Search

Abstract Background Methylmalonic acidemia (MMA) is one of the most common hereditary organic acid metabolism disorders that endangers the lives and health of infants and children. Early detection and intervention before the appearance of a newborn’s clinical symptoms can control disease progression and prevent or mitigate its serious consequences. Methods 42,004 newborns from two Chinese populations were included in the study. The small molecular metabolite analytes were detected from the dried blood spot (DBS) samples by MS/MS. Genetic analysis of 68 Chinese MMA cases were performed by whole-exome sequencing and Sanger sequencing. Random forest classifiers (RFC) were constructed to improve the MMA screening performance and genotype prediction in two Chinese populations. Meanwhile, other six machine learning models were trained to separate MMA patients from normal newborns. Model performance was assessed using accuracy, sensitivity, specificity, false positive rate (FPR), and positive predictive value (PPV) and the area under the receiver operating characteristic curve (AUC). Results In the total 42,004 newborn samples, 68 MMA cases were identified by genetic analysis, 42 cases of which were caused by variants in MMACHC, 24 cases by variants in MMUT, and two cases by variants in MMAA. Three novel variants including c.449T>G (p.I150R) of MMACHC, c.1151C>T (p.S384F) and c.1091_1108delins (p.Y364Sfs*4) in MMUT were identified in the MMA patients. RFC for newborn screening of MMA performed best as compared to several other classification models based on machine learning with 100% sensitivity, low FPR, excellent PPV and AUC. In addition, the subdivision RFC for MMA genotype prediction was constructed with superior performance. Conclusions It can be seen that RFC is extremely helpful for detection and genotype prediction in the newborn MMA screening. In addition, our findings extend the variant spectrum of genes related to MMA.

Abstract Traumatic brain injury (TBI) represents a common and severe medical condition necessitating prompt risk stratification to enhance patient outcomes. Although substantial research has been conducted on the prognostic utility of various biomarkers for TBI, no single biomarker has been definitively recognized as the most precise predictor of disease outcomes. In comparison to other markers, the neutrophil-albumin ratio (NAR) has emerged as a cost-effective and reproducible inflammatory biomarker, demonstrating potential in evaluating the severity of inflammation and prognosticating outcomes in infections and cerebrovascular diseases. This study evaluated the prognostic significance of the NAR in comparison to two other readily accessible and cost-effective composite indices: the Neutrophil-Lymphocyte Ratio (NLR) and the Platelet-Lymphocyte Ratio (PLR) in individuals with TBI. We conducted a retrospective cohort analysis involving 297 hospitalized TBI patients, gathering comprehensive demographic, anthropometric, medical, clinical, laboratory, and imaging data to assess the expression changes of these biomarkers. Our findings suggest that both the NAR and the NLR possess predictive value regarding prognosis following TBI. However, receiver operating characteristic (ROC) curve analysis revealed that NAR outperformed NLR as a prognostic predictor. In conclusion, our examination of blood biochemistry composite indicators indicates that, while both NAR and NLR serve as significant prognostic markers, NAR is a more effective predictor of outcomes in patients with TBI.

Abstract Background About one in four Chinese people might suffer or have already suffered from anxiety conditions, with a lifetime prevalence rate of 4.8%. However, many of those who could have benefited from psychological or pharmacological treatments fail to be recognized or treated due to the lack of timely recognition and accurate diagnosis. Objective This study used a topic modeling approach to explore people’s anxiety-related concerns raised on a computer-mediated Chinese health platform, YOU WEN BI DA (questioning and answering), to provide implications for accurate diagnosis, targeted education, tailored intervention, and informed policy-making in the course of addressing this condition of public concern. Methods First, we extracted data from YOU WEN BI DA between May 2022 and February 2023. After cleaning the extracted data both using the Python text processing tool spaCy and manually, we ascertained the optimal number of topics by drawing on the coherence scores and used latent Dirichlet allocation (LDA) topic modeling to generate the most salient topics and related terms. We then categorized the topics ascertained into different classes of themes by plotting them onto a 2D plane via multidimensional scaling using the pyLDAvis visualization tool. Finally, we analyzed these topics and themes qualitatively to better understand people’s anxiety-related concerns. Results 5 topics with different overall prevalence were ascertained through data analysis. Topic 2 (tinnitus phobia-incurred concerns, n = 639) is the most popular dominant topic, occurring in 25.1% of the 2545 collected concerns, closely followed by Topics 1 (neurosis-incurred concerns, n = 512;) and 3 (sleep, dyskinesia, bipolar, cognitive, and somatic disorders-incurred concerns, n = 619), which appeared in 20.1% and 24.3% of the 2545 concerns respectively. Topic 5 (social phobia-incurred concerns, n = 428) ranks as the fourth most popular dominant topic, showing up in 16.8% of the 2545 concerns. Topic 4 (autonomic nerve dysfunction-incurred concerns, n = 347) accounts for 13.6% of the 2545 concerns. The t-distributed Stochastic Neighbor Embedding analysis reveals partial similarities between Topics 2 and 5 as well as between Topics 4 and 5 because many concerns involved in Topics 2 and 5 pertain to people’s psychological status of fear and anxiety and the relief and dispelling of such symptoms through medication, and many concerns involved in Topics 4 and 5 relate to people’s worries about the negative impact on their nerves and the adjustment and conditioning of such effects through medication. Conclusion This was the first study that investigated Chinese people’s anxiety-related concerns raised on YOU WEN BI DA using the topic modeling technique. The automatic text analysis and complementary manual interpretation of the collected data allowed for the discovery of the dominant topics hidden in the data and the categorization of these topics into different themes to reveal the overall status of people’s anxiety-related concerns. The research findings can provide some practice implications for health and medical educators, practitioners, and policy-makers to make joint efforts to address this common public concern effectively and efficiently.

Abstract Background Cognitive fusion MRI-guided targeted biopsy (cTB) has been widely used in the diagnosis of prostate cancer (PCa). However, cTB relies heavily on the operator’s experience and confidence in MRI readings. Our objective was to compare the cancer detection rates of MRI artificial intelligence-guided cTB (AI-cTB) and routine cTB and explore the added value of using AI for the guidance of cTB. Methods This was a prospective, single-institution randomized controlled trial (RCT) comparing clinically significant PCa (csPCa) and PCa detection rates between AI-cTB and cTB. A total of 380 eligible patients were randomized to the AI-cTB group (n = 191) or the cTB group (n = 189). The AI-cTB group underwent AI-cTB plus systematic biopsy (SB) and the cTB group underwent routine cTB plus SB. The primary outcome was the detection rate of csPCa. The reference standard was the pathological results of the combination of TB (AI-cTB/cTB) and SB. Comparisons of detection rates of csPCa and PCa between groups were performed using the chi-square test or Fisher’s exact test. Results The overall csPCa and PCa detection rates of the whole inclusion cohort were 58.8% and 61.3%, respectively. The csPCa detection rates of TB combined with SB in the AI-cTB group were significantly greater than those in the cTB group at both the patient level (58.64% vs. 46.56%, p = 0.018) and per-lesion level (61.47% vs. 47.79%, p = 0.004). Compared with cTB, the AI-cTB could detect a greater proportion of patients with csPCa at both the per-patient level (69.39% vs. 49.71%, p

Abstract Objective The use of clear aligners (CAs) for orthodontic treatment has substantially increased in recent decades. However, limited empirical evidence exists regarding their potential effects on the temporomandibular joint (TMJ). The aim of this study was to assess the effect of maxillary molar distalization on the positional and dimensional TMJ parameters between CAs and conventional fixed orthodontic appliances (FAs) in skeletal class II malocclusion. Methods This is a retrospective cohort study examined 70 adult patients with skeletal class II malocclusion with similar baseline characteristics based on American Board of Orthodontics (ABO) discrepancy index scores. The patients were treated by maxillary distalization movement by CAs or FAs, of which there were two equal groups of 35 patients were included in each group. CBCTs on TMJs were performed before and after treatment through Anatomage Invivo Dental 6.0. The measured parameters included inclination, position, condyle and articular fossa dimensions, and the volumetric joint spaces. Results In both groups, linear measurements of the maxillary molar position revealed significant improvement after treatment (P

Background: Kidney disease has become a growing public health problem worldwide, and there is an urgent need to develop reliable models for investigating novel and effective treatment strategies. In recent years, kidney organoids, as novel models different from traditional two-dimensional cells and model animals, have attracted more and more attention. Current advances have allowed the generation of kidney organoids from the directed differentiation of induced pluripotent stem cells (iPSCs), which possess similar characteristics to embryonic stem cells (ESCs), but bypass ethical constraints and have a wide range of sources. Summary: Herein, the methods of generating renal organoids from iPSCs, the applications of iPSC-derived renal organoids in disease modeling, drug effectiveness detection, and regenerative medicine as well as the challenges were reviewed. Key messages: iPSC-derived renal organoids can be used to model kidney diseases, and are great models for studying kidney injury and toxicity. Many efforts are needed to finally apply organoids into clinical application.

