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Deoxyribonucleic acid (DNA) methylation plays a key role in gene regulation and is critical for development and human disease. Techniques such as whole-genome bisulfite sequencing (WGBS) and reduced representation bisulfite sequencing (RRBS) allow DNA methylation analysis at the genome scale, with Illumina NovaSeq 6000 and MGI Tech DNBSEQ-T7 being popular due to their efficiency and affordability. However, detailed comparative studies of their performance are not available. In this study, we constructed 60 WGBS and RRBS libraries for two platforms using different types of clinical samples and generated approximately 2.8 terabases of sequencing data. We systematically compared quality control metrics, genomic coverage, CpG methylation levels, intra- and interplatform correlations, and performance in detecting differentially methylated positions. Our results revealed that the DNBSEQ platform exhibited better raw read quality, although base quality recalibration indicated potential overestimation of base quality. The DNBSEQ platform also showed lower sequencing depth and less coverage uniformity in GC-rich regions than did the NovaSeq platform and tended to enrich methylated regions. Overall, both platforms demonstrated robust intra- and interplatform reproducibility for RRBS and WGBS, with NovaSeq performing better for WGBS, highlighting the importance of considering these factors when selecting a platform for bisulfite sequencing.

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Islas de CpG , Metilación de ADN , Análisis de Secuencia de ADN , Humanos , Análisis de Secuencia de ADN/métodos , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Sulfitos/química , Emparejamiento Base , Secuenciación Completa del Genoma/métodos , Reproducibilidad de los Resultados

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BACKGROUND: Chronic atrophy gastritis (CAG) is a high-risk pre-cancerous lesion for gastric cancer (GC). The early and accurate detection and discrimination of CAG from benign forms of gastritis (e.g. chronic superficial gastritis, CSG) is critical for optimal management of GC. However, accurate non-invasive methods for the diagnosis of CAG are currently lacking. Cytokines cause inflammation and drive cancer transformation in GC, but their utility as a diagnostic for CAG is poorly characterized. METHODS: Blood samples were collected, and 40 cytokines were quantified using a multiplexed immunoassay from 247 patients undergoing screening via endoscopy. Patients were divided into discovery and validation sets. Each cytokine importance was ranked using the feature selection algorithm Boruta. The cytokines with the highest feature importance were selected for machine learning (ML), using the LightGBM algorithm. RESULTS: Five serum cytokines (IL-10, TNF-α, Eotaxin, IP-10 and SDF-1a) that could discriminate between CAG and CSG patients were identified and used for predictive model construction. This model was robust and could identify CAG patients with high performance (AUC = 0.88, Accuracy = 0.78). This compared favorably to the conventional approach using the PGI/PGII ratio (AUC = 0.59). CONCLUSION: Using state-of-the-art ML and a blood-based immunoassay, we developed an improved non-invasive screening method for the detection of precancerous GC lesions. FUNDING: Supported in part by grants from: Jiangsu Science and Technology Project (no. BK20211039); Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (BJ2023008); Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021010), Wuxi Science and Technology Bureau Project (no. N20201004); Scientific Research Program of Wuxi Health Commission (Z202208, J202104).

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Thrombotic diseases, emerging as a global public health hazard with high mortality and disability rates, pose a significant threat to human health and longevity. Although current antithrombotic therapies are effective in treating these conditions, they often carry a substantial risk of bleeding, highlighting the urgent need for safer therapeutic alternatives. Recent evidence has increasingly pointed to a connection between elastase activity and thrombosis. In the current study, we investigated the antithrombotic effects of ShSPI, an elastase inhibitor peptide derived from the venom of Scolopendra hainanum. Results showed that ShSPI significantly attenuated carrageenan-induced thrombosis in vivo. Furthermore, ShSPI effectively inhibited the carrageenan-induced decrease in serum superoxide dismutase (SOD) activity and increase in prothrombin time, fibrinogen level, and endothelial nitric oxide synthase (eNOS) activity. In addition, ShSPI reduced intracerebral thrombosis and improved functional outcomes following ischemic stroke in a transient middle cerebral artery occlusion (tMCAO) mouse model. Collectively, these findings suggest that ShSPI is a promising candidate for the development of novel thrombotic therapies.

