Search

Abstract The study investigates the global impact of land property rights on land use efficiency (LUE), as measured by the key indicator for United Nations Sustainable Development Goal 11.3.1, namely Land Consumption Rate to Population Growth Rate. By utilizing human-land change data from 165 countries spanning the period between 1990 and 2020, we have developed a fixed effects model and employed legal origins as an instrumental variable to examine the influence of land property rights security on LUE. Our findings demonstrate that the security of land property rights significantly influences LUE, with common law countries exhibiting higher levels of LUE compared to civil law countries while controlling for other variables. Stability in property rights encourages long-term investments in infrastructure and sustainable land management practices, thereby enhancing land productivity and mitigating urban sprawl. Furthermore, safeguarding property rights limits governments’ power to expropriate lands, facilitating rational and efficient land transactions that contribute towards achieving Sustainable Development Goals.

Abstract Continued evolution of SARS-CoV-2 generates variants to challenge antibody immunity established by infection and vaccination. A connection between population immunity and genesis of virus variants has long been suggested but its molecular basis remains poorly understood. Here, we identify a class of SARS-CoV-2 neutralizing public antibodies defined by their shared usage of VL6-57 light chains. Although heavy chains of diverse genotypes are utilized, convergent HCDR3 rearrangements have been observed among these public antibodies to cooperate with germline VL6-57 LCDRs to target a convergent epitope defined by RBD residues S371-S373-S375. Antibody repertoire analysis identifies that this class of VL6-57 antibodies is present in SARS-CoV-2-naive individuals and is clonally expanded in most COVID-19 patients. We confirm that Omicron-specific substitutions at S371, S373 and S375 mediate escape of antibodies of the VL6-57 class. These findings support that this class of public antibodies constitutes a potential immune pressure promoting the introduction of S371L/F-S373P-S375F in Omicron variants. The results provide further molecular evidence to support that antigenic evolution of SARS-CoV-2 is driven by antibody mediated population immunity.

Abstract Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

Traditional diagnostic techniques including visual examination, ultrasound (US), and magnetic resonance imaging (MRI) have limitations of in-depth information for the detection of nail disorders, resolution, and practicality. This pilot study, for the first time, evaluates a dual-modality imaging system that combines photoacoustic tomography (PAT) with the US for the multiparametric quantitative assessment of human nail. The study involved a small cohort of five healthy volunteers who underwent PAT/US imaging for acquiring the nail unit data. The PAT/US dual-modality imaging successfully revealed the fine anatomical structures and microvascular distribution within the nail and nail bed. Moreover, this system utilized multispectral PAT to analyze functional tissue parameters, including oxygenated hemoglobin, deoxyhemoglobin, oxygen saturation, and collagen under tourniquet and cold stimulus tests to evaluate changes in the microcirculation of the nail bed. The quantitative analysis of multispectral PAT reconstructed images demonstrated heightened sensitivity in detecting alterations in blood oxygenation levels and collagen content within the nail bed, under simulated different physiological conditions. This pilot study highlights the potential of PAT/US dual-modality imaging as a real-time, noninvasive diagnostic modality for evaluating human nail health and for early detection of nail bed pathologies.

ABSTRACTNeutralizing antibodies are a key component in protective humoral immunity against SARS-CoV-2. Currently, available technologies cannot track epitope-specific antibodies in global antibody repertoires. Thus, the comprehensive repertoire of spike-specific neutralizing antibodies elicited by SARS-CoV-2 infection is not fully understood. We therefore combined high-throughput immunoglobulin heavy chain (IgH) repertoire sequencing, and structural and bioinformatics analysis to establish an antibodyomics pipeline, which enables tracking spike-specific antibody lineages that target certain neutralizing epitopes. We mapped the neutralizing epitopes on the spike and determined the epitope-preferential antibody lineages. This analysis also revealed numerous overlaps between immunodominant neutralizing antibody-binding sites and mutation hotspots on spikes as observed so far in SARS-CoV-2 variants. By clustering 2677 spike-specific antibodies with 360 million IgH sequences that we sequenced, a total of 329 shared spike-specific antibody clonotypes were identified from 33 COVID-19 convalescents and 24 SARS-CoV-2-naïve individuals. Epitope mapping showed that the shared antibody responses target not only neutralizing epitopes on RBD and NTD but also non-neutralizing epitopes on S2. The immunodominance of neutralizing antibody response is determined by the occurrence of specific precursors in human naïve B-cell repertoires. We identified that only 28 out of the 329 shared spike-specific antibody clonotypes persisted for at least 12 months. Among them, long-lived IGHV3-53 antibodies are likely to evolve cross-reactivity to Omicron variants through accumulating somatic hypermutations. Altogether, we created a comprehensive atlas of spike-targeting antibody lineages in COVID-19 convalescents and antibody precursors in human naïve B cell repertoires, providing a valuable reference for future vaccine design and evaluation.

Summary: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein continues to evolve antigenically, impacting antibody immunity. D1F6, an affinity-matured non-stereotypic VH1-2 antibody isolated from a patient infected with the SARS-CoV-2 ancestral strain, effectively neutralizes most Omicron variants tested, including XBB.1.5. We identify that D1F6 in the immunoglobulin G (IgG) form is able to overcome the effect of most Omicron mutations through its avidity-enhanced multivalent S-trimer binding. Cryo-electron microscopy (cryo-EM) and biochemical analyses show that three simultaneous epitope mutations are generally needed to substantially disrupt the multivalent S-trimer binding by D1F6 IgG. Antigenic mutations at spike positions 346, 444, and 445, which appeared in the latest variants, have little effect on D1F6 binding individually. However, these mutations are able to act synergistically with earlier Omicron mutations to impair neutralization by affecting the interaction between D1F6 IgG and the S-trimer. These results provide insight into the mechanism by which accumulated antigenic mutations facilitate evasion of affinity-matured antibodies.

The host transcription factor p53 is a critical tumor suppressor in HPV-induced carcinogenesis, regulating target genes involved in cell cycle arrest and apoptosis. However, the p53 targets have not been thoroughly analyzed in HPV-infected cells. In this study, p53 signaling in HPV16 and HPV18 cells was activated by depleting the viral oncoprotein E6. Subsequently, p53-regulated genes were identified by comparing them with genes altered in p53-silenced cells. True p53 targets were defined as genes with at least one overlapping p53 binding site and ChIP peak near their locus. Our analysis revealed that while some p53 targets were common to both the HPV16 and HPV18 cells, the majority of the targets differed between these two types, potentially contributing to the varying prevalence of HPV16 and HPV18 in cervical cancer. Additionally, we identified SCN2A as a novel p53 target involved in p53-induced cell cycle arrest in HPV-related carcinogenesis. This study provides new insights into the mechanisms by which p53 inhibits HPV-induced carcinogenesis.

BackgroundSoft tissue tumors (STTs) are benign or malignant superficial neoplasms arising from soft tissues throughout the body with versatile pathological types. Although Ultrasonography (US) is one of the most common imaging tools to diagnose malignant STTs, it still has several drawbacks in STT diagnosis that need improving.ObjectivesThe study aims to establish this deep learning (DL) driven Artificial intelligence (AI) system for predicting malignant STTs based on US images and clinical indexes of the patients.MethodsWe retrospectively enrolled 271 malignant and 462 benign masses to build the AI system using 5-fold validation. A prospective dataset of 44 malignant masses and 101 benign masses was used to validate the accuracy of system. A multi-data fusion convolutional neural network, named ultrasound clinical soft tissue tumor net (UC-STTNet), was developed to combine gray scale and color Doppler US images and clinic features for malignant STTs diagnosis. Six radiologists (R1-R6) with three experience levels were invited for reader study.ResultsThe AI system achieved an area under receiver operating curve (AUC) value of 0.89 in the retrospective dataset. The diagnostic performance of the AI system was higher than that of one of the senior radiologists (AUC of AI vs R2: 0.89 vs. 0.84, p=0.022) and all of the intermediate and junior radiologists (AUC of AI vs R3, R4, R5, R6: 0.89 vs 0.75, 0.81, 0.80, 0.63; p

Abstract Uncovering the mechanisms regulating hematopoietic specification not only would overcome current limitations related to hematopoietic stem and progenitor cell (HSPC) transplantation, but also advance cellular immunotherapies. However, generating functional human induced pluripotent stem cell (hiPSC)-derived HSPCs and their derivatives has been elusive, necessitating a better understanding of the developmental mechanisms that trigger HSPC specification. Here, we reveal that early activation of the Nod1-Ripk2-NF-kB inflammatory pathway in endothelial cells (ECs) primes them to switch fate towards definitive hemogenic endothelium, a pre-requisite to specify HSPCs. Our genetic and chemical embryonic models show that HSPCs fail to specify in the absence of Nod1 and its downstream kinase Ripk2 due to a failure on hemogenic endothelial (HE) programming, and that small Rho GTPases coordinate the activation of this pathway. Manipulation of NOD1 in a human system of definitive hematopoietic differentiation indicates functional conservation. This work establishes the RAC1-NOD1-RIPK2-NF-kB axis as a critical intrinsic inductor that primes ECs prior to HE fate switch and HSPC specification. Manipulation of this pathway could help derive a competent HE amenable to specify functional patient specific HSPCs and their derivatives for the treatment of blood disorders.

Abstract Background/aims Early diagnosis of Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis with non-invasive imaging modalities benefiting is crucial to guarantee prompt treatments decision-making and good prognosis for patients. The present study aimed to explore the correlation of MRI features with brain metabolism characteristics of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and to describe the metabolic patterns in Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis at acute and subacute phases. Twenty-four patients with anti-NMDAR encephalitis confirmed by serum and/or CSF tests at acute and subacute phases, 9 females and 15 males, with an age range of 6–80 years, were enrolled in this retrospective study as encephalitis group. 18F-FDG PET and MRI findings of all patients were investigated and interpreted with visual analysis. Chi-square test was performed to compare the diagnostic sensitivity between MRI and PET. Independent sample t-test was used to compare the standardized uptake value ratio (SUVR) of each ROI between the encephalitis group and control group, which consisted of 24 healthy volunteers of the same age and gender. Results There was no statistical difference in the diagnostic sensitivity between FDG PET (23/24, 95.83%) and MRI (18/24, 75.00%) in anti-NMDAR encephalitis patients (P > 0.05). Three categories of abnormalities shown on T2 FLAIR, including shallow of sulci and swelling of brain tissue, increased signal in the sulci, increased signal on brain gray matter or adjacent white matter presented hypermetabolism on PET, excepting increased signal in brain linear structure with hypometabolism of the basal ganglia on PET. We identified 19 brain regions with hypermetabolism and 16 brain regions with hypometabolism that exhibited statistically significant changes in SUVRs between anti-NMDAR encephalitis group and control group (FDR P

Large language models (LLMs) have brought significant advancements to artificial intelligence, particularly in understanding and generating human language. However, concerns over management burden and data security have grown alongside their capabilities. To solve the problem, we design a blockchain-based distributed LLM framework, where LLM works in the distributed mode and its outputs can be stored and verified on a blockchain to ensure integrity, transparency, and traceability. In addition, a multiparty signature-based authentication mechanism is necessary to ensure stakeholder consensus before publication. To address these requirements, we propose a threshold elliptic curve digital signature algorithm that counters malicious adversaries in environments with three or more participants. Our approach relies on discrete logarithmic zero-knowledge proofs and Feldman verifiable secret sharing, reducing complexity by forgoing multiplication triple protocols. When compared with some related schemes, this optimization speeds up both the key generation and signing phases with constant rounds while maintaining security against malicious adversaries.

Abstract Background and Objective Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by ineffective hematopoiesis due to stem cell abnormalities. Monosomy 7q aberrations are a common cytogenetic abnormality in MDS. Specifically, an unbalanced translocation der(1;7)(q10;p10) [der(1;7)] has been identified in MDS patients, which is a monosomy 7q aberration variant like −7/del(7q). However, knowledge of der(1;7)'s features remains limited. Existing studies have compared the clinical and genetic characteristics of der(1;7) to those of −7/del(7q) but yielded inconsistent findings. Accordingly, we conducted meta‐analyses comparing der(1;7) to −7/del(7q). Methods Publications were searched from the following databases up to January 10, 2023: Pubmed, Web of Science, Embase, Cochrane, and ClinicalTrials.gov. Eligible studies were assessed for risks of bias. Relevant data were extracted from included studies and analyzed using random‐effects models. Publication bias was evaluated and sensitivity analyses were performed. Results The comparative meta‐analyses included 405 MDS patients with der(1;7) from nine studies. The analysis revealed that der(1;7) was associated with a greater male preponderance (86.1% vs. 68.3%, Odds Ratios (ORs) 2.007, p

Abstract Magnetic fields are proposed to be a clean and powerful tool to boost the heterogeneous reaction processes, from the simple two‐electron transfer hydrogen evolution to the complicated proton‐coupling of multi‐electron transfer reactions. Although many mechanisms are proposed to explain the field‐assistant enhancement of activities, it remains an open question of how to understand the contradictory experiment results. In this study, the interplay between the alternating magnetic field (AMF) and the working electrodes from the viewpoint of their relative geometric positions is investigated. It is found that the HER current is almost doubled at an AMF of 25 mT when Pt foil and AMF are parallelly arranged, which is more significant than the perpendicularly arranged configuration. A significant increase in solution resistance is observed, which is in contradiction to previous works. The changing of currents with the AMF strength is investigated for the diamagnetic Cu, ferromagnetic Ni, and paramagnetic Ti and Pt wire, all suggesting the vital role of the induced electromotive force, which is a result of the relative geometric positions between the electrode and AMF. The findings provide an alternative mechanism for the magnetic field‐assisted electrocatalytic processes, which is helpful for the rational design of high‐performance catalysts.

ABSTRACT Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in chronically simian immunodeficiency virus (SIV)-infected macaques. In this study, we further investigated the effect of As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-only treatment significantly increased the CD4/CD8 ratio, improved SIV-specific T cell responses, and reactivated viral latency in chronically SIVmac239-infected macaques. RNA-sequencing analysis revealed that As2O3 treatment downregulated the expression levels of genes related to HIV entry and infection, while the expression levels of genes related to transcription initiation, cell apoptosis, and host restriction factors were significantly upregulated. Importantly, we found that As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 might not only impact viral latency, but also induce the apoptosis of HIV-infected cells and thus block the secondary infection of bystanders. Moreover, we investigated the therapeutic potential of this regimen in acutely SIVmac239-infected macaques and found that As2O3 + ART treatment effectively restored the CD4+ T cell count, delayed disease progression, and improved survival in acutely SIV-infected macaques. In sum, this work provides new insights to develop As2O3 as a component of the “shock-and-kill” strategy toward HIV functional cure. IMPORTANCE Although antiretroviral therapy (ART) can effectively suppress the viral load of AIDS patients, it cannot functionally cure HIV infection due to the existence of HIV reservoir. Strategies toward HIV functional cure are still highly anticipated to ultimately end the pandemic of AIDS. Herein, we investigated the direct role of As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 has the potential to be launched into the “shock-and-kill” strategy to suppress HIV/SIV reservoir due to its latency-reversing and apoptosis-inducing properties.

In this study, authors identified neutralizing antibodies by isolating B cells from SARS-CoV-2 Delta infected patients and detect altered structural features, likely introduced by somatic hypermutation, that are involved in epitope binding and increase neutralization breadth against virus variants.

The development of robust catalysts that could work under industrial-scale current densities is a challenge for hydrogen production. Here, the authors report an in-situ activation method to produce ferromagnetic Ru clusters that can catalyze the hydrogen evolution reaction at high current densities.

SARS-CoV-2 variants continue to emerge facing established herd immunity. L452R, previously featured in the Delta variant, quickly emerged in Omicron subvariants, including BA.4/BA.5, implying a continued selection pressure on this residue. The underlying links between spike mutations and their selective pressures remain incompletely understood. Here, by analyzing 221 structurally characterized antibodies, we found that IGHV1-69-encoded antibodies preferentially contact L452 using germline-encoded hydrophobic residues at the tip of HCDR2 loop. Whereas somatic hypermutations or VDJ rearrangements are required to acquire L452-contacting hydrophobic residues for non-IGHV1-69 encoded antibodies. Antibody repertoire analysis revealed that IGHV1-69 L452-contacting antibody lineages are commonly induced among COVID-19 convalescents but non-IGHV1-69 encoded antibodies exhibit limited prevalence. In addition, we experimentally demonstrated that L452R renders most published IGHV1-69 antibodies ineffective. Furthermore, we found that IGHV1-69 L452-contacting antibodies are enriched in convalescents experienced Omicron BA.1 (without L452R) breakthrough infections but rarely found in Delta (with L452R) breakthrough infections. Taken together, these findings support that IGHV1-69 population antibodies contribute to selection pressure for L452 substitution. This study thus provides a better understanding of SARS-CoV-2 variant genesis and immune evasion.

In vaccinees who were infected with SARS-CoV in 2003, we observed greater antibody responses against spike and nucleoprotein of both SARS-CoV-2 and SARS-CoV after a single dosage of inactivated SARS-CoV-2 vaccine. After receiving the second vaccination, antibodies against RBD of SARS-CoV-2 Wuhan, Beta, Delta, and recently emerged Omicron are significantly higher in SARS-CoV experienced vaccinees than in SARS-CoV naïve vaccinees. Neutralizing activities measured by authentic viruses and pseudoviruses of SARS-CoV, SARS-CoV-2 Wuhan, Beta, and Delta are greater in SARS-CoV experienced vaccinees. In contrast, only weak neutralizing activities against SARS-CoV-2 and variants were detected in SARS-CoV naïve vaccinees. By 6 months after the second vaccination, neutralizing activities were maintained at a relatively higher level in SARS-CoV experienced vaccinees but were undetectable in SARS-CoV naïve vaccinees. These findings suggested a great possibility of developing a universal vaccine by heterologous vaccination using spike antigens from different SARS-related coronaviruses.

Abstract There are considerable new data on mutation topography in persons with myelodysplastic syndromes (MDS). These data have been used to update conventional risk models such as the Revised International Prognostic Scoring System (IPSS-R). Whether the molecular IPSS (IPSS-M) which includes these data improves survival prediction accuracy is untested. To answer this question, we compared survival prediction accuracies of the IPSS-R and IPSS-M in 852 consecutive subjects with de novo MDS. Concordance statistics (C-statistics) of the IPSS-R and IPSS-M in the entire cohort were similar, 0.67 (95% Confidence Interval [CI] 0.64, 0.71) and 0.68 (0.64, 0.71). Average numbers of mutations and of IPSS-M related mutations were greater in persons ≥ 60 years (2.0 [Interquartile Range [IQR], 1, 3] vs. 1.6 [0, 2], P = 0.003; 1.6 [0, 2] vs. 1.3 [0, 2], P = 0.006). Subjects ≥ 60 years had a higher incidence of mutations in RUNX1, TP53, TET2, SRSF2, DNMT3A, STAG2, EZH2 and DDX41. In contrast, mutations in U2AF1 were more common in persons

ABSTRACT Mice are refractory to infection with human-tropic hepatitis C virus (HCV), although distantly related rodent hepaciviruses (RHV) circulate in wild rodents. To investigate whether liver intrinsic host factors can exhibit broad restriction against these distantly related hepaciviruses, we focused on Shiftless (Shfl), an interferon (IFN)-regulated gene (IRG) which restricts HCV in humans. Unusually, and in contrast to selected classical IRGs, human and mouse SHFL orthologues (hSHFL and mSHFL, respectively) were highly expressed in hepatocytes in the absence of viral infection, weakly induced by IFN, and highly conserved at the amino acid level (>95%). Replication of both HCV and RHV subgenomic replicons was suppressed by ectopic expression of mSHFL in human or rodent hepatoma cell lines. Gene editing of endogenous mShfl in mouse liver tumor cells increased HCV replication and virion production. Colocalization of mSHFL protein with viral double-stranded RNA (dsRNA) intermediates was confirmed and could be ablated by mutational disruption of the SHFL zinc finger domain, concomitant with a loss of antiviral activity. In summary, these data point to an evolutionarily conserved function for this gene in humans and rodents: SHFL is an ancient antiviral effector which targets distantly related hepaciviruses via restriction of viral RNA replication. IMPORTANCE Viruses have evolved ways to evade or blunt innate cellular antiviral mechanisms within their cognate host species. However, these adaptations may fail when viruses infect new species and can therefore limit cross-species transmission. This may also prevent development of animal models for human-pathogenic viruses. HCV shows a narrow species tropism likely due to distinct human host factor usage and innate antiviral defenses limiting infection of nonhuman liver cells. Interferon (IFN)-regulated genes (IRGs) partially inhibit HCV infection of human cells by diverse mechanisms. Here, we show that mouse Shiftless (mSHFL), a protein that interferes with HCV replication factories, inhibits HCV replication and infection in human and mouse liver cells. We further report that the zinc finger domain of SHFL is important for viral restriction. These findings implicate mSHFL as a host factor that impairs HCV infection of mice and provide guidance for development of HCV animal models needed for vaccine development.

Abstract Elemental vacancies are proposed as an effective approach to tuning the electronic structure of catalysts that are critical for energy conversion. However, for reactions such as the sluggish oxygen evolution reaction, the excess of oxygen vacancies (VO) is inevitable and detrimental to catalysts’ electrochemical stability and activities, e.g., in the most active RuO2. While significant work is carried out to hinder the formation of VO, the development of a fast and efficient strategy is limited. Herein, a protection SrO layer produced successfully at the surface of RuO2 with the in situ exsolution method with perovskite SrRuO3 as the precatalyst, which could significantly hinder the generation of VO. Benefited from the suppression of VO, the surface‐modified RuO2 requires a low overpotential of 290 mV at 100 mA cm−2, accompanied by remarkably high electrochemical stability (100 h) and Faraday efficiency (≈100%). Theoretical investigation reveals that the formation energy of VO in RuO2 is almost doubled in the exsolved RuO2 phase as a result of the weakened RuO bond covalency. This work not only provides insight into the structural evolution of perovskite oxide catalysts but also demonstrates the feasibility of controlling vacancy formation via in situ exsolution.

ObjectiveAn analysis of the clinical features of autoimmune encephalitis accompanied by anti-amphiphysin antibodies.MethodsThe data of encephalitis patients with anti-amphiphysin antibodies were retrospectively evaluated, including demographics, neurological and laboratory findings, imaging, treatment, and prognostic predictions.ResultsTen patients aged between 29 and 78 years (median age 52 years) were included. The male: female ratio was 4:6. Limbic encephalitis was found in nine patients while epileptic seizures were present in seven patients. All patients showed anti-amphiphysin antibody positivity in sera while one ninth was positive for CSF antibody. The EEG findings were abnormal, including reductions in background activity, and the presence of diffuse slow waves, sharp waves, and spikes and waves. Five patients showed signs of increased T2 signals in the medial temporal lobe on MRI while PET showed either hyper- or hypo-metabolic changes in several brain regions, including the temporal lobe, hippocampus, basal ganglia, frontal and parietal cortices. Nine of ten patients were treated with immunotherapy, with improvements of varying degrees. There was a significant reduction in seizure frequency, and all patients were seizure-free at last follow-up.ConclusionAutoimmune encephalitis with anti-amphiphysin antibodies has a variety of clinical manifestations. The most common symptom is limbic encephalitis. Although relief from seizures can be achieved relatively easily, many patients suffer psychiatric, cognitive, and sleep sequelae. The disease was found to be associated with a lower incidence of cancer than has been previously reported for paraneoplastic neurologic syndromes.

BackgroundBartter syndrome (BS) type III is a rare autosomal recessive genetic disease. Its clinical features are polyuria, hypokalemia, hypochloremia, metabolic alkalosis, and hyperreninaemia. A few BS type III can be complicated with chronic kidney disease.Case presentationWe report a 14-year-old boy with Bartter syndrome caused by a c.1792C > T (p.Q598*) mutation in the CLCNKB gene. He was a no deafness and full-term baby, and he had renal dysplasia and chronic kidney disease (CKD). In addition, we summarize all cases of BS type III complicated with CKD.ConclusionsWe report a case of Bartter syndrome complicated by chronic kidney disease caused by a new mutation of CLCNKB. As we all know, BS type IV is usually combined with chronic kidney disease, and BS type III can also integrate with CKD. We don't find BS type III with glomerular dysplasia in the literature. So renal damage in BS type III is not only FSGS; clinicians must also be aware of glomerular dysplasia.

Abstract The difficulties in designing high-performance hydrogen evolution reaction (HER) catalysts lie in the manipulation of adsorption behaviors of transition metals (TMs). Topological chiral semimetals with super-long Fermi arc surface states provide an ideal platform for engineering the catalytic performance of TMs through the metal-support interaction. We found the adsorption trends of TMs can be modified significantly when deposited at the surface of the PdGa chiral crystal. The electron transfer from the TMs to the surface states of the PdGa reshapes the d band structure of TMs and weakens the hydrogen intermediate bonding. Especially, W/PdGa is expected to be a good HER catalyst with close to zero Gibbs free energy. Experimentally, we found a Pt-like exchange current density and turnover frequency when depositing W atoms at the PdGa nanostructures surface. The findings provide a way to develop high-efficient electrocatalysts by the interplay between topological surface states and metal-support interaction.

Cardiac resynchronization therapy (CRT) is recognized as the first-line management for patients with heart failure (HF) and conduction disorders. As a conventional mode for delivering CRT, biventricular pacing (BVP) improves cardiac function and reduces HF hospitalizations and mortality, but there are still limitations given the high incidence of a lack of response rates. Alternative pacing methods are needed either for primary or rescue therapy. In recent years, conduction system pacing (CSP) has emerged as a more physiological pacing modality for simultaneous stimulation of the ventricles, including His bundle pacing (HBP) and left bundle branch pacing (LBBP). CSP activates the His-Purkinje system, allowing normal ventricular stimulation. However, HBP is technically challenging with a relatively low success rate, high pacing threshold, and failure to correct distal conduction abnormalities. Therefore, LBBP stands out as a novel ideal physiological pacing modality for CRT. Several non-randomized studies compared the feasibility and safety of LBBP with BVP and concluded that LBBP is superior to BVP for delivering CRT with a narrower QRS and greater improvements in left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional class. Concurrently, some studies showed lower and stable pacing thresholds and greater improvement of B-type natriuretic peptide (BNP) levels, as well as better mechanical synchronization and efficiency. LBBP ensures better ventricular electromechanical resynchronization than BVP. In this review, we discuss current knowledge of LBBP, compare LBBP with BVP, and explore the potential of LBBP to serve as an alternative primary therapy to realize cardiac resynchronization.

BackgroundLittle is known regarding the role of responsive caregiving in the association between maternal psychological stress and child neurodevelopment. We, therefore, herein investigated the relationship between maternal psychological stress during pregnancy and children's neurodevelopment with modifications in responsive caregiving.MethodsA total of 3,603 mother–child pairs were recruited from the Shanghai Maternal-Child Pairs Cohort, and we assessed maternal psychological stress using the Life Events Scale for Pregnant Women (LESPW) during early and late pregnancy. Early neurodevelopment of infants at 6 and 12 months of age was also evaluated using the Age and Stage Questionnaire, Third Edition (ASQ-3). The 2-month-old infant nursing-care questionnaire was designed based on the Five Elements of Parenting Care Framework released by the World Health Organization (WHO) and used to evaluate the levels of early responsive caregiving for infants. Multivariate logistic regression analysis was then applied to determine the association between maternal psychological stress during pregnancy and child development.ResultsThe suspected developmental delay rate of infants aged 6 and 12 months ranged between 13.3% and 24.5%. After adjusting for confounders, we noted that high maternal subjective events stress during early pregnancy was associated with an increased risk of suspected developmental delay in problem-solving domains at 12 months of age [adjusted OR (aOR) = 1.51; 95% confidence interval (CI), 1.09–2.20]. High general negative objective events’ stress during late pregnancy also constituted a risk factor for development in the personal–social domain at 12 months of age (aOR = 1.57; 95% CI, 1.13–2.19). Remarkably, we noted in infants with insufficient responsive caregiving that there were greater associations between the risk of general maternal negative objective events during late pregnancy and personal–social domain at 12 months of age (aOR = 2.06; 95% CI, 1.15–3.68). Similarly, there was a greater association between the risk for maternal subjective events during early pregnancy and problem-solving at 12 months of age (aOR = 1.55; 95% CI, 1.11–2.34).ConclusionsMaternal psychological stress during pregnancy was predominantly associated with suspected developmental delay in infants at 6 and 12 months of age, and these associations were modified by early responsive caregiving.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma with unique tumor characteristics, which is rare in children. Herein, we present the immunophenotype, treatment, and prognosis of three children with ASPS from The Second Xiangya Hospital of Central South University, and 51 children with ASPS have been reported in the previous literature, along with a focused review of the clinical features, pathological features, differential diagnosis, treatment, and prognosis of ASPS in pediatric patients.

Monoclonal antibodies (mAbs) encoded by IGHV3-53 (VH3-53) targeting the spike receptor-binding domain (RBD) have been isolated from different COVID-19 patients. However, the existence and prevalence of shared VH3-53-encoded antibodies in the antibody repertoires is not clear. Using antibody repertoire sequencing, we found that the usage of VH3-53 increased after SARS-CoV-2 infection. A highly shared VH3-53-J6 clonotype was identified in 9 out of 13 COVID-19 patients. This clonotype was derived from convergent gene rearrangements with few somatic hypermutations and was evolutionary conserved. We synthesized 34 repertoire-deduced novel VH3-53-J6 heavy chains and paired with a common IGKV1-9 light chain to produce recombinant mAbs. Most of these recombinant mAbs (23/34) possess RBD binding and virus-neutralizing activities, and recognize ACE2 binding site via the same molecular interface. Our computational analysis, validated by laboratory experiments, revealed that VH3-53 antibodies targeting RBD are commonly present in COVID-19 patients’ antibody repertoires, indicating many people have germline-like precursor sequences to rapidly generate SARS-CoV-2 neutralizing antibodies. Moreover, antigen-specific mAbs can be digitally obtained through antibody repertoire sequencing and computational analysis.

ABSTRACTThe Zika virus (ZIKV) is a mosquito-borne flavivirus that causes neonatal abnormalities and other disorders. Antibodies to the ZIKV envelope (E) protein can block infection. In this study, next-generation sequencing (NGS) of immunoglobulin heavy chain (IgH) mRNA transcripts was combined with single-cell PCR cloning of E-binding monoclonal antibodies for analysing antibody response in a patient from the early stages of infection to more than one year after the clearance of the virus. The patient's IgH repertoire 14 and 64 days after symptom onset showed dramatic dominant clonal expansion but low clonal diversity. IgH repertoire 6 months after disease-free status had few dominant clones but increased diversity. E-binding antibodies appeared abundantly in the repertoire during the early stages of infection but quickly declined after clearance of the virus. Certain VH genes such as VH5-10-1 and VH4-39 appeared to be preferentially enlisted for a rapid antibody response to ZIKV infection. Most of these antibodies require relatively few somatic hypermutations to acquire the ability to bind to the E protein, pointing to a possible mechanism for rapid defence against ZIKV infection. This study provides a unique and holistic view of the dynamic changes and characteristics of the antibody response to ZIKV infection.

The 2016 revised World Health Organization classification identified myeloid neoplasms with germline predisposition as a new diagnostic category. Germline loss-of-function mutations in G6b (G6b-B, C6orf25 or MPIG6B) are associated with congenital macro-thrombocytopenia with focal myelofibrosis, a rare autosomal recessive disease. It is unclear whether germline G6b variants increase the risk of developing a myeloid neoplasm. Here we describe an adult with Myelodysplastic syndromes and a homozygous germline G6b mutation who achieved hematopoietic reconstitution by hematopoietic stem cell transplantation. As far as we know, this is the first report of adult Myelodysplastic syndromes with germline G6b homozygous variant in the literatures.

Genetic analyses showed nearly 30 amino acid mutations occurred in the spike protein of the Omicron variant of SARS-CoV-2. However, how these mutations occurred and changed during the generation and development of Omicron remains unclear. In this study, 6.7 million (all publicly available data from 2020/04/01 to 2022/04/01) SARS-CoV-2 genomes were analyzed to track the origin and evolution of Omicron variants and to reveal the genetic pathways of the generation of core mutations in Omicron. The haplotype network visualized the pre-Omicron, intact-Omicron, and post-Omicron variants and revealed their evolutionary direction. The correlation analysis showed the correlation feature of the core mutations in Omicron. Moreover, we found some core mutations, such as 142D, 417N, 440K, and 764K, reversed to ancestral residues (142G, 417K, 440N, and 764N) in the post-Omicron variant, suggesting the reverse mutations provided sources for the emergence of new variants. In summary, our analysis probed the origin and further evolution of Omicron sub-variants, which may add to our understanding of new variants and facilitate the control of the pandemic.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical setting. Its pathogenesis was associated with metabolic disorder, especially defective fatty acids oxidation (FAO). However, whether promoting FAO could prevent AF occurrence and development remains elusive. In this study, we established a mouse model of obesity-related AF through high-fat diet (HFD) feeding, and used l-carnitine (LCA, 150 mg/kg⋅BW/d), an endogenous cofactor of carnitine palmitoyl-transferase-1B (CPT1B; the rate-limiting enzyme of FAO) to investigate whether FAO promotion can attenuate the AF susceptibility in obesity. All mice underwent electrophysiological assessment for atrial vulnerability, and echocardiography, histology and molecular evaluation for AF substrates and underlying mechanisms, which were further validated by pharmacological experiments in vitro. HFD-induced obese mice increased AF vulnerability and exhibited apparent atrial structural remodeling, including left atrial dilation, cardiomyocyte hypertrophy, connexin-43 remodeling and fibrosis. Pathologically, HFD apparently leads to defective cardiac FAO and subsequent lipotoxicity, thereby evoking a set of pathological reactions including oxidative stress, DNA damage, inflammation, and insulin resistance. Enhancing FAO via LCA attenuated lipotoxicity and lipotoxicity-induced pathological changes in the atria of obese mice, resulting in restored structural remodeling and ameliorated AF susceptibility. Mechanistically, LCA activated AMPK/PGC1α signaling both in vivo and in vitro, and pharmacological inhibition of AMPK via Compound C attenuated LCA-induced cardio-protection in palmitate-treated primary atrial cardiomyocytes. Taken together, our results demonstrated that FAO promotion via LCA attenuated obesity-mediated AF and structural remodeling by activating AMPK signaling and alleviating atrial lipotoxicity. Thus, enhancing FAO may be a potential therapeutic target for AF.