Abstract Herpes Simplex Virus-1 (HSV-1) Kaposi varicelliform eruption (KVE) is a rare and severe cutaneous manifestation, clinically characterized by the presence of widespread vesicles and pustules. A case report details a patient with a history of Atopic Dermatitis (AD) and recent SARS-CoV-2 infection who developed a severe KVE subsequent to the viral illness. The patient, a 35-year-old male, presented with severe atopic dermatitis (AD) subsequent to a SARS-CoV-2 infection. In a period of four months, the dermatological eruption underwent a rapid progression to a severe state, characterised by the presence of extensive vesicles and pustules, in addition to the emergence of symptoms. In conjunction with a chest CT scan, plasma and antigen testing, the patient was confirmed to be positive for HSV-1 positive. The patient exhibited elevated levels of IgE and a notable reduction in the absolute number of immune cells. The patient was treated with valaciclovir, piperacillin-tazobactam, IVIG at the same time. Within seven days of treatment, the blisters had dried up and the scabs had fallen off without any pain, pruritus, or fever. This case highlights the potential for severe viral eruptions, such as KVE in individuals with underlying dermatological conditions following viral infections.

Abstract The increasing prevalence of carbapenem-resistant Enterobacter cloacae complex (CREC) poses great challenges to infection treatment in the clinical setting. In this study, we reported the emergence of carbapenemase in a rare species, Enterobacter chuandaensis, belonging to the Enterobacter cloacae complex (ECC). We elucidated the genetic characteristics of carbapenem-resistant isolate FAHZZU5885, co-harboring bla NDM−1 and bla KPC−2. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and average nucleotide identity (ANI) analysis were used to identify E. chuandaensis. S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting were used to clarify the number and size of the plasmids in FAHZZU5885. Antimicrobial phenotypes were identified by antimicrobial susceptibility testing (AST), and the characteristics of the strain were examined with whole-genome sequencing (WGS). The conjugation experiment and stability assay were conducted to verify the transferability and stability of the plasmid carrying carbapenemase-encoding genes. E. chuandaensis FAHZZU5885 was isolated from a perianal swab of a patient admitted to the ICU. This strain simultaneously carried bla NDM−1 and two bla KPC−2 genes. FAHZZU5885 was resistant to most of the tested antibiotics except for amikacin, tigecycline, and colistin. Two bla KPC−2 were located separately on two different plasmids, the ~ 120 kb IncFIA-IncFII plasmid and the ~ 80 kb IncR plasmid. Both plasmids shared the conserved sequence klcA-korC-ISkpn6-bla KPC−2 -ISkpn27-tnpR-tnpA. The bla NDM−1-bearing plasmid had the potential to transfer and can remain stable after successive passages. In addition, the bla NDM−1 was carried on a ~ 80 kb IncFII plasmid with the conserved sequence ISAba125-bla NDM−1-ble-trpF-dsbD-cutA-groS-groL. In summary, this study marks the first report of the multidrug-resistant E. chuandaensis strain FAHZZU5885 harboring two bla KPC−2-bearing plasmids, indicating the potential for the further dissemination of carbapenemase-encoding genes in novel species. The findings contribute to enhancing our understanding of CREC strains, emphasizing the need for continued and comprehensive surveillance of this species.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS. Methods We used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2. Results APG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment. Conclusions Our results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS. Graphical Abstract

Abstract Objective As research into preclinical rheumatoid arthritis (pre-RA) has advanced, a growing body of evidence suggests that abnormalities in RA-affected joint cartilage precede the onset of arthritis. Thus, early prevention and treatment strategies are imperative. In this study, we aimed to explore the protective effects of mesenchymal stem cell (MSC)-derived microvesicles (MVs) on cartilage degradation in a collagen-induced arthritis (CIA) mouse model. Methods A CIA mouse model was established to observe early pathological changes in cartilage (days 21-25) through histological and radiological examinations. On day 22, MSCs-MVs were intravenously injected into the mice with CIA. Radiological, histological, and flow cytometric examinations were conducted to observe inflammation and cartilage changes in these mice compared to the mice with CIA and the control mice. In vitro, chondrocytes were cultured with inflammatory factors such as IL-1β and TNFα to simulate inflammatory damage to cartilage. After the addition of MVs, changes in inflammatory levels and collagen expression were measured via Western blotting, immunofluorescence, enzyme-linked immunosorbent assays (ELISAs), and quantitative PCR to determine the role of MVs in maintaining chondrocytes. Results MSC–MVs expressed vesicular membrane proteins (CD63 and Annexin V) and surface markers characteristic of MSCs (CD44, CD73, CD90, and CD105). In the early stages of CIA in mice, a notable decrease in collagen content was observed in the joint cartilage. In mice with CIA, injection of MSCs-MVs resulted in a significant reduction in the peripheral blood levels of IL-1β, TNFα, and IL-6, along with a decrease in the ratio of proinflammatory T and B cells. Additionally, MSC-MVs downregulated the expression of IL-1β, TNFα, MMP-13, and ADAMTS-5 in cartilage while maintaining the stability of type I and type II collagen. These MVs also attenuated the destruction of cartilage, which was evident on imaging. In vitro experiments demonstrated that MSC-MVs effectively suppressed the secretion of the inflammatory factors IL-1β, TNFα, and IL-6 in stimulated peripheral blood mononuclear cells (PBMCs). Conclusions MSCs-MVs can inhibit the decomposition of the inflammation-induced cartilage matrix by regulating immune cell inflammatory factors to attenuate cartilage destruction. MSC-MVs are promising effective treatments for the early stages of RA. Graphical Abstract

Abstract Background and objectives Methionine adenosyltransferase I/III deficiency used to be considered a relatively benign disease. This study aims to elucidate the clinical characteristics of methionine adenosyltransferase I/III deficiency patients with neurological manifestations. Methods The clinical data, blood amino acids, plasma total homocysteine, gene variants, brain imaging, treatments and outcomes of 15 patients with methionine adenosyltransferase I/III deficiency were retrospectively analyzed. Results Of these 15 patients, 10 demonstrated neurological abnormalities, with delayed language development, learning difficulties or abnormal brain imaging findings. Eleven patients were identified by newborn screening. Patients with demyelination showed significantly higher blood methionine concentrations at baseline (1102 vs. 396 µmol/L), and their blood methionine remained markedly elevated despite a low-methionine diet. Their plasma total homocysteine was normal to moderate elevated. One patient underwent liver transplantation aged 8 years, which reduced his serum methionine concentration to normal. Compound heterozygous and homozygous MAT1A variants were identified from the patients. Among the 21 variants observed, nine have been reported previously, while 12 were novel. Conclusions Methionine adenosyltransferase I/III deficiency is not just a benign disease. Severe persistent hypermethioninemia can cause brain injuries, especially in the white matter. Liver transplantation may be a potential treatment option for refractory methionine adenosyltransferase I/III deficiency.

Abstract Acute kidney injury (AKI) is a serious condition characterized by decreased urine output, often accompanied by psychiatric symptoms like depression. However, there are limited pharmacological treatments available for AKI and its associated depressive symptoms. In this study, we investigated whether cisplatin-induced AKI in mice leads to depression-like behaviors and whether ketamine could alleviate both the kidney injury and these behaviors. Mice with cisplatin-induced AKI exhibited elevated levels of creatinine and urea, kidney damage, increased kidney injury molecule-1 protein, and pathological changes in the liver, colon, and spleen. They also showed depression-like behaviors and reduced expression of synaptic proteins in the prefrontal cortex. Remarkably, a single dose of ketamine significantly reduced these symptoms and pathological changes. Interestingly, the beneficial effects of ketamine on the kidneys, other organs, and depression-like behaviors, were reversed by the tropomyosin receptor kinase B (TrkB) inhibitor ANA-12. Western blot analysis revealed the involvement of the TrkB and ERK (extracellular signal-regulated kinase)-CREB (cAMP response element binding protein) signaling pathway. Additionally, metabolomics analysis indicated that blood metabolites, such as C16-ceramide, may contribute to the effects of ketamine in this model. These findings suggest that cisplatin-induced nephrotoxicity in AKI mice contributes to depression-like behaviors, and ketamine can alleviate both kidney damage and depression-like symptoms by modulating the TrkB and ERK-CREB signaling pathways, as well as altering blood metabolites. However, the role of the kidney-brain axis in these depression-like behaviors remains unclear. Furthermore, ketamine may have therapeutic potential for treating kidney diseases such as AKI, along with associated depressive symptoms.

Abstract Obstructed atomic insulator is recently proposed as an unconventional material, in which electric charge centers localized at sites away from the atoms. A half-filling surface state would emerge at specific interfaces cutting through these charge centers and avoid intersecting any atoms. In this article, we utilized photoemission spectroscopy and density functional theory calculations to study one of the obstructed atomic insulator candidates, NiP2. A floating surface state with large effective mass that is close to the Fermi level and isolated from all bulk states is resolved on the (100) cleavage plane, implying better catalytic activity in this plane than the previously studied surfaces. Density functional theory calculation results elucidate that this floating surface state is originated from the obstructed Wannier charge centers, albeit underwent surface reconstruction. Our findings not only shed lights on the study of obstructed atomic insulators, but also provide possible route for development of new catalysts.

