Assessment of pathogenicity and functional characterization of APPL1 gene mutations in diabetic patients.

BACKGROUND: Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) plays a crucial role in regulating insulin signaling and glucose metabolism. Mutations in the APPL1 gene have been associated with the development of maturity-onset diabetes of the young type 14 (MODY14). Currently, only two mutations [c.1655T>A (p.Leu552*) and c.281G>A p.(Asp94Asn)] have been identified in association with this disease. Given the limited understanding of MODY14, it is imperative to identify additional cases and carry out comprehensive research on MODY14 and APPL1 mutations. AIM: To assess the pathogenicity of APPL1 gene mutations in diabetic patients and to characterize the functional role of the APPL1 domain. METHODS: Patients exhibiting clinical signs and a medical history suggestive of MODY were screened for the study. Whole exome sequencing was performed on the patients as well as their family members. The pathogenicity of the identified APPL1 variants was predicted on the basis of bioinformatics analysis. In addition, the pathogenicity of the novel APPL1 variant was preliminarily evaluated through in vitro functional experiments. Finally, the impact of these variants on APPL1 protein expression and the insulin pathway were assessed, and the potential mechanism underlying the interaction between the APPL1 protein and the insulin receptor was further explored. RESULTS: A total of five novel mutations were identified, including four missense mutations (Asp632Tyr, Arg633His, Arg532Gln, and Ile642Met) and one intronic mutation (1153-16A>T). Pathogenicity prediction analysis revealed that the Arg532Gln was pathogenic across all predictions. The Asp632Tyr and Arg633His variants also had pathogenicity based on MutationTaster. In addition, multiple alignment of amino acid sequences showed that the Arg532Gln, Asp632Tyr, and Arg633His variants were conserved across different species. Moreover, in in vitro functional experiments, both the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were found to downregulate the expression of APPL1 on both protein and mRNA levels, indicating their pathogenic nature. Therefore, based on the patient's clinical and family history, combined with the results from bioinformatics analysis and functional experiment, the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were classified as pathogenic mutations. Importantly, all these mutations were located within the phosphotyrosine-binding domain of APPL1, which plays a critical role in the insulin sensitization effect. CONCLUSION: This study provided new insights into the pathogenicity of APPL1 gene mutations in diabetes and revealed a potential target for the diagnosis and treatment of the disease.

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

Advances in epileptic network findings of hypothalamic hamartomas.

Hypothalamic hamartomas (HHs) are congenital developmental malformations located in the hypothalamus. They are associated with a characteristic clinical manifestation known as gelastic seizures (GS). However, the traditional understanding of HHs has been limited, resulting in insufficient treatment options and high recurrence rates of seizures after surgery. This is consistent with the network hypothesis of focal epilepsy that the epileptogenic zone is not only limited to HH but may also involve the distant cerebral cortex external to the HH mass. The epilepsy network theory, on the other hand, provides a new perspective. In this study, we aim to explore HH-related epilepsy as a network disease, challenging the conventional notion of being a focal lesional disease. We analyze various aspects of HHs, including genes and signaling pathways, local circuits, the whole-brain level, phenotypical expression in terms of seizure semiology, and comorbidities. By examining HHs through the lens of network theory, we can enhance our understanding of the condition and potentially identify novel approaches for more effective management and treatment of epilepsy associated with HHs.

Hypothalamic hamartomas (HHs) are unusual brain malformations present from birth in the hypothalamus region. They often lead to a distinctive type of seizures known as GSs. However, our current understanding of HHs is limited, and this has made it challenging to treat them effectively. Many patients continue to experience seizures even after surgery. We've typically considered HH-related epilepsy as a localized problem, but a new theory suggests that it may involve a network of brain areas. In our study, we aim to change the way we view HH-related epilepsy. Instead of thinking of it as a single lesion in the brain, we explore the idea that it's a network disease. To do this, we'll investigate various aspects of HHs, such as the genes and pathways involved, how different parts of the brain interact, the impact on the whole brain, the types of seizures experienced, and any related health issues. By looking at HHs through this network theory, we hope to gain a deeper understanding of the condition and potentially discover new ways to manage and treat epilepsy associated with HHs. This shift in perspective could offer hope to those living with HH-related epilepsy and lead to more effective treatments, ultimately improving their quality of life.

Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse.

T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape.

High-resolution analyses of associations between medications, microbiome, and mortality in cancer patients.

Discerning the effect of pharmacological exposures on intestinal bacterial communities in cancer patients is challenging. Here, we deconvoluted the relationship between drug exposures and changes in microbial composition by developing and applying a new computational method, PARADIGM (parameters associated with dynamics of gut microbiota), to a large set of longitudinal fecal microbiome profiles with detailed medication-administration records from patients undergoing allogeneic hematopoietic cell transplantation. We observed that several non-antibiotic drugs, including laxatives, antiemetics, and opioids, are associated with increased Enterococcus relative abundance and decreased alpha diversity. Shotgun metagenomic sequencing further demonstrated subspecies competition, leading to increased dominant-strain genetic convergence during allo-HCT that is significantly associated with antibiotic exposures. We integrated drug-microbiome associations to predict clinical outcomes in two validation cohorts on the basis of drug exposures alone, suggesting that this approach can generate biologically and clinically relevant insights into how pharmacological exposures can perturb or preserve microbiota composition. The application of a computational method called PARADIGM to a large dataset of cancer patients' longitudinal fecal specimens and detailed daily medication records reveals associations between drug exposures and the intestinal microbiota that recapitulate in vitro findings and are also predictive of clinical outcomes.

The TaxUMAP atlas: Efficient display of large clinical microbiome data reveals ecological competition in protection against bacteremia.

Longitudinal microbiome data provide valuable insight into disease states and clinical responses, but they are challenging to mine and view collectively. To address these limitations, we present TaxUMAP, a taxonomically informed visualization for displaying microbiome states in large clinical microbiome datasets. We used TaxUMAP to chart a microbiome atlas of 1,870 patients with cancer during therapy-induced perturbations. Bacterial density and diversity were positively associated, but the trend was reversed in liquid stool. Low-diversity states (dominations) remained stable after antibiotic treatment, and diverse communities had a broader range of antimicrobial resistance genes than dominations. When examining microbiome states associated with risk for bacteremia, TaxUMAP revealed that certain Klebsiella species were associated with lower risk for bacteremia localize in a region of the atlas that is depleted in high-risk enterobacteria. This indicated a competitive interaction that was validated experimentally. Thus, TaxUMAP can chart comprehensive longitudinal microbiome datasets, enabling insights into microbiome effects on human health.

Enhanced Feature Selection for Microbiome Data using FLORAL: Scalable Log-ratio Lasso Regression.

Identifying predictive biomarkers of patient outcomes from high-throughput microbiome data is of high interest, while existing computational methods do not satisfactorily account for complex survival endpoints, longitudinal samples, and taxa-specific sequencing biases. We present FLORAL (https://vdblab.github.io/FLORAL/), an open-source computational tool to perform scalable log-ratio lasso regression and microbial feature selection for continuous, binary, time-to-event, and competing risk outcomes, with compatibility of longitudinal microbiome data as time-dependent covariates. The proposed method adapts the augmented Lagrangian algorithm for a zero-sum constraint optimization problem while enabling a two-stage screening process for extended false-positive control. In extensive simulation and real-data analyses, FLORAL achieved consistently better false-positive control compared to other lasso-based approaches, and better sensitivity over popular differential abundance testing methods for datasets with smaller sample size. In a survival analysis in allogeneic hematopoietic-cell transplant, we further demonstrated considerable improvement by FLORAL in microbial feature selection by utilizing longitudinal microbiome data over only using baseline microbiome data.

Effect of multidisciplinary health education based on lifestyle medicine on menopausal syndrome and lifestyle behaviors of menopausal women: A clinical controlled study.

Background: Menopausal women may experience menopausal syndrome and long-term effects caused by low estrogen levels, such as senile dementia and osteoporosis in the elderly. Most menopausal women may have misconceptions about menopause and low use of pharmacological interventions. These misconceptions may damage the quality of life and miss the critical period for preventing senile diseases. Thus, enhancing the awareness of menopausal women regarding psychosocial and physical changes through health education programs was a way to improve positive attitudes toward menopause and make further treatment options. Objectives: This study aimed to evaluate the effect of multidisciplinary health education based on lifestyle medicine on menopausal syndrome and lifestyle behaviors of menopausal women. Methods: The study was conducted in several hospitals in Chongqing, China. The two groups were from different hospitals with similar medical levels in order to reduce information contamination. It was designed as a clinical controlled trial in which the intervention group (n = 100) and control group (n = 87) were matched for age, age at menarche, menopausal symptoms and drug use status at enrollment. Women in the intervention group received multidisciplinary health education based on lifestyle medicine for 2 months while those in the control group received routine outpatient health guidance. Menopausal syndrome, physical activity and dietary status of participants were assessed before and after the intervention. Paired t-tests and Independent-sample t-tests were adopted for comparison within and between groups, respectively, in the normal variables. Wilcoxon signed-rank tests and Mann-Whitney U tests were adopted for comparison within and between group, respectively, in the abnormal variables. Categorical variables were tested using Pearson's χ2. P-value < 0.05 was statistically significant in statistical tests. Results: Post intervention testing indicated that menopausal syndrome of participants was significantly improved in the intervention group compared to the control group (P < 0.001). Between-group comparison showed a significant improvement of weekly energy expenditure of total physical activity (P = 0.001) and participation in exercise (P < 0.001) in the intervention group compared to the control group after the intervention. The dietary status of participants was significantly improved in the intervention group compared to the control group (P < 0.001). In the intervention group, the menopausal syndrome of participants improved more in the hormone drug group than in the non-hormone group (P = 0.007), as did the control group (P = 0.02). In the hormone drug group, the physical activity (P = 0.003) and dietary status (P = 0.001) mproved more in the intervention group than in the control group. Conclusions: The multidisciplinary health education based on lifestyle medicine was effective in improving the menopausal syndrome and healthy lifestyle behaviors of menopausal women. Studies with extended observation period and larger sample size are in need to evaluate the long-term scale-up effects of the multidisciplinary health education.

Effect of different plant communities on NO2 in an urban road greenbelt in Nanjing, China.

As an important part of urban ecosystems, plants can reduce NO2 concentrations in the air. However, there is little evidence of the effects of different plant communities on NO2 concentrations in street-scale green spaces. We used a multifunctional lifting environmental detector to investigate the impact of environmental factors and small plant communities on NO2 concentrations in street green spaces during the summer and winter in Nanjing, China. The results showed that temperature, atmospheric pressure, and noise were significantly (P < 0.05) correlated with seasonal changes, temperature and humidity significantly (P < 0.01) influenced NO2 concentrations in winter and summer, and the average NO2 concentration in summer was generally higher than in winter. By comparing NO2 concentrations in different plant community structures and their internal spaces, we found that the plant community structure with tree-shrub-grass was more effective in reducing pollution. These findings will help predict the impact of plant communities on NO2 concentrations in urban streets and help city managers and planners effectively reduce NO2 pollution.

Research progress on pyrolysis of nitrogen-containing biomass for fuels, materials, and chemicals production.

Pyrolysis of nitrogen-containing biomass holds tremendous potential for producing varieties of high value-added products, alleviating energy depletion. Based on the research status about nitrogen-containing biomass pyrolysis, the effect of biomass feedstock composition on pyrolysis products is first introduced from the aspects of elemental analysis, proximate analysis, and biochemical composition. The properties of biomass with high and low nitrogen used in pyrolysis are briefly summarized. Then, with the pyrolysis of nitrogen-containing biomass as the core, biofuel characteristics, nitrogen migration during pyrolysis, the application prospects, unique advantages of nitrogen-doped carbon materials for catalysis, adsorption and energy storage are introduced, as well as their feasibility in producing nitrogen-containing chemicals (acetonitrile and nitrogen heterocyclic) are reviewed. The future outlook for the application of the pyrolysis of nitrogen-containing biomass, specifically, how to realize the denitrification and upgrading of bio-oil, performance improvement of nitrogen-doped carbon materials, as well as separation and purification of nitrogen-containing chemicals, are addressed.

CT-measured body composition radiomics predict lymph node metastasis in localized pancreatic ductal adenocarcinoma.

BACKGROUND: To explored the value of CT-measured body composition radiomics in preoperative evaluation of lymph node metastasis (LNM) in localized pancreatic ductal adenocarcinoma (LPDAC). METHODS: We retrospectively collected patients with LPDAC who underwent surgical resection from January 2016 to June 2022. According to whether there was LNM after operation, the patients were divided into LNM group and non-LNM group in both male and female patients. The patient's body composition was measured by CT images at the level of the L3 vertebral body before surgery, and the radiomics features of adipose tissue and muscle were extracted. Multivariate logistic regression (forward LR) analyses were used to determine the predictors of LNM from male and female patient, respectively. Sexual dimorphism prediction signature using adipose tissue radiomics features, muscle tissue radiomics features and combined signature of both were developed and compared. The model performance is evaluated on discrimination and validated through a leave-one-out cross-validation method. RESULTS: A total of 196 patients (mean age, 60 years ± 9 [SD]; 117 men) were enrolled, including 59 LNM in male and 36 LNM in female. Both male and female CT-measured body composition radiomics signatures have a certain predictive power on LNM of LPDAC. Among them, the female adipose tissue signature showed the highest performance (area under the ROC curve (AUC), 0.895), and leave one out cross validation (LOOCV) indicated that the signature could accurately classify 83.5% of cases; The prediction efficiency of the signature can be further improved after adding the muscle radiomics features (AUC, 0.924, and the accuracy of the LOOCV was 87.3%); The abilities of male adipose tissue and muscle tissue radiomics signatures in predicting LNM of LