectively. Additionally, METTL14 promotes the growth and migration of ERα+ BCa via the USP22-ERα-Cyclin D1 axis. Enforced expression of USP22/ERα significantly reverses the METTL14 depletion-induced growth and migration inhibition in BCa. Moreover, our analysis of clinical samples shows that the expression of METTL14, USP22, and ERα is upregulated and correlated in BCa tissues. Overall, our findings reveal the key role of the METTL14-USP22-ERα axis in BCa progression, which further provides a druggable target to treat BCa.

Lithium-ion battery (LIB) is the most widely used secondary battery and has been extensively studied in the past few decades due to its many advantages compared to other secondary batteries, such as higher energy density and better cycling performance. Considering the potential risks of environmental pollution and fire hazard induced by leakage or overheating of conventional electrolytes composed of flammable organic solvent-dissolving Li salts, non-flammable solid electrolytes (SEs), especially ceramic electrolytes with different structural types have been developed to improve the safety performance of LIBs. As the properties of SEs significantly depend on the microstructure, this review systemically summarized the recent progress in inorganic solid electrolytes based on the classification of microstructure and presented the relevant discussion in detail, including the microstructures, the mechanisms of Li ionic migration and performance optimization. Additionally, several challenges for realizing industrial application of SEs, such as lower ionic conductivities compared to liquid electrolytes and unsatisfactory stability in ambient atmosphere were mentioned. To effectively boost the development of SEs, more advanced transmission electron microscopy and atom probe tomography should be considered to deeply investigate the relationship between microstructure and properties in the future.

Background Chondrocyte viability, apoptosis, and migration are closely related to cartilage injury in osteoarthritis (OA) joints. Exosomes are identified as potential therapeutic agents for OA.Objective This study aimed to investigate the role of exosomes derived from osteocytes in OA, particularly focusing on their effects on cartilage repair and molecular mechanisms.Methods An injury cell model was established by treating chondrocytes with IL-1β. Cartilage repair was evaluated using cell counting kit-8, flow cytometry, scratch test, and Western Blot. Molecular mechanisms were analyzed using quantitative real-time PCR, bioinformatic analysis, and Western Blot. An OA mouse model was established to explore the role of exosomal DLX2 in vivo.Results Osteocyte-released exosomes promoted cell viability and migration, and inhibited apoptosis and extracellular matrix (ECM) deposition. Moreover, exosomes upregulated DLX2 expression, and knockdown of DLX2 activated the Wnt pathway. Additionally, exosomes attenuated OA in mice by transmitting DLX2.Conclusion Osteocyte-derived exosomal DLX2 alleviated IL-1β-induced cartilage repair and inactivated the Wnt pathway, thereby alleviating OA progression. The findings suggested that osteocyte-derived exosomes may hold promise as a treatment for OA.