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Accidente Cerebrovascular Isquémico , Trombosis , Animales , Ratones , Trombosis/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Masculino , Modelos Animales de Enfermedad , Óxido Nítrico Sintasa de Tipo III/metabolismo , Superóxido Dismutasa/metabolismo , Ratones Endogámicos C57BL , Carragenina , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéutico

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Nucleoside-modified mRNA technology has revolutionized vaccine development with the success of mRNA COVID-19 vaccines. We used modified mRNA technology for the design of envelopes (Env) to induce HIV-1 broadly neutralizing antibodies (bnAbs). However, unlike SARS-CoV-2 neutralizing antibodies that are readily made, HIV-1 bnAb induction is disfavored by the immune system because of the rarity of bnAb B cell precursors and the cross-reactivity of bnAbs targeting certain Env epitopes with host molecules, thus requiring optimized immunogen design. The use of protein nanoparticles (NPs) has been reported to enhance B cell germinal center responses to HIV-1 Env. Here, we report our experience with the expression of Env-ferritin NPs compared with membrane-bound Env gp160 when encoded by modified mRNA. We found that well-folded Env-ferritin NPs were a minority of the protein expressed by an mRNA design and were immunogenic at 20 µg but minimally immunogenic in mice at 1 µg dose in vivo and were not expressed well in draining lymph nodes (LNs) following intramuscular immunization. In contrast, mRNA encoding gp160 was more immunogenic than mRNA encoding Env-NP at 1 µg dose and was expressed well in draining LN following intramuscular immunization. Thus, analysis of mRNA expression in vitro and immunogenicity at low doses in vivo are critical for the evaluation of mRNA designs for optimal immunogenicity of HIV-1 immunogens.IMPORTANCEAn effective HIV-1 vaccine that induces protective antibody responses remains elusive. We have used mRNA technology for designs of HIV-1 immunogens in the forms of membrane-bound full-length envelope gp160 and envelope ferritin nanoparticle. Here, we demonstrated in a mouse model that the membrane-bound form induced a better response than envelope ferritin nanoparticle because of higher in vivo protein expression. The significance of our research is in highlighting the importance of analysis of mRNA design expression and low-dose immunogenicity studies for HIV-1 immunogens before moving to vaccine clinical trials.

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Ferritinas , VIH-1 , Nanopartículas , Animales , VIH-1/inmunología , VIH-1/genética , Ratones , Ferritinas/inmunología , Ferritinas/genética , Humanos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , ARN Mensajero/inmunología , ARN Mensajero/genética , Anticuerpos Anti-VIH/inmunología , Femenino , Anticuerpos Neutralizantes/inmunología , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/genética , Ratones Endogámicos BALB C , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Inmunogenicidad Vacunal , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología

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OBJECTIVE: The study aimed to investigate the correlation and consistency between resting full-cycle ratio (RFR) and fractional flow reserve (FFR) in functional assessment of coronary arteries in a Chinese real-world cohort with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). DESIGN: Retrospective study. SETTING: A single-centre study in China. PARTICIPANTS: A total of 292 diseased vessels of 226 Chinese patients with NSTE-ACS at Cangzhou Central Hospital of Hebei Medical University from September 2021 to June 2023 were included. METHODS: The correlation between RFR and FFR, resting ratio of distal coronary artery pressure (Pd) to aortic pressure (Pa) and FFR were analysed by using Person correlation, and the consistency between RFR and FFR, resting Pd/Pa and FFR were assessed by Bland-Altman test. The diagnostic values of RFR and resting Pd/Pa for predicting FFR≤0.80 were evaluated according to the receiver operating characteristic (ROC) curves. RESULTS: RFR and resting Pd/Pa were significantly correlated with FFR, and correlation coefficients were 0.787 (p<0.001) and 0.765 (p<0.001), respectively. We found no significant differences between RFR and FFR or between resting Pd/Pa and FFR. The areas under the ROC curves for predicting FFR≤0.80 were 0.883 (p<0.001) for RFR and 0.858 (p<0.001) for resting Pd/Pa, and the optimal critical values were 0.91 for RFR and 0.93 for resting Pd/Pa. The accuracy, sensitivity, specificity and positive and negative predictive values of RFR≤0.91 for predicting FFR≤0.80 were 79.1%, 84.0%, 76.6%, 65.1% and 90.2%, respectively. CONCLUSION: The current study suggests that RFR exhibits a good correlation and consistency with FFR in patients with NSTE-ACS. RFR is expected to significantly enhance the application of coronary artery functional assessment in clinical practice, thereby providing patients with more precise revascularisation strategies.

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Síndrome Coronario Agudo , Vasos Coronarios , Reserva del Flujo Fraccional Miocárdico , Humanos , Reserva del Flujo Fraccional Miocárdico/fisiología , Estudios Retrospectivos , Femenino , Masculino , Persona de Mediana Edad , Síndrome Coronario Agudo/fisiopatología , Síndrome Coronario Agudo/diagnóstico , China , Anciano , Vasos Coronarios/fisiopatología , Angiografía Coronaria , Curva ROC , Pueblos del Este de Asia

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We report on a high-power continuous-wave (CW) laser at 2.8 µm employing erbium (Er)-doped fluorite crystals as gain materials. With an optimized Er3+ ion concentration, thin "slab" geometry of the sample matching with the tailored pump beam profile and compensated negative thermal lens using a pair of concave mirrors cavity configuration, a highest power of 14.5 W is achieved from a dual-end-pumped Er:CaF2 laser, which, to the best of our knowledge, presents the record power from the room-temperature Er-bulk lasers in the 3-µm spectral range. In addition, 8.05 W output power is obtained from the Er:SrF2 laser with an RMS power stability of 0.35%. This work indicates that Er-doped fluorite crystals with large-scale available fabrication are promising candidates for high-power laser emission at ∼3 µm.

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Red sandstone tests were conducted on the rock mechanics test system to clarify the strength and failure characteristics of red sandstone under triaxial loading and different unloading confining pressure rates. Strength change rules of the red sandstone in various stress spaces were analyzed. Results show that a large initial confining pressure indicates a long yield section and large axial strain. A small unloading confining pressure rate indicates a long yield section and large axial strain at failure under the identical initial confining pressure. The confining pressure reduction increases with the unloading confining pressure rate increasing when the red sandstone fails. The stress path of unloading confining pressure weakens the red sandstone cohesion and strengthens its internal friction angle. The general octahedral shear stress formula for judging whether the red sandstone fails under loading and different unloading rates was acquired on the basis of the octahedral shear stress characteristics of the red sandstone. In addition, a 3D empirical criterion for evaluating the red sandstone strength was constructed through the deviator plane function of Eekelen and the strength envelope curve on the meridian plane. A great initial confining pressure indicates serious internal damage of the red sandstone at failure under the identical unloading rate of confining pressure. A low unloading rate of confining pressure indicates internal serious damage of the red sandstone at failure when the initial confining pressure is the same. The analysis of macroscopic failure characteristics revealed that the stress path significantly influences the failure mechanism of the red sandstone. The results are instructive for determining the stability of underground engineering of the red sandstone.

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BACKGROUND: Conventional neoadjuvant chemoradiotherapy (nCRT) yields a pathologic complete response (pCR) rate of 15%-30% for locally advanced rectal cancer (LARC). This study ventures to shift this paradigm by incorporating short-course nCRT with immunotherapy, specifically Envafolimab, to achieve improved treatment efficacy and possibly redefine the standard of care for LARC. MATERIALS AND METHODS: The PRECAM study is a prospective, single-arm, phase 2 clinical trial for LARC in patients with microsatellite stable (MSS) tumors. Participants received short-course radiotherapy (25Gy/5f), followed by two cycles of CAPEOX chemotherapy and six weekly doses of Envafolimab, a PD-L1 antibody, before total mesorectal excision surgery. The primary endpoint was the pCR rate. RESULTS: From April to December 2022, 34 patients were enrolled, of whom 32 completed the study, each diagnosed with an MSS rectal adenocarcinoma. All patients underwent preoperative CRT combined with Envafolimab. Remarkably, a pCR rate of 62.5% (20/32) was attained, and a significant pathologic response rate of 75% (24/32) was achieved. Additionally, 21 of 32 participants achieved a neoadjuvant rectal (NAR) score below 8, suggesting an effective treatment response. Common adverse events included tenesmus (78.1%), diarrhea (62.5%), and leukocyte decrease (40.6%). Two Grade 3 adverse events were noted, one related to liver function abnormality and the other to a decrease in platelet count. Surgical procedures were performed in all cases, with minor complications, including ileus, infections, and anastomotic leakage. As of this report, there have been no reported cases of recurrence or death during the follow-up period, ranging from 12 to 20 months. CONCLUSION: In LARC patients exhibiting MSS tumors, combining short-course nCRT with Envafolimab demonstrated favorable efficacy, leading to a significant pCR rate. Minor adverse effects and surgical complications were observed. These preliminary but promising results underscore the potential of this approach and call for further exploration and validation through a randomized controlled trial.

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Background: This study investigated factors influencing discrepancies between fractional flow reserve (FFR) and resting full-cycle ratio (RFR) in the functional assessment of coronary artery stenosis in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods: We included 320 diseased vessels from 253 consecutive patients with NSTE-ACS. Vessels were categorized into four groups based on FFR ≤ 0.80 and RFR ≤ 0.89 thresholds: group 1 concordant negative (RFR-/FFR-), group 2 positive RFR and negative FFR (RFR+/FFR-), group 3 negative RFR and positive FFR (RFR-/FFR+), and group 4 concordant positive (RFR+/FFR+). Univariate and multivariate logistic regression analyses were conducted to identify predictors of diagnostic discrepancy between FFR and RFR. Results: Of the 320 diseased vessels, 182 (56.9%) were in group 1 (RFR-/FFR-), 33 (10.3%) in group 2 (RFR+/FFR-), 31 (9.7%) in group 3 (RFR-/FFR+), and 74 (23.1%) in group 4 (RFR+/FFR+). The concordance between FFR and RFR was 80.0%. Notably, left anterior descending artery (LAD) lesions exhibited significantly lower consistency compared to non-LAD lesions (p = 0.001), with distinct differences in FFR and RFR values between these groups (p < 0.001). The presence of a LAD lesion emerged as an independent predictor of diagnostic inconsistency between positive RFR and negative FFR measurements (p = 0.001). Conclusions: LAD involvement independently predicts diagnostic discrepancies between FFR and RFR in evaluating functional coronary artery stenosis in NSTE-ACS patients.

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Reconfigurable metamaterial absorbers (MAs), consisting of tunable elements or deformable structures, are able to transform their absorbing bandwidth and amplitude in response to environmental changes. Among the options for building reconfigurable MAs, origami/kirigami structures show great potential because of their ability to combine excellent mechanical and electromagnetic (EM) properties. However, neither the trial-and-error-based design method nor the complex fabrication process can meet the requirement of developing high-performance MAs. Accordingly, this work introduces a deep-learning-based algorithm to realize the fast inverse design of origami MAs. Then, an accordion-origami coding MA is generated with reconfigurable EM responses that can be smoothly transformed between ultrabroadband absorption (5.5-20 GHz, folding angle α = 82°) and high reflection (2-20 GHz, RL > -1.5 dB, α = 0°) under y-polarized waves. However, the asymmetric coding pattern and accordion-origami deformation lead to typical polarization-sensitive absorbing performance (2-20 GHz, RL > -4 dB, α < 90°) under x-polarized waves. For the first time, a kirigami polarization rotation surface with switchable operation band is adapted to balance the absorbing performance of accordion-origami MA under orthogonal polarized waves. As a result, the stacked origami-kirigami MA maintains polarization-insensitive ultrabroadband absorption (4.4-20 GHz) at ß = 0° and could be transformed into a narrowband absorber through deformation. Besides, the adapted origami/kirigami structures possess excellent mechanical properties such as low relative density, negative Poisson's ratio, and tunable specific energy absorption. Moreover, by modulating the PEDOT:PSS conductive bridges among MXene nanosheets, a series of low-concentration MXene-PEDOT:PSS inks (∼46 mg·mL-1) with adjustable square resistance (5-32.5 Ω/sq) are developed to fabricate the metamaterials via screen printing. Owing to the universal design scheme, this work supplies a promising paradigm for developing low-cost and high-performance reconfigurable EM absorbers.

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Heterogeneous Information Networks (HINs) are information networks with multiple types of nodes and edges. The concept of meta-path, i.e., a sequence of entity types and relation types connecting two entities, is proposed to provide the meta-level explainable semantics for various HIN tasks. Traditionally, meta-paths are primarily used for schema-simple HINs, e.g., bibliographic networks with only a few entity types, where meta-paths are often enumerated with domain knowledge. However, the adoption of meta-paths for schema-complex HINs, such as knowledge bases (KBs) with hundreds of entity and relation types, has been limited due to the computational complexity associated with meta-path enumeration. Additionally, effectively assessing meta-paths requires enumerating relevant path instances, which adds further complexity to the meta-path learning process. To address these challenges, we propose SchemaWalk, an inductive meta-path learning framework for schema-complex HINs. We represent meta-paths with schema-level representations to support the learning of the scores of meta-paths for varying relations, mitigating the need of exhaustive path instance enumeration for each relation. Further, we design a reinforcement-learning based path-finding agent, which directly navigates the network schema (i.e., schema graph) to learn policies for establishing meta-paths with high coverage and confidence for multiple relations. Extensive experiments on real data sets demonstrate the effectiveness of our proposed paradigm.

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Natural killer (NK) cells kill target cells following triggering via germline-encoded receptors interacting with target cell-expressed ligands (direct killing), or via antibody-dependent cellular cytotoxicity (ADCC) mediated by FcγRIIIa. NK cytotoxicity is modulated by signaling through activating or inhibitory receptors. A major checkpoint is mediated by the NK inhibitory receptor NKG2A/CD94 and its target cell ligand, HLA-E, which is complexed with HLA signal sequence-derived peptides termed VL9 (HLA-E-VL9). We have previously reported the isolation of a murine HLA-E-VL9-specific IgM antibody 3H4 and the generation of a higher affinity IgG version (3H4v3). Here we have used phage display library selection to generate a high affinity version of 3H4v3, called 3H4v31, with an ∼700 fold increase in binding affinity. We show using an HLA-E-VL9+ K562 tumor model that, in vitro, the addition of 3H4v31 to target cells increased direct killing of targets by CD16-negative NK cell line NK-92 and also mediated ADCC by NK-92 cells transfected with CD16. Moreover, ADCC by primary NK cells was also enhanced in vitro by 3H4v31. 3H4v31 was also able to bind and enhance target cell lysis of endogenously expressed HLA-E-VL9 on human cervical cancer and human pancreatic cancer cell lines. In vivo, 3H4v31 slowed the growth rate of HLA-E-VL9+ K562 tumors implanted into NOD/SCID/IL2rγ null mice compared to isotype control when injected with NK-92 cells intratumorally. Together, these data demonstrate that mAb 3H4v31 can enhance NK cell killing of HLA-E-VL9-expressing tumor cells in vitro by both direct killing activity and by ADCC. Moreover, mAb 3H4v31 can enhance NK cell control of tumor growth in vivo. We thus identify HLA-E-VL9 monoclonal antibodies as a promising novel anti-tumor immunotherapy. One Sentence Summary: A high affinity monoclonal antibody against HLA-E-VL9 enhances natural killer cell anti-tumor killing by checkpoint inhibition and antibody dependent cellular cytotoxicity.

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Dual-agent treatment has become more and more popular in clinical trials. We have developed an approach called rapid enrollment dual-agent design (REDD) for dose-finding in Phase I clinical trials. This approach aims to administer treatment to patients using a dose combination that is highly probable to be the target dose combination. Unlike other non-model-based designs, rapid enrollment designs (RED and REDD) do not require waiting for all patients to complete an assessment before the assignment of the next participant. Simulations showed that across several scenarios, the average performance of REDD is comparable to that of the Bayesian optimal interval (BOIN) design and the partial order continual reassessment method (POCRM). The simulation results of REDD for late-onset toxicity assessments demonstrated that assigning patients to a dose combination as they are being enrolled, without waiting for the most recent cohort of patients to complete their follow-up, does not significantly compromise the quality of the maximum tolerated dose (MTD) estimation. Instead, it saves a considerable amount of time in clinical trial enrollment. User-friendly online applications have also been created to further facilitate the adoption of rapid enrollment designs in Phase I trials. In summary, being similar to BOIN and POCRM in performance, REDD is an approach that is easily comprehensible, straightforward to implement and offers an advantage of enrolling patients without having to wait for all current patients to complete their follow-ups for toxicity.