The Diospyros genus (Ebenaceae) has significant economic value. During field surveys, we discovered a Diospyros specimen showing morphological overlap with both D. oleifera and D. kaki var. silvestris, provisionally named Diospyros aff. oleifera. To resolve its taxonomy, we sequenced and analyzed its chloroplast genome. The complete chloroplast genome is 157,732 bp with a quadripartite structure. mVISTA analysis revealed unique sequence variations compared to related species. Phylogenetic analysis using 75 protein-coding genes grouped it with D. oleifera, indicating their close relationship. Our findings suggest this specimen likely represents a novel, undescribed species. This study provides insights into Diospyros diversity and a foundation for future research.

Q345B/2205 dissimilar steel multi-layer multi-pass welded joints were prepared using gas metal arc welding (GMAW). The effects of heat inputs on the microstructures and properties of welded joints were studied. The morphology and composition distribution of Q345B base metal near the fusion line were investigated. The results showed that the welded joints under different heat inputs were all present “carbon depleted zone” and “carburized zones” on both sides of the Q345B base metal and transition layer interface. The microstructure of the “carburized zones” was composed of martensite phase and granular bainite phase. It was found that only the welded joints with heat inputs of 1.765 kJ/mm and 2.860 kJ/mm met the usage requirements. The corrosion behavior and characteristics of the welded joint with a heat input of 1.765 kJ/mm in a 3.5 wt % NaCl solution were investigated intensively. During the soaked process of 14 days, the total impedance value of the welded joint showed first increasing and then decreasing. The maximum value of 8.7 kΩ cm2 was obtained on the 5th day. As the soaked time increased, the corrosion products of the welded joint underwent the formation, thickening, cracking and detachment, which was the main reason of the change in the corrosion resistance. The research results of this article have significant implications for the application of low-alloy steel and stainless steel welded joints in engineering.

Gold–Platinum (Au–Pt) alloy demonstrates considerable promise as a material for spacecraft proof mass, due to its ultra-low magnetic susceptibility. This study systematically investigates the effect of heat treatment on the microstructure evolution, magnetic properties, and mechanical performance of the Au72Pt28 alloy. The results indicate that the Pt-rich phase can be precipitated by discontinuous precipitation (DP) and continuous precipitation (CP) reactions. There is a competition between the two precipitation behaviors of Pt-rich phase, which is closely related to their diffusion path. With increasing ageing time and temperature, the discontinuous precipitates gradually coarsen and extend from grain boundaries into grain interior, while the Pt-rich phase nanoparticles precipitated by CP reaction uniformly distribute in the grain interior. Besides, the volume fraction of Pt-rich phase gradually increases, resulting in the increase of magnetic susceptibility. The coarsening of discontinuous precipitates is the main reason for the decrease in the nanoindentation hardness, and it increases rapidly due to a large number of intragranular Pt-rich phase nanoparticles.

The tunable and reversible manufacturing function of stealth metamaterials is of great practical significance to adapt to complex electromagnetic environment. However, the low fault tolerance of existing manufacturing methods limits their further development and utilization. In this article, the microstructure evolution and phase transition mechanism of germanium telluride (GeTe) film under different deposition conditions, laser modes, and scanning parameters were investigated. The experimental results show that sputtering pressure and laser pulse width have important effects on the deposition and modulation of GeTe. There are sputtering pressure threshold (SPT) and pulse width threshold (PWT), which determine the crystallization evolution mode and phase transition performance of GeTe film, respectively. For each sputtering pressure and laser pulse width, there are optimal sputtering power and repetition induction times to achieve the best film deposition quality and reverse phase transition function. Finally, the rewritable broadband lossy absorber (RBLA) is fabricated based on laser induction research, which can achieve low reflection stealth function in the range of 8.4–15.7 GHz. After repeated induction, the performance of RBLA remains the same, which is consistent with simulation results. The process and mechanism of GeTe in the fabrication and modulation stage are systematically analyzed and discussed for the first time, which provides a new solution and good candidate for the fabrication and modulation of stealth materials.

Abstract Ultrahigh-voltage electricity systems are a vital part of energy networks, often across wide regions passing through mountainous terrains. The instability of slopes forming tower foundations along transmission lines poses a large risk to the entire energy network. Moreover, the tower foundations along extra-high-voltage electricity transmission lines are a very special type of element that are also highly vulnerable to landslides. In this study, an integrative risk assessment framework, including a hazard assessment, vulnerability analysis for the specified element at risk, and consequence estimation, is proposed to quantify the direct and indirect risks of landslides to power transmission lines. The Yanzi landslide, where a tower of the major ultrahigh-voltage transmission line from Sichuan (western China) to Shanghai (eastern China) has just been constructed, is taken as a case study. The correlation between landslide displacement and tower structure tilting is studied. In terms of the precipitation return period, factors of safety, failure probability, and deformation are simulated. A physical vulnerability curve is fitted by assuming a Weibull relationship between the horizontal deformation (hazard intensity) of the landslide and the tower inclination ratio. The total risk is calculated as the sum of the direct and indirect losses, among which the potential indirect risk due to tower damage is much greater than the direct risk. This work demonstrates the importance of landslide treatment strategies along electricity transmission lines by considering the potential indirect risks. The risk assessment model of landslides affecting ultrahigh-voltage electricity transmission lines proposed in this study could be useful for other types of indirect landslide risk evaluations.

Abstract Background FLNC gene variants have predominantly been reported in adult populations with cardiomyopathies, and early-onset cases are less common. The genotype–phenotype relationship indicates that dilated cardiomyopathy (DCM) is often associated with FLNC truncating variants. Methods We conducted a comprehensive genetic analysis using next generation sequencing (NGS) to identify FLNC variants in patients with cardiovascular conditions. Detailed phenotypic and variant analyses were performed to characterize the clinical features and genetic alterations. Minigene assays and structural modeling were used to investigate the pathogenicity caused by the identified variants. Results In a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies, respectively. The c.3962A > T variant disrupted normal splicing, as demonstrated through the splicing prediction tool and minigene studies, further emphasizing its pathogenic potential. Conclusion For missense variants of FLNC in patients with DCM, the splicing effect of the variant should be carefully checked. Early detection and intervention are crucial given the high risk of sudden cardiac death and severe cardiac complications.

Abstract Introduction Smoking has been recognized as a contributing factor to frailty in older adults. Nevertheless, it remains uncertain whether the degree of smoking has a discernible impact on frailty among older smokers. This cross-sectional study was conducted to investigate the correlation between serum cotinine levels, a biomarker reflecting tobacco exposure, and the presence of frailty within a nationally representative cohort of older adults. Method A total of 1626 individuals aged ≥ 60 who identified as smokers were included in the analysis. Participants were selected based on self-reported current smoking status. According to the Fried Phenotype, frailty is assessed through five dimensions: unintentional weight loss, slow walking speed, weakness, self-reported exhaustion, and low physical activity. Participants with three or more of these conditions were categorized as frailty, those with at least one but less than three as pre-frailty, and those with none as robust. Multinomial logistic regression models were employed to explore the relationship between serum cotinine level quartiles, with the lowest quartile as the reference group, and the various frailty statuses, with robustness as the reference category. These models were adjusted for covariates, including age, sex, race/ethnicity, alcohol drinking, daily protein intake, systolic blood pressure, serum albumin level, depressive symptoms, and cognitive function. The data used for this analysis were sourced from the National Health and Nutrition Examination Survey for the years 2011 to 2014. Results The median age of the participants was 69.0 years. The majority were male (62.2%) and non-Hispanic White (49.0%). The distribution of frailty statuses among the participants revealed that the highest proportion had pre-frailty (50.7%), followed by robustness (41.1%), and frailty (8.2%). Multinomial logistic regression showed that participants in the 4th quartile of serum cotinine level exhibited a higher probability of pre-frailty versus robustness (Odds ratio [OR] 1.599, 95% confidence interval [CI] 1.017, 2.513, P = 0.042). Participants in the 3rd quartile of serum cotinine level had higher odds of frailty versus robustness (OR 2.403, 95% CI 1.125, 5.134, P = 0.024). Moreover, participants whose serum cotinine levels were higher than the literature cutoffs (≥ 15 ng/ml) were more likely to be pre-frail (Odds ratio [OR] 1.478, 95% confidence interval [CI] 1.017, 2.150, P = 0.035) or frail (Odds ratio [OR] 2.141, 95% confidence interval [CI] 1.054, 4.351, P = 0.041). Conclusions A higher serum cotinine level is linked to an elevated probability of pre-frailty and frailty among older smokers. Initiatives geared towards assisting older smokers in reducing or quitting their smoking habits might possibly play a crucial role in preventing pre-frailty and frailty.

Abstract Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician’s Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control.