In the event of an acute ischemic stroke, saving the penumbra is the most important aspect of early treatment. The rapid and accurate identification of ischemic penumbra plays a key role in its comprehensive treatment. At present, the identification method and evaluation standard of ischemic penumbra have not been unified. Numerous pieces of software identifying ischemic penumbra have been developed, such as rapid processing of perfusion and diffusion (RAPID), Sphere, Vitrea, and computed tomography perfusion+ (CTP+). The RAPID software, analyzing and integrating multi-mode image data (mainly based on perfusion weighted imaging (PWI) or computed tomography perfusion (CTP) images, shows good performance in identifying ischemic penumbra and has been utilized for the assessment of ischemic penumbra in many ischemic stroke clinical studies, achieving good outcomes and promoting the transition from “time window” to “tissue window” in the treatment of early stage AIS. To obtain a comprehensive understanding of the RAPID software and its accuracy in evaluating ischemic penumbra, this paper reviews the background and development of the RAPID software, summarizes the published acute cerebral infarction trials using the RAPID software, generalizes the threshold parameters in different time windows, and further discusses its application and limitations.

In order to avoid erroneous braking responses when vehicle drivers are faced with a stressful setting, a K-order propagation number algorithm–Feature selection–Classification System (KFCS) is developed in this paper to detect emergency braking intentions in simulated driving scenarios using electroencephalography (EEG) signals. Two approaches are employed in KFCS to extract EEG features and to improve classification performance: the K-Order Propagation Number Algorithm is the former, calculating the node importance from the perspective of brain networks as a novel approach; the latter uses a set of feature extraction algorithms to adjust the thresholds. Working with the data collected from seven subjects, the highest classification accuracy of a single trial can reach over 90%, with an overall accuracy of 83%. Furthermore, this paper attempts to investigate the mechanisms of brain activeness under two scenarios by using a topography technique at the sensor-data level. The results suggest that the active regions at two states is different, which leaves further exploration for future investigations.

Topological distortion seriously affects spatial cognition. To solve this problem caused by the integration of vector features in discrete global grid systems (DGGs), a topology-preserving gridding method for vector features is proposed. The method proposed determines the topological distortion according to the relationship between grid cells and then increases the local resolution of vector features by employing the multi-level resolution characteristic of DGGs, to repair three kinds of topological distortions. Experimental results show that the proposed method can effectively maintain the topological relationship between the original vector features, and the amount of data is stable, thus ensuring the correct integration of vector features in the DGGs.

Shidu is the Chinese transliteration for ‘losing an only child,’ which indicates the death of the only child in the family. Shidu is a unique social phenomenon resulting from the One-Child Policy implemented in China for several decades. Shiduers are parents who have lost their only child. The grief research scholar Neimeyer (2012) argued that grief research should consider the role of different cultures in the grieving process. Familism culture is a collectivist culture that has a profound effect on Chinese society and is likely to produce a significant effect on the grieving process of shiduers; however, this effect has not yet received systematic attention in research. To explore the effect of familism culture on the grief of shiduers, we conducted semi-structured personal interviews in Beijing, China, with seven shiduers. The study results show that the effect of familism culture on the grief of shiduers includes three levels: cognition, emotion, and behavior. These levels are reflected in a variety of relationships, including relationships with ancestors, the deceased child, the spouse, relatives, Tong Ming Ren (the Chinese transliteration of ‘people who share the same fate’), and the country. The first four types of relationships are reflections of ‘direct familism culture,’ and the latter two types of relationships are reflections of ‘extended familism culture’. The relationships with the deceased child, relatives, and Tong Ming Ren are mainly supportive; the relationship with ancestors is mainly stressful; the relationship with the spouse has a dual nature; and the relationship with the country is contradictory. Over time, shiduers have abandoned the concept of familism culture and have moved toward reducing stress and increasing supportiveness. Psychological professionals, social workers, and government staff may refer to the results of this study to help shiduers obtain support and reduce stress from the described relationships. Specific suggestions are provided in the text.