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INTRODUCTION: In China, standard smoking cessation practices are rarely used by healthcare service providers (HSPs). WeChat, a popular social media app, has been widely used in China. METHODS: In this single-blind, randomized trial, undertaken in China with 8-week interventions and follow-up to 34 weeks, 1887 HSPs were randomly selected to the intervention (n=942) or control group (n=945) from Oct 2020 to Oct 2021. The intervention group received regular smoking cessation training program messages from the professional team for 8 weeks and followed for 34 weeks. The control group received thanks messages for 8 weeks, and follow-up to 34 weeks. Both groups received a hard copy of the manual after randomization. The primary outcome measure was the utilization rate of behavioral and pharmacotherapy interventions for smoking patients from 9 to 34 weeks. This trial is registered at ClinicalTrials.gov (number NCT03556774). RESULTS: HSPs in the intervention group demonstrated a better overall utilization rate of smoking cessation at 20-week follow-up compared to the control group (35.54% vs 31.41%, p=0.036). Additionally, both groups showed a significant increase in the adoption of various components of the 5A's model - including "Assess", "Assist: set a quit date", "Assist: recommend cessation program", "Assist: provide information", "Assist: recommend medication", and "Arrange" - at the 9-week follow-up relative to baseline. Notably, at the 20-week follow-up, the intervention group reported significantly enhanced utilization rates for all these components, except "Assist: set a quit date". CONCLUSIONS: The "Wechat Wequit" training program effectively enhanced smoking cessation intervention adoption among Chinese HSPs. IMPLICATION: 'WeChat WeQuit' training program was effective in increasing the provision of effective tobacco cessation interventions by Chinese-speaking HSPs to patients with cigarette smoking, which could provide valuable insights into bridging the gap between need and services for smoking cessation in China.

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The application of sodium metal battery is hampered by the large volume change and uncontrollable top growth of Na metal. Herein, a dual strategy including constructing a three-dimensional gradient ZnO/Fe0.7Co0.3 (ZFC) framework of decreasing sodiophilic capability from bottom to top, and imposing magnetic fields based on magnetohydrodynamic (MHD) effect, is proposed to regulate the sodium deposition/stripping behavior and realize the bottom-up deposition of Na. Therefore, the ZFC framework under a magnetic field of 200 mT exhibits high electrochemical reversibility with a Coulombic efficiency of 99.77% at 1 mA cm-2 and 1 mAh cm-2. Meanwhile, the ZFC composite anode (ZFC@Na) with the magnetic field of 200 mT delivers a small polarization voltage of approximately10 mV and long cycle life of more than 2500 hours at 5 mA cm-2 and 5 mAh cm-2 in symmetric cells, along with good cycle stability in ZFC@Na||Na3V2(PO4)3 full cells (200 cycles at 1C with a high capacity retention of 98%). Accordingly, the novel strategy of combining magnetic fields and sodiophilic gradient frameworks provides a perspective to solve the issues of sodium dendrite growth.

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PURPOSE: In this prospective study, the diagnosis accuracy of nanopore sequencing-based Mycobacterium tuberculosis (MTB) detection was determined through examining bronchoalveolar lavage fluid (BALF) samples from pulmonary tuberculosis (PTB) -suspected patients. Compared the diagnostic performance of nanopore sequencing, mycobacterial growth indicator tube (MGIT) culture and Xpert MTB/rifampin resistance (MTB/RIF) assays. METHODS: Specimens collected from suspected PTB cases across China from September 2021 to April 2022 were tested then assay diagnostic accuracy rates were compared. RESULTS: Among the 111 suspected PTB cases that were ultimately diagnosed as PTB, the diagnostic rate of nanopore sequencing was statistically significant different from other assays (P < 0.05). Fleiss' kappa values of 0.219 and 0.303 indicated fair consistency levels between MTB detection results obtained using nanopore sequencing versus other assays, respectively. Respective PTB diagnostic sensitivity rates of MGIT culture, Xpert MTB/RIF and nanopore sequencing of 36.11%, 40.28% and 83.33% indicated superior sensitivity of nanopore sequencing. Analysis of area under the curve (AUC), Youden's index and accuracy values and the negative predictive value (NPV) indicated superior MTB detection performance for nanopore sequencing (with Xpert MTB/RIF ranking second), while the PTB diagnostic accuracy rate of nanopore sequencing exceeded corresponding rates of the other methods. CONCLUSIONS: In comparison with MGIT culture and Xpert MTB/RIF assays, BALF's nanopore sequencing provided superior MTB detection sensitivity and thus is suitable for testing of sputum-scarce suspected PTB cases. However, negative results obtained using these assays should be confirmed based on additional evidence before ruling out a PTB diagnosis.

Asunto(s)

Líquido del Lavado Bronquioalveolar , Mycobacterium tuberculosis , Secuenciación de Nanoporos , Tuberculosis Pulmonar , Humanos , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/microbiología , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Estudios Prospectivos , China , Secuenciación de Nanoporos/métodos , Masculino , Femenino , Líquido del Lavado Bronquioalveolar/microbiología , Adulto , Persona de Mediana Edad , Sensibilidad y Especificidad , Esputo/microbiología , Anciano , Adulto Joven

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Antibodies perform both neutralizing and non-neutralizing effector functions that protect against certain pathogen-induced diseases. A human antibody directed at the SARS-CoV-2 Spike N-terminal domain (NTD), DH1052, was recently shown to be non-neutralizing, yet it protected mice and cynomolgus macaques from severe disease. The mechanisms of NTD non-neutralizing antibody-mediated protection are unknown. Here we show that Fc effector functions mediate NTD non-neutralizing antibody (non-nAb) protection against SARS-CoV-2 MA10 viral challenge in mice. Though non-nAb prophylactic infusion did not suppress infectious viral titers in the lung as potently as neutralizing antibody (nAb) infusion, disease markers including gross lung discoloration were similar in nAb and non-nAb groups. Fc functional knockout substitutions abolished non-nAb protection and increased viral titers in the nAb group. Fc enhancement increased non-nAb protection relative to WT, supporting a positive association between Fc functionality and degree of protection from SARS-CoV-2 infection. For therapeutic administration of antibodies, non-nAb effector functions contributed to virus suppression and lessening of lung discoloration, but the presence of neutralization was required for optimal protection from disease. This study demonstrates that non-nAbs can utilize Fc-mediated mechanisms to lower viral load and prevent lung damage due to coronavirus infection.

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Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Fragmentos Fc de Inmunoglobulinas , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , SARS-CoV-2/inmunología , Ratones , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Anticuerpos Antivirales/inmunología , Anticuerpos Neutralizantes/inmunología , Fragmentos Fc de Inmunoglobulinas/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Humanos , Femenino , Dominios Proteicos/inmunología , Carga Viral , Pulmón/virología , Pulmón/inmunología , Pulmón/patología

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Molecular doping plays an important role in controlling the carrier concentration of organic semiconductors. However, the introduction of dopant counterions often results in increased energetic disorder and traps due to the molecular packing disruption and Coulomb potential wells. To date, no general strategy has been proposed to reduce the counterion-induced structural and energetic disorder. Here, we demonstrate the critical role of non-covalent interactions (NCIs) between counterions and polymers. Employing a computer-aided approach, we identified the optimal counterions and discovered that NCIs determine their docking positions, which significantly affect the counterion-induced energetic disorder. With the optimal counterions, we successfully reduced the energetic disorder to levels even lower than that of the undoped polymer. As a result, we achieved a high n-doped electrical conductivity of over 200 S cm-1 and an eight-fold increase in the thermoelectric power factor. We found that the NCIs have substantial effects on doping efficiency, polymer backbone planarity, and Coulomb potential landscape. Our work not only provides a general strategy for identifying the most suitable counterions but also deepens our understanding of the counterion effects on doped polymeric semiconductors.

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BACKGROUND: Previous observational evidence has indicated the potential involvement of the gut microbiota (GM) in the development of endometriosis. However, the causal relationship of the association remains to be investigated. METHOD: Genome-wide association study (GWAS) data of GM was obtained from the MiBioGen consortium, and GWAS for endometriosis data was from the FinnGen consortium. Initially, a two-sample Mendelian randomisation (MR) analysis was performed to identify specific bacteria associated with endometriosis. Inverse variance-weighted (IVW) was used as the main MR analysis to infer causal relationships. The other four popular MR methods including MR-Egger regression, weighted mode, weighted median, and simple mode were used for secondary confirmation. Subsequently, these selected bacteria were employed as exposure to investigate their causal effects on six sub-types of endometriosis. Furthermore, reverse MR analysis was implemented to evaluate the reverse causal effects. Cochran's Q statistics was used to test the heterogeneity of instrumental variables (IVs); MR-Egger regression was used to test horizontal pleiotropy; MR-PRESSO and leave-one-out sensitivity analysis were applied to find significant outliers. RESULT: A total of 1131 single nucleotide polymorphisms (SNPs) were collected as IVs for 196 GM taxa with endometriosis as the outcome. We identified 12 causal relationships between endometriosis and GM taxa including 1 phylum, 3 families, 2 orders, and 6 genera (Rikenellaceae RC9 gut group, Eubacterium ruminantium group, Faecalibacterium, Peptococcus, Clostridium sensu stricto 1, and Ruminococcaceae UCG005). Utilizing the Bonferroni method, we identified phylum Cyanobacteria as the strongest associated GM taxa. Subsequently, 6 significant causal effects were uncovered between the 12 selected specific GM and 6 sub-types of endometriosis. Meanwhile, no reverse causal relationship was found. Further, no horizontal pleiotropy and no significant outliers were detected in the sensitive analysis. CONCLUSIONS: This MR analysis revealed significant causal effects between GM and endometriosis and phylum Cyanobacteria had the strongest association.

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The imbalance of gut microbiota (GM) is suggested to be involved in the development of endometriosis while the causal relationship between GM and endometriosis remains undetermined. This two-sample mendelian randomisation analysis firstly demonstrated the potential association between GM and the risk of endometriosis including 6 sub-types. We revealed 12 causal relationships between endometriosis and GM taxa including 1 phylum, 3 families, 2 orders, and 6 genera while Phylum Cyanobacteria was the strongest associated GM taxa by using Bonferroni method. Meanwhile, we identified 6 significant causal effects between 12 selected specific GM and 6 sub-types of endometriosis. Meanwhile, the result from reverse MR analysis showed that there was no causal effect of endometriosis on the identified specific GM taxa. Thus, we revealed the causal relationship between GM and endometriosis. It is necessary to further study its potential mechanism, which may contribute to the prevention and treatment of Endometriosis.

Asunto(s)

Endometriosis , Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Endometriosis/microbiología , Endometriosis/genética , Humanos , Femenino , Microbioma Gastrointestinal/genética , Causalidad

RESUMEN

BACKGROUND: For patients with metastatic non-small cell lung cancer, timely molecular testing is essential to determine the appropriate course of therapy. Initial treatment with platinum chemotherapy and/or an immune checkpoint inhibitor (ICI) is the standard of care for patients without actionable genomic alterations. OBJECTIVE: We aimed to assess treatment patterns and clinical outcomes among patients with metastatic non-small cell lung cancer, no actionable genomic alterations, and with prior ICI and platinum-based chemotherapy in a community oncology setting. METHODS: This retrospective observational study examined electronic health records from adult patients with an initial metastatic non-small cell lung cancer diagnosis without actionable genomic alterations from 2017 to 2019. Patients had received a subsequent line of therapy (LOT) [index] after discontinuing platinum-based chemotherapy plus an ICI in the previous one or two LOTs. Patient demographics and clinical characteristics were analyzed descriptively. Clinical outcomes were evaluated using Kaplan-Meier analyses. RESULTS: Among the study population (n = 961), the most common index LOT regimens were non-platinum-based chemotherapies (57.3%), platinum-based chemotherapies (12.9%), ICI-based chemotherapies (12.7%), platinum + ICI-based chemotherapies (9.4%), and other (7.7%). The most common post-index LOT regimens were non-platinum based (61.2%), ICI based (15.3%), platinum based (10.7%), platinum + ICI based (3.2%), and other (2.5%). Median time to treatment discontinuation, time to next treatment, and overall survival were numerically longest with index LOT ICI-based regimens (6.5, 9.9, and 18.9 months, respectively) and shortest with platinum-based regimens (2.8, 5.3, and 8.0 months, respectively) and non-platinum-based regimens (2.6, 5.0, and 7.8 months, respectively). CONCLUSIONS: Among patients with metastatic non-small cell lung cancer without actionable genomic alterations previously treated with platinum + ICIs, non-platinum chemotherapy agents were most commonly prescribed in the index LOT. Clinical outcomes including time to treatment discontinuation, time to next treatment, and overall survival were short, highlighting the unmet need for more effective later-line treatments.