Abstract Purpose We aim to thoroughly compare past and current methods that leverage baseline covariate information to estimate the average treatment effect (ATE) using data from of randomized clinical trials (RCTs). We especially focus on their performance, efficiency gain, and power. Methods We compared 6 different methods using extensive Monte-Carlo simulation studies: the unadjusted estimator, i.e., analysis of variance (ANOVA), the analysis of covariance (ANCOVA), the analysis of heterogeneous covariance (ANHECOVA), the inverse probability weighting (IPW), the augmented inverse probability weighting (AIPW), and the overlap weighting (OW) as well as the augmented overlap weighting (AOW) estimators. The performance of these methods is assessed using the relative bias (RB), the root mean square error (RMSE), the model-based standard error (SE) estimation, the coverage probability (CP), and the statistical power. Results Even with a well-executed randomization, adjusting for baseline covariates by an appropriate method can be a good practice. When the outcome model(s) used in a covariate-adjusted method is closer to the correctly specified model(s), the efficiency and power gained can be substantial. We also found that most covariate-adjusted methods can suffer from the high-dimensional curse, i.e., when the number of covariates is relatively high compared to the sample size, they can have poor performance (along with lower efficiency) in estimating ATE. Among the different methods we compared, the OW performs the best overall with smaller RMSEs and smaller model-based SEs, which also result in higher power when the true effect is non-zero. Furthermore, the OW is more robust when dealing with the high-dimensional issue. Conclusion To effectively use covariate adjustment methods, understanding their nature is important for practical investigators. Our study shows that outcome model misspecification and high-dimension are two main burdens in a covariate adjustment method to gain higher efficiency and power. When these factors are appropriately considered, e.g., performing some variable selections if the data dimension is high before adjusting covariate, these methods are expected to be useful.

Abstract Background Blood biomarkers predictive of the progression of idiopathic pulmonary fibrosis (IPF) would be of value for research and clinical practice. We used data from the IPF-PRO Registry to investigate whether the addition of “omics” data to risk prediction models based on demographic and clinical characteristics improved prediction of the progression of IPF. Methods The IPF-PRO Registry enrolled patients with IPF at 46 sites across the US. Patients were followed prospectively. Median follow-up was 27.2 months. Prediction models for disease progression included omics data (proteins and microRNAs [miRNAs]), demographic factors and clinical factors, all assessed at enrollment. Data on proteins and miRNAs were included in the models either as raw values or based on clusters in various combinations. Least absolute shrinkage and selection operator (Lasso) Cox regression was applied for time-to-event composite outcomes and logistic regression with L1 penalty was applied for binary outcomes assessed at 1 year. Model performance was assessed using Harrell’s C-index (for time-to-event outcomes) or area under the curve (for binary outcomes). Results Data were analyzed from 231 patients. The models based on demographic and clinical factors, with or without omics data, were the top-performing models for prediction of all the time-to-event outcomes. Relative changes in average C-index after incorporating omics data into models based on demographic and clinical factors ranged from 1.7 to 3.2%. Of the blood biomarkers, surfactant protein-D, serine protease inhibitor A7 and matrix metalloproteinase-9 (MMP-9) were among the top predictors of the outcomes. For the binary outcomes, models based on demographics alone and models based on demographics plus omics data had similar performances. Of the blood biomarkers, CC motif chemokine 11, vascular cell adhesion protein-1, adiponectin, carcinoembryonic antigen and MMP-9 were the most important predictors of the binary outcomes. Conclusions We identified circulating protein and miRNA biomarkers associated with the progression of IPF. However, the integration of omics data into prediction models that included demographic and clinical factors did not materially improve the performance of the models. Trial registration ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.clinicaltrials.gov .

Abstract Objective Intraoral photographic images are instrumental in the early screening and clinical diagnosis of oral diseases. In addition, people have been trying to apply artificial intelligence to these images. The purpose of this study is to investigate and evaluate a deep learning system designed to segment intraoral photographic images for the detection of dental caries, dental calculus, and gingivitis, and to assess the degree of dental calculus based on the overall features of the tooth surface and gingival margin. Material and methods This cross-sectional study collected 3,365 oral endoscopic images, randomly distributed in training datasets (2,019 images), validation dataset (673 images), and test dataset (673 images). The training set and verification set images are manually labeled. An oral endoscopic image segmentation method based on Mamba (Oral-Mamba) and an intelligent evaluation model of dental calculus degree were proposed, achieving the segmentation of two types of oral diseases, namely gingivitis and dental caries, as well as the segmentation of dental calculus regions, and the intelligent evaluation of the degree of dental calculus. Results Oral-Mamba demonstrated high accuracy in segmentation, with accuracy rates for gingivitis, dental caries, and dental calculus at 0.83, 0.83, and 0.81, respectively. In particular, these rates surpassed those of the U-Net model in IoU, accuracy, and recall metrics. Furthermore, Oral-Mamba runs 25% faster than U-Net.The accuracy of degree classification in the intelligent evaluation model of dental calculus degree is 85%. Conclusion The proposed deep learning system is expected to be used for the detection of two types of oral diseases and dental calculus, and the degree judgment of photographic images from an intraoral camera. This system offers a practical method to assist in the oral screening of dental caries, dental calculus, and gingivitis, providing benefits such as intuitive use, time efficiency, cost-effectiveness, and ease of deployment.

Abstract How the lung achieves immune homeostasis after a pulmonary infection is not fully understood. Here, we analyzed the spatiotemporal changes in the lungs over a 2-week natural recovery from severe pneumonia in a Syrian hamster model of SARS-CoV-2 infection. We find that SARS-CoV-2 infects multiple cell types and causes massive cell death at the early stage, including alveolar macrophages. We identify a group of monocyte-derived Slamf9 + macrophages, which are induced after SARS-CoV-2 infection and resistant to impairment caused by SARS-CoV-2. Slamf9 + macrophages contain SARS-CoV-2, recruit and interact with Isg12 + Cst7 + neutrophils to clear the viruses. After viral clearance, Slamf9 + macrophages differentiate into Trem2 + and Fbp1 + macrophages, contributing to inflammation resolution at the late stage, and finally replenish alveolar macrophages. These findings are validated in a SARS-CoV-2-infected hACE2 mouse model and confirmed with publicly available human autopsy single-cell RNA-seq data, demonstrating the potential role of Slamf9 + macrophages and their coordination with neutrophils in post-injury tissue repair and inflammation resolution.

Abstract How immune cells are spatiotemporally coordinated in the lung to effectively monitor, respond to, and resolve infection and inflammation in primed form needs to be fully illustrated. Here we apply immunocartography, a high-resolution technique that integrates spatial and single-cell RNA sequencing (scRNA-seq) through deconvolution and co-localization analyses, to the SARS-CoV-2-infected Syrian hamster model. We generate a comprehensive transcriptome map of the whole process of pulmonary infection from physiological condition, infection initiation, severe pneumonia to natural recovery at organ scale and single-cell resolution, with 142,965 cells and 45 lung lobes from 25 hamsters at 5 time points. Integrative analysis identifies that alveolar dendritic cell–T cell immunity hubs, where Ccr7 + Ido1 + dendritic cells, Cd160 + Cd8 + T cells, and Tnfrsf4 + Cd4 + T cells physiologically co-localize, rapidly expand during SARS-CoV-2 infection, eliminate SARS-CoV-2 with the aid of Slamf9 + macrophages, and then restore to physiological levels after viral clearance. We verify the presence of these cell subpopulations in the immunity hubs in normal and SARS-CoV-2-infected hACE2 mouse models, as well as in publicly available human scRNA-seq datasets, demonstrating the potential broad relevance of our findings in lung immunity.

Abstract Background Polycystic ovary syndrome (PCOS) affects 6–20% of women worldwide, with insulin resistance and hyperinsulinemia occurring in 50-70% of patients. Hyperinsulinemia exacerbates oxidative stress, contributing to PCOS pathogenesis. N-acetylcysteine (NAC) is an antioxidant and insulin sensitizer that shows promise as a therapeutic for PCOS. Our current study aimed to investigate the effects of NAC supplementation on endocrine-metabolic parameters in PCOS mice and its effect on ovulation induction (OI) efficacy in women with PCOS. Methods Female C57BL/6 mice were orally administered letrozole (LE) to induce PCOS and then randomly divided into groups receiving daily oral administration of 160 mg/kg NAC (PCOS + NAC group), 200 mg/kg metformin (PCOS + Met group), or 0.5% carboxymethyl cellulose (drug solvent) (pure PCOS group) for 12 days. Healthy female mice served as pure controls. Estrous cycles were monitored during the intervention. Metabolic and hormone levels, ovarian phenotypes, antioxidant activity in ovarian tissues, and oxidative stress levels in oocytes were assessed post-intervention. Furthermore, a pragmatic, randomized, controlled clinical study was conducted with 230 PCOS women, randomly assigned to the NAC group (1.8 g/day oral NAC, n = 115) or the control group (n = 115). Patients in both groups underwent ≤ 3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups. Results Similar to metformin, NAC supplementation significantly improved the estrous cycles and ovarian phenotypes of PCOS mice; reduced the LH concentration, LH/FSH ratio, and T level; and increased glucose clearance and insulin sensitivity. Notably, NAC significantly reduced oocyte ROS levels and increased the mitochondrial membrane potential in PCOS mice. Additionally, NAC significantly enhanced enzymatic and nonenzymatic antioxidant activities in PCOS mouse ovaries, whereas metformin had no such effect. In the clinical trial, compared to women in the control group, women receiving NAC had significantly lower average uFSH dosage and duration (p

Abstract The prevalence of human Demodex mites has surged in recent years, prompting significant concern among both patients and the medical community. This study aimed to investigate the survival duration and morphological alterations of Demodex folliculorum under diverse temperature conditions and in various culture media. We employed the eyelash sampling technique to procure the mites. The collected specimens were then subjected to culture at two distinct temperature ranges (16–22 °C and 4 °C) across a spectrum of media, including 30% tea tree oil (TTO), phosphate-buffered saline (PBS), pure water, 0.9% physiological saline, 5 µg/ml propidium iodide (PI), liquid paraffin, glycerol, and a blank culture medium. Post-administration, the mites’ activity and morphological changes were meticulously documented. Our findings indicate that the survival span of Demodex mites within the same medium was notably extended at 4 °C compared to room temperature. Specifically, under 4 °C, the use of liquid paraffin as a culture medium yielded the longest survival time of 12 days, surpassing all other conditions. Remarkably, the morphological integrity of the mites in this group remained largely unaltered. These results suggest that 4 °C is the optimal temperature for the in vitro cultivation of Demodex mites, offering insights into the environmental preferences of these organisms and potentially informing future therapeutic strategies.

Abstract Pathogens detection is a crucial measure in the prevention of foodborne diseases. This study developed a novel multicolor colorimetric assay to visually detect Salmonella Typhimurium (S. Typhimurium), by utilizing the etching process of gold nanorods (AuNRs) with TMB2+. The strategy involved the construction of nanozyme by assembling magnetic covalent organic framework (MCOF) with aptamer-conjugated AuNPs (Apt-AuNPs), exhibiting remarkable peroxidase-like activity to catalyze the oxidation of TMB/H2O2 and inducing the etching of AuNRs. The presence of S. Typhimurium could inhibit this process, resulting in the generation of vivid colors. The multicolor colorimetric assay could specifically determine S. Typhimurium from 102 to 108 CFU mL−1 in 60 min with visual detection limit of 102 CFU mL−1, and instrumental detection limit of 2.3 CFU mL−1. Moreover, detecting S. Typhimurium in chicken, milk, pork and lettuce samples has shown promise in practical applications.

Solanum pseudocapsicum Linnaeus 1753, a popular indoor potted plant known for its ornamental fruits, had its chloroplast genome sequenced in this study to determine its phylogenetic relationship with other related species and to construct a phylogenetic analysis tree. The research findings are as follows: 1. The chloroplast genome of S. pseudocapsicum comprises a large single-copy (LSC) region of 86,260 base pairs, a small single-copy (SSC) region of 18,325 base pairs, and two inverted repeat (IR) regions, each measuring 25,390 base pairs in length. 2. The G + C content of the entire chloroplast genome is 37.59%, with the highest G + C content found in the IR regions, reaching 43.03%; followed by the LSC region, which has a G + C content of 35.68%; and the lowest in the SSC region, with a G + C content of 31.53%. 3. The genome contains 127 genes, including 82 protein-coding genes, 37 tRNA genes, and 8 rRNA genes, with 18 genes duplicated in the IR regions. 4. Phylogenetic analysis revealed that S. pseudocapsicum, Solanum betaceum, Solanum laciniatum, and Solanum nitidum are genetically closely related and are located on the same branch of the phylogenetic tree, indicating a close relationship among them. This study provides a foundation for the identification, classification, and exploration of genetic diversity within the Solanum genus.

Integrated multi-trophic aquaculture has attracted widespread attention and is considered an effective way to purify the water environment and improve the sustainability of aquaculture. However, the biodeposition produced by large-scale, high-density raft-type shellfish and seaweed aquaculture activities has been shown to be the main reason for the enrichment of organic matter in sediments. Organic matter enrichment changes the biogeochemistry of sediment, which is the main reason for hypoxia in the benthic environment. Especially in the summer, water column stratification in terms of water and salinity can lead to hypoxia in the benthic environment. Besides, the hypoxic conditions in sediment promote anaerobic metabolism and sulfate reduction, which increase the dissolved sulfide concentration in the interstitial water. It was reported that dissolved oxygen (DO) in the sediment is depleted within a range of a few millimeters to a few centimeters in surface sediments. The diffusion boundary layer (DBL), which generally varies between a tenth of a millimeter and a few millimeters above the sediment, greatly influences substance exchange across the sediment-water interface. Current studies on the environmental effect of aquaculture mainly focus on the influence of aquaculture activities on the environment, and the influence mechanism of aquaculture activities on the sediment microenvironment remains unknown. Therefore, it is necessary to study the influence of aquaculture activities on the sediment microenvironment and to explore the influence mechanism of aquaculture activities on the distribution of physical and chemical factors in the sediment microenvironment.In this study, microscale variations in the distribution and consumption of oxygen at the sediment-water interface under high temperature conditions was investigated in the summer of 2022 in Sanggou Bay, a typical integrated multi-trophic aquaculture area in northern China. A high-resolution microelectrode system was used to investigate the profile distributions of DO, hydrogen sulfide (H2S), and pH in sediments with a spatial resolution of 1 mm collected from the shellfish monoculture area (SF), shellfish and seaweed polyculture area (SF-SW), seaweed monoculture area (SW), and offshore area (OF). The thickness of the DBL of different aquaculture areas was determined according to the DO distribution at the sediment-water interface and the inflection point of the profile distribution. Sediment cores were sliced at a thickness of 1 cm and the profile distribution of sediment organic carbon, the median grain size, and other factors in the surface sediment in different aquaculture areas were measured. The diffusive oxygen flux at the water-sediment interface was calculated from the gradient of the DO concentration in the DBL, and the sediment oxygen consumption rate in different aquaculture areas was calculated from the DO profile distribution in the sediment.The results showed that the mean thickness of the DBL in the SF, SF-SW, SW, and OF areas were (1.5±0.3), (1.0±0.3), (2.0±0.8), and (1.3±0.2) mm, respectively; there was no significant difference between different aquaculture areas. The mean sediment oxygen penetration depth (OPD) was (12.49±1.59), (12.17±0.09), (15.49±0.79), and (14.87±1.27) mm, respectively. The sediment OPDs in the SF-SW and SF areas were significantly lower than those in the SW and OF areas. The maximum concentrations of H2S were (5.73±0.04), (4.80±0.08), (3.30±0.19), and (3.97±0.38) μmol/L, respectively. The mean diffusive oxygen flux in the SF, SF-SW, SW, and OF areas were (24.10±1.89), (49.53±10.24), (26.69±13.13), and (24.79±7.95) mmol/(m2·d), respectively. The diffusive oxygen flux in the shellfish and kelp polyculture area was significantly higher than that in other areas. The diffusive oxygen flux at the sediment-water interface was affected by the DO concentration of the overlying water and the sediment oxygen consumption rate. The diffusive oxygen flux in the SF area was influenced by the thickness of the DBL, the DO concentration of the overlying water, and the DO concentration at the sediment-water interface. The main factor influencing the diffusive oxygen flux in the SW and SF-SW areas was the DO concentration of the overlying water.In conclusion, the biodeposition produced by aquaculture activities significantly affects material cycling in surface sediments, which promotes sediment oxygen consumption and the production of hydrogen sulfide. The influence of biodeposition produced by shellfish farming on the sediment chemical characteristics and microprofiles may be stronger than that of kelp debris. The DO concentration of the water environment is the main reason affecting organic matter mineralization in the sediments of aquaculture areas. This study also provides scientific and technological support for an in-depth understanding of the influence of aquaculture on the sediment microenvironment and the benthic carbon cycle.

Abstract Being a respiratory climacteric fruit, kiwifruit is susceptible to age and decay rapidly in the postharvest stage. Therefore, the development of efficient postharvest methods to maintain the kiwifruit quality has been a long‐standing goal. This review summarizes the preservation and disease control methods of kiwifruit conducted over the past 5 years, and the characteristics, advantages, and action mechanisms of various methods are thoroughly discussed. Physical, chemical, and biotechnological methods, such as low‐temperature, essential oil, and endophytic yeast treatment, can enhance postharvest kiwifruit quality to a certain extent by controlling disease, delaying chilling injury, alleviating oxidative damage, inhibiting oversoftening and off‐flavor development. However, all these techniques have limitations per se, such as the inability to prevent secondary infections and potential side effects on human health. Novel approaches such as pulsed light and cold plasma or a synergistic application of several techniques may be the future direction for kiwifruit postharvest preservation.

Background: Exploring and identifying novel alleles of noncombined DNA Index System (CODIS) short tandem repeat (STR) loci in different ethnic groups is important for the establishment of forensic reference databases and study of population genetics. AIM: This study is aimed to explore the genetic polymorphism of 22 non-CODIS autosomal STR loci (D6S477, D18S535, D19S253, D15S659, D11S2368, D20S470, D1S1656, D22-GATA198B05, D8S1132, D4S2366, D21S1270, D13S325, D9S925, D3S3045, D14S608, D10S1435, D12S391, D7S3048, D17S1290, D5S2500, D2S1338, and D16S539) in Sierra Leone population and analyze the population genetic relationships in comparison with other populations. MATERIALS AND METHODS: The samples of a total of 495 unrelated individuals (274 females and 221 males) from Sierra Leone were examined by the Microreader™ 23SP ID System, and their genetic polymorphisms and associated forensic parameters were calculated. The genetic relationships between Sierra Leone population and other populations were evaluated as well. Results: A total of 287 alleles were observed with allelic frequencies ranging from 0.001 to 0.399. The cumulative power of discrimination (CPD) of the 22 autosomal STR loci was 0.999999999999999 99999999999999538. The cumulative probability of exclusion (CPE) of the 22 autosomal STR loci was 0.9999998514 (CPEdous) and 0.999999 9999826 (CPEtrios). All of the STR loci reached the Hardy–Weinberg equilibrium after Bonferroni correction. The population genetics analysis results demonstrated that Sierra Leone population exhibited distinctive genetic characteristics compared to those of East Asian populations and it had relatively close genetic distances to the Uygur population. Conclusion: The results of this study could enrich the forensic databases with Sierra Leone population. The 22 STR loci are highly polymorphic and could be used for forensic practice and population genetics studies.

Abstract Background Structural variations (SVs) are key genetic contributors to neurodevelopmental disorders (NDDs). Exome sequencing (ES), the current first-line tool for genetic testing of NDDs, falls short in SVs detection. This diagnostic gap is being actively addressed by new methods such as optical genome mapping (OGM). Methods This study evaluated the utility of combining OGM and RNA-seq in the detection and interpretation of SVs in ES-negative NDDs. OGM was performed in 43 patients with NDDs with inconclusive ES results. Candidate SVs were selected based on disease association and pathogenicity evaluation, and further validated or reconstructed by alternative methods, including long-read sequencing for a complex rearrangement event. RNA-Seq was performed on blood samples from patients with candidate SVs to facilitate interpretation of pathogenicity. Results OGM detected four candidate SVs, and RNA-seq confirmed the pathogenicity of three SVs in the patient cohort. This combined approach solved three cases—two cases with de novo SVs in genes associated with autosomal dominant NDDs, including a deletion encompassing the promoter and 5′UTR of MBD5 and an intragenic duplication of PAFAH1B1, and a third case possessing an intragenic duplication in trans with a pathogenic single-nucleotide variant of PLA2G6, associated with autosomal recessive NDDs. The expression alteration of the affected genes and the tandem positioning of two intragenic duplications were confirmed by RNA-seq. In the fourth case, OGM detected a complex rearrangement involving chromosomes 2 and 6, much more complex than the de novo t(2:6)(q13;q15) indicated by conventional cytogenetic analysis. Reconstruction showed that 17 segments of 6q15 spanning 9.3 Mb were disarranged and joined 2q11.2, with four breakpoints detected in the 5′ and 3′ non-coding region of the NDD-associated gene SYNCRIP. RNA-seq revealed largely preserved SYNCRIP expression, leaving the pathogenicity of this complex rearrangement event uncertain. Conclusions SVs in ES-negative NDDs can be identified by OGM, which is particularly useful for SVs in non-coding regions not covered by ES. OGM helps to construct complex SVs and provides information on the location and orientation of duplications, which is crucial for pathogenicity interpretation. The integration of RNA-seq facilitates the interpretation of the functional consequences of SVs at the transcriptional level. These findings demonstrate the utility and feasibility of combining OGM and RNA-seq in ES-negative cases with NDDs.

Abstract Background Relapsed and refractory acute myeloid leukemia (AML) carries a dismal prognosis. CAR T cells have shown limited efficacy in AML, partially due to dysfunctional autologous T cells and the extended time for generation of patient specific CAR T cells. Allogeneic NK cell therapy is a promising alternative, but strategies to enhance efficacy and persistence may be necessary. Proteasome inhibitors (PI) induce changes in the surface proteome which may render malignant cells more vulnerable to NK mediated cytotoxicity. Here, we investigated the potential benefit of combining PIs with CAR-expressing allogeneic NK cells against AML. Methods We established the IC50 concentrations for Bortezomib and Carfilzomib against several AML cell lines. Surface expression of class-I HLA molecules and stress-associated proteins upon treatment with proteasome inhibitors was determined by multiparameter flow cytometry. Using functional in vitro assays, we explored the therapeutic synergy between pre-treatment with PIs and the anti-leukemic efficacy of NK cells with or without expression of AML-specific CAR constructs against AML cell lines and primary patient samples. Also, we investigated the tolerability and efficacy of a single PI application strategy followed by (CAR-) NK cell infusion in two different murine xenograft models of AML. Results AML cell lines and primary AML patient samples were susceptible to Bortezomib and Carfilzomib mediated cytotoxicity. Conditioned resistance to Azacitidine/Venetoclax did not confer primary resistance to PIs. Treating AML cells with PIs reduced the surface expression of class-I HLA molecules on AML cells in a time-and-dose dependent manner. Stress-associated proteins were upregulated on the transcriptional level and on the cell surface. NK cell mediated killing of AML cells was enhanced in a synergistic manner. PI pre-treatment increased effector-target cell conjugate formation and Interferon-γ secretion, resulting in enhanced NK cell activity against AML cell lines and primary samples in vitro. Expression of CD33- and CD70-specific CARs further improved the antileukemic efficacy. In vivo, Bortezomib pre-treatment followed by CAR-NK cell infusion reduced AML growth, leading to prolonged overall survival. Conclusions PIs enhance the anti-leukemic efficacy of CAR-expressing allogeneic NK cells against AML in vitro and in vivo, warranting further exploration of this combinatorial treatment within early phase clinical trials.

Abstract The various mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pose a substantial challenge in mitigating the viral infectivity. The identification of novel host factors influencing SARS-CoV-2 replication holds potential for discovering new targets for broad-spectrum antiviral drugs that can combat future viral mutations. In this study, potential host factors regulated by SARS-CoV-2 infection were screened through different high-throughput sequencing techniques and further identified in cells. Subsequent analysis and experiments showed that the reduction of m6A modification level on ACTN4 (Alpha-actinin-4) mRNA leads to a decrease in mRNA stability and translation efficiency, ultimately inhibiting ACTN4 expression. In addition, ACTN4 was demonstrated to target nsp12 for binding and characterized as a competitor for SARS-CoV-2 RNA and the RNA-dependent RNA polymerase complex, thereby impeding viral replication. Furthermore, two ACTN4 agonists, YS-49 and demethyl-coclaurine, were found to dose-dependently inhibit SARS-CoV-2 infection in both Huh7 cells and K18-hACE2 transgenic mice. Collectively, this study unveils the pivotal role of ACTN4 in SARS-CoV-2 infection, offering novel insights into the intricate interplay between the virus and host cells, and reveals two potential candidates for future anti-SARS-CoV-2 drug development.

Abstract The spalt (Sal) gene family has four members (Sall1-4) in vertebrates, all of which play pivotal roles in various biological processes and diseases. However, the expression and function of SALL2 in development are still less clear. Here, we first charted SALL2 protein expression pattern during mouse embryo development by immunofluorescence, which revealed its dominant expression in the developing nervous system. With the establishment of Sall2 deficient mouse embryonic stem cells (ESCs), the in vitro neural differentiation system was leveraged to interrogate the function of SALL2, which showed impaired neural differentiation of Sall2 knockout (KO) ESCs. Furthermore, neural stem cells (NSCs) could not be derived from Sall2 KO ESCs and the generation of neural tube organoids (NTOs) was greatly inhibited in the absence of SALL2. Meanwhile, transgenic expression of E1 isoform of SALL2 restored the defects of neural differentiation in Sall2 KO ESCs. By chromatin immunoprecipitation sequencing (ChIP-seq), Tuba1a was identified as downstream target of SALL2, whose function in neural differentiation was confirmed by rescuing neural phenotypes of Sall2 KO ESCs when overexpressed. In sum, by elucidating SALL2 expression dynamics during early mouse development and mechanistically characterizing its indispensable role in neural differentiation, this study offers insights into SALL2’s function in human nervous system development, associated pathologies stemming from its mutations and relevant therapeutic strategy.

Abstract Antimicrobial resistance (AMR) is one of the major challenges humans are facing this century. Understanding the mechanisms behind the rise of AMR is therefore crucial to tackling this global threat. The presence of transition metals is one of the growth-limiting factors for both environmental and pathogenic bacteria, and the mechanisms that bacteria use to adapt to and survive under transition metal toxicity resemble those correlated with the rise of AMR. A deeper understanding of transition metal toxicity and its potential as an antimicrobial agent will expand our knowledge of AMR and assist the development of therapeutic strategies. In this study, we investigate the antimicrobial effect of two transition metal ions, namely cobalt (Co2+) and nickel (Ni2+), on the non-tuberculous environmental mycobacterium and the opportunistic human pathogen Mycobacterium abscessus. The minimum inhibitory concentrations of Co2+ and Ni2+ on M. abscessus were first quantified and their impact on the bacterial intracellular metallome was investigated. A multi-omics strategy that combines transcriptomics, bioenergetics, metabolomics, and phenotypic assays was designed to further investigate the mechanisms behind the effects of transition metals. We show that transition metals induced growth defect and changes in transcriptome and carbon metabolism in M. abscessus, while the induction of the glyoxylate shunt and the WhiB7 regulon in response to metal stresses could be the key response that led to higher AMR levels. Meanwhile, transition metal treatment alters the bacterial response to clinically relevant antibiotics and enhances the uptake of clarithromycin into bacterial cells, leading to increased efficacy. This work provides insights into the tolerance mechanisms of M. abscessus to transition metal toxicity and demonstrates the possibility of using transition metals to adjuvant the efficacy of currently using antimicrobials against M. abscessus infections.

Abstract Background Metabolic reprogramming plays a pivotal role in tumorigenesis and development of lung adenocarcinoma (LUAD). However, the precise mechanisms and potential targets for metabolic reprogramming in LUAD remain elusive. Our prior investigations revealed that the mitochondrial ribosomal protein MRPL12, identified as a novel mitochondrial transcriptional regulatory gene, exerts a critical influence on mitochondrial metabolism. Despite this, the role and regulatory mechanisms underlying MRPL12’s transcriptional activity in cancers remain unexplored. Methods Human LUAD tissues, Tp53 fl/fl ;Kras G12D -driven LUAD mouse models, LUAD patient-derived organoids (PDO), and LUAD cell lines were used to explored the expression and function of MRPL12. The posttranslational modification of MRPL12 was analyzed by mass spectrometry, and the oncogenic role of key phosphorylation sites of MRPL12 in LUAD development was verified in vivo and in vitro. Results MRPL12 was upregulated in human LUAD tissues, Tp53 fl/fl ;Kras G12D -driven LUAD tissues in mice, LUAD PDO, and LUAD cell lines, correlating with poor patient survival. Overexpression of MRPL12 significantly promoted LUAD tumorigenesis, metastasis, and PDO formation, while MRPL12 knockdown elicited the opposite phenotype. Additionally, MRPL12 deletion in a Tp53 fl/fl ;Kras G12D -driven mouse LUAD model conferred a notable survival advantage, delaying tumor onset and reducing malignant progression. Mechanistically, we discovered that MRPL12 promotes tumor progression by upregulating mitochondrial oxidative phosphorylation. Furthermore, we identified UBASH3B as a specific binder of MRPL12, dephosphorylating tyrosine 60 in MRPL12 (MRPL12 Y60) and inhibiting its oncogenic functions. The decrease in MRPL12 Y60 phosphorylation impeded the binding of MRPL12 to POLRMT, downregulating mitochondrial metabolism in LUAD cells. In-depth in vivo, in vitro, and organoid models validated the inhibitory effect of MRPL12 Y60 mutation on LUAD. Conclusion This study establishes MRPL12 as a novel oncogene in LUAD, contributing to LUAD pathogenesis by orchestrating mitochondrial metabolism reprogramming towards oxidative phosphorylation (OXPHOS). Furthermore, it confirms Y60 as a specific phosphorylation modification site regulating MRPL12’s oncogenic functions, offering insights for the development of LUAD-specific targeted drugs and clinical interventions. Graphical Abstract

Abstract Background To assess the characteristics of patients enrolled in the ILD-PRO Registry. Methods The ILD-PRO Registry is a multicentre US registry of patients with progressive pulmonary fibrosis. This registry is enrolling patients with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis who have reticular abnormality and traction bronchiectasis on HRCT, and who meet criteria for ILD progression within the prior 24 months. Patient characteristics were analysed based on the number of patients with available data. Results Of the first 491 patients enrolled, the majority were white (75.4%) and female (60.6%); 47.4% had a history of smoking. Reported ILDs were autoimmune disease-associated ILDs (47.2%), hypersensitivity pneumonitis (17.5%), idiopathic non-specific interstitial pneumonia (9.1%), interstitial pneumonia with autoimmune features (8.9%), unclassifiable ILD (7.6%), other ILDs (9.7%). At enrolment, median (Q1, Q3) FVC % predicted was 62.2 (49.4, 72.4) and DLco % predicted was 39.2 (30.2, 49.2). Median (Q1, Q3) total score on the St. George’s Respiratory Questionnaire was 50.8 (35.9, 64.7). The most common comorbidities were gastroesophageal reflux disease (61.1%) and sleep apnoea (29.6%). Overall, 64.5% of patients were receiving immunosuppressive or cytotoxic therapy, 61.1% proton-pump inhibitors, 53.2% oral steroids, 19.8% nintedanib and 3.6% pirfenidone. Conclusions Patients enrolled into the ILD-PRO Registry have a variety of ILD diagnoses, marked impairment in lung function and health-related quality of life, and high medication use. Longitudinal data from this registry will further our knowledge of the course of progressive pulmonary fibrosis. Trial Registration ClinicalTrials.gov, NCT01915511; registered August 5, 2013.

Abstract The study aims to investigate the potential of training efficient deep learning models by using 2.5D (2.5-Dimension) masks of sICH. Furthermore, it intends to evaluate and compare the predictive performance of a joint model incorporating four types of features with standalone 2.5D deep learning, radiomics, radiology, and clinical models for early expansion in sICH. A total of 254 sICH patients were enrolled retrospectively and divided into two groups according to whether the hematoma was enlarged or not. The 2.5D mask of sICH is constructed with the maximum axial, coronal and sagittal planes of the hematoma, which is used to train the deep learning model and extract deep learning features. Predictive models were built on clinic, radiology, radiomics and deep learning features separately and four type features jointly. The diagnostic performance of each model was measured using the receiver operating characteristic curve (AUC), Accuracy, Recall, F1 and decision curve analysis (DCA). The AUCs of the clinic model, radiology model, radiomics model, deep learning model, joint model, and nomogram model on the train set (training and Cross-validation) were 0.639, 0.682, 0.859, 0.807, 0.939, and 0.942, respectively, while the AUCs on the test set (external validation) were 0.680, 0.758, 0.802, 0.857, 0.929, and 0.926. Decision curve analysis showed that the joint model was superior to the other models and demonstrated good consistency between the predicted probability of early hematoma expansion and the actual occurrence probability. Our study demonstrates that the joint model is a more efficient and robust prediction model, as verified by multicenter data. This finding highlights the potential clinical utility of a multifactorial prediction model that integrates various data sources for prognostication in patients with intracerebral hemorrhage. The Critical Relevance Statement: Combining 2.5D deep learning features with clinic features, radiology markers, and radiomics signatures to establish a joint model enabling physicians to conduct better-individualized assessments the risk of early expansion of sICH.

Abstract Necroptosis is intimately associated with the initiation and progression of colon adenocarcinoma (COAD). However, studies on necroptosis-related genes (NRGs) and the regulating long non-coding RNAs (NRGlncRNAs) in the context of COAD are limited. We retrieved the cancer genome atlas (TCGA) to collect datasets of NRGs and NRGlncRNAs on COAD patients. The risk model constructed using Cox and least absolute shrinkage and selection operator (LASSO) regression was then employed to identify NRGs and NRGlncRNAs with prognostic significance. Subsequently, we validated the results using gene expression omnibus (GEO) datasets from different populations, conducted Mendelian randomization (MR) analysis to explore the potential causal relationships between prognostic NRGs and COAD, and conducted cell experiments to verify the expression of prognostic NRGlncRNAs in COAD. Furthermore, we explored potential pathways and regulatory mechanisms of these prognostic NRGlncRNAs and NRGs in COAD through enrichment analysis, immune cell correlation analysis, tumor microenvironment analysis, immune checkpoint analysis, tumor sample clustering, and so on. We identified eight NRGlncRNAs (AC245100.5, AP001619.1, LINC01614, AC010463.3, AL162595.1, ITGB1-DT, LINC01857, and LINC00513) used for constructing the prognostic model and nine prognostic NRGs (AXL, BACH2, CFLAR, CYLD, IPMK, MAP3K7, ATRX, BRAF, and OTULIN) with regulatory relationships with them, and their validation was performed using GEO and GWAS datasets, as well as cell experiments, which showed largely consistent results. These prognostic NRGlncRNAs and NRGs modulate various biological functions, including immune inflammatory response, oxidative stress, immune escape, telomere regulation, and cytokine response, influencing the development of COAD. Additionally, stratified analysis of the high-risk and low-risk groups based on the prognostic model revealed elevated expression of immune cells, increased expression of tumor microenvironment cells, and upregulation of immune checkpoint gene expression in the high-risk group. Finally, through cluster analysis, we identified tumor subtypes, and the results of cluster analysis were essentially consistent with the analysis between risk groups. The prognostic NGRlncRNAs and NRGs identified in our study serve as prognostic indicators and potential therapeutic targets for COAD, providing a theoretical basis for the clinical diagnosis and treatment of COAD and offering guidance for further research.

Abstract The CRISPR-Cas12a system has revolutionized nucleic acid testing (NAT) with its rapid and precise capabilities, yet it traditionally required RNA pre-amplification. Here we develop rapid fluorescence and lateral flow NAT assays utilizing a split Cas12a system (SCas12a), consisting of a Cas12a enzyme and a split crRNA. The SCas12a assay enables highly sensitive, amplification-free, and multiplexed detection of miRNAs and long RNAs without complex secondary structures. It can differentiate between mature miRNA and its precursor (pre-miRNA), a critical distinction for precise biomarker identification and cancer progression monitoring. The system’s specificity is further highlighted by its ability to detect DNA and miRNA point mutations. Notably, the SCas12a system can quantify the miR-21 biomarker in plasma from cervical cancer patients and, when combined with RPA, detect HPV at attomole levels in clinical samples. Together, our work presents a simple and cost-effective SCas12a-based NAT platform for various diagnostic settings.

Abstract RNA-binding proteins (RBPs) modulate all aspects of RNA metabolism, but a comprehensive picture of RBP expression across tissues is lacking. Here, we describe our development of the method we call HARD-AP that robustly retrieves RBPs and tightly associated RNA regulatory complexes from cultured cells and fresh tissues. We successfully use HARD-AP to establish a comprehensive atlas of RBPs across mouse primary organs. We then systematically map RNA-binding sites of these RBPs using machine learning-based modeling. Notably, the modeling reveals that the LIM domain as an RNA-binding domain in many RBPs. We validate the LIM-domain-only protein Csrp1 as a tissue-dependent RNA binding protein. Taken together, HARD-AP is a powerful approach that can be used to identify RBPomes from any type of sample, allowing comprehensive and physiologically relevant networks of RNA-protein interactions.

In the era of antiretroviral therapy (ART), mortality among people living with the human immunodeficiency virus (HIV) has significantly decreased, yet the population of people living with HIV remains substantial. Among people living with HIV (PLWH), HIV-associated lymphoma (HAL) has surpassed Kaposi’s sarcoma to become the most common tumor in this population in developed countries. However, there remains a dearth of comprehensive and systematic understanding regarding HIV-associated lymphomas. This review aims to shed light on the changes in the immune system among PLWH and the characteristics of the immune microenvironment in HIV-associated lymphoma, with a specific focus on the immune system’s role in these individuals. Additionally, it seeks to explore recent advancements in immunotherapy for the treatment of HIV-associated lymphoma, intending to enhance strategies for immunotherapy in this specific population.

Abstract The wide‐angle electromagnetic scattering problems can be rapidly solved by using the method of moments in conjunction with compressive sensing theory. The method mainly has two computational parts: measurement and recovery. To further enhance the performance, an improved orthogonal matching pursuit algorithm with a randomised atom selection process is proposed, significantly reducing the computational complexity of the recovery part. Additionally, a restart mechanism is designed to eliminate possible errors that might occur during the random process, ensuring the accuracy of recovery results. Numerical experiments with objects of different shapes validate the effectiveness and efficiency of the proposed scheme.

The escalating challenges in water treatment, exacerbated by climate change, have catalyzed the emergence of innovative solutions. Novel adsorption separation and membrane filtration methodologies, achieved through molecular structure manipulation, are gaining traction in the environmental and energy sectors. Separation technologies, integral to both the chemical industry and everyday life, encompass concentration and purification processes. Macrocycles, recognized as porous materials, have been prevalent in water treatment due to their inherent benefits: stability, adaptability, and facile modification. These structures typically exhibit high selectivity and reversibility for specific ions or molecules, enhancing their efficacy in water purification processes. The progression of purification methods utilizing macrocyclic frameworks holds promise for improved adsorption separations, membrane filtrations, resource utilization, and broader water treatment applications. This review encapsulates the latest breakthroughs in macrocyclic host-guest chemistry, with a focus on adsorptive and membrane separations. The aim is to spotlight strategies for optimizing macrocycle designs and their subsequent implementation in environmental and energy endeavors, including desalination, elemental extraction, seawater energy harnessing, and sustainable extraction. Hopefully, this review can guide the design and functionality of macrocycles, offering a significantly promising pathway for pollutant removal and resource utilization.

Abstract Background Black spot disease in tree peony caused by the fungal necrotroph A. alternata, is a primary limiting factor in the production of the tree peony. The intricate molecular mechanisms underlying the tree peony resistance to A. alternata have not been thoroughly investigated. Results The present study utilized high-throughput RNA sequencing (RNA-seq) technology to conduct global expression profiling, revealing an intricate network of genes implicated in the interaction between tree peony and A. alternata. RNA-Seq libraries were constructed from leaf samples and high-throughput sequenced using the BGISEQ-500 sequencing platform. Six distinct libraries were characterized. M1, M2 and M3 were derived from leaves that had undergone mock inoculation, while I1, I2 and I3 originated from leaves that had been inoculated with the pathogen. A range of 10.22–11.80 gigabases (Gb) of clean bases were generated, comprising 68,131,232 − 78,633,602 clean bases and 56,677 − 68,996 Unigenes. A grand total of 99,721 Unigenes were acquired, boasting a mean length of 1,266 base pairs. All these 99,721 Unigenes were annotated in various databases, including NR (Non-Redundant, 61.99%), NT (Nucleotide, 45.50%), SwissProt (46.32%), KEGG (Kyoto Encyclopedia of Genes and Genomes, 49.33%), KOG (clusters of euKaryotic Orthologous Groups, 50.18%), Pfam (Protein family, 47.16%), and GO (Gene Ontology, 34.86%). In total, 66,641 (66.83%) Unigenes had matches in at least one database. By conducting a comparative transcriptome analysis of the mock- and A. alternata-infected sample libraries, we found differentially expressed genes (DEGs) that are related to phytohormone signalling, pathogen recognition, active oxygen generation, and circadian rhythm regulation. Furthermore, multiple different kinds of transcription factors were identified. The expression levels of 10 selected genes were validated employing qRT-PCR (quantitative real-time PCR) to confirm RNA-Seq data. Conclusions A multitude of transcriptome sequences have been generated, thus offering a valuable genetic repository for further scholarly exploration on the immune mechanisms underlying the tree peony infected by A. alternata. While the expression of most DEGs increased, a few DEGs showed decreased expression.

Abstract In response to the escalating antibiotic resistance in multidrug-resistant pathogens, we propose an innovative phagemid-based capsid system to generate CRISPR-Cas13a-loaded antibacterial capsids (AB-capsids) for targeted therapy against multidrug-resistant Staphylococcus aureus. Our optimized phagemid system maximizes AB-capsid yield and purity, showing a positive correlation with phagemid copy number. Notably, an 8.65-fold increase in copy number results in a 2.54-fold rise in AB-capsid generation. Phagemids carrying terL-terS-rinA-rinB (prophage-encoded packaging site genes) consistently exhibit high packaging efficiency, and the generation of AB-capsids using lysogenized hosts with terL-terS deletion resulted in comparatively lower level of wild-type phage contamination, with minimal compromise on AB-capsid yield. These generated AB-capsids selectively eliminate S. aureus strains carrying the target gene while sparing non-target strains. In conclusion, our phagemid-based capsid system stands as a promising avenue for developing sequence-specific bactericidal agents, offering a streamlined approach to combat antibiotic-resistant pathogens within the constraints of efficient production and targeted efficacy.

Abstract Numerous geothermal systems are hosted by extensional rifts that transect the Himalayas and Lhasa block in the Himalayan–Tibetan orogen. However, the relationships between hydrogeological processes and geothermal fluid circulation in different tectonic units remain unclear. Here, we report an integrated dataset of chemical and isotopic compositions (including major and trace elements, δD, δ18O, and 87Sr/86Sr) of thermal spring water from the Tingri-Tangra Yumco rift to assess their origins and circulation processes. δ18O (− 21.3 to − 17.0‰) and δD (− 166 to − 135‰) values of thermal springs indicate dominant recharge of meteoric waters from areas with elevation of > 6000 m and minor addition of magmatic fluids. Meteoric water could infiltrate to depths of about 1700–2900 m along the faults, whereby it is influenced by geothermal gradient and/or conductive heat transfer of magmatic fluids. The thermal spring waters are mainly Na-HCO3 type and are controlled by dissolution of silicate and carbonate minerals and mixing with deep fluids. The results of chemical and multicomponent geothermometers indicate reservoir temperatures of 115 − 195 ℃, corresponding to a convection heat flux of 3.96 × 105 J/s to 1.78 × 107 J/s from geothermal systems, which are comparable to that of the low-enthalpy geothermal systems in southern Italy. Geochemical modeling is conducted to assess the water–mineral equilibria in the reservoir. Trace elements and 87Sr/86Sr data suggest spatially variable controlling factors for the rift-related geothermal systems: (1) interaction with granitoid and carbonate in the Himalayas; (2) cold groundwater mixing with that leaching from granite and volcanic rocks in the Lhasa block; (3) the input of vapors from magmatic degassing. The geochemistry of thermal springs associated with extensional rift is largely induced by the interaction between fluid and different reservoir rocks in the Himalayas and Lhasa block. Based on these findings, a genetic model is proposed for exploration and development of geothermal resources in the Tingri-Tangra Yumco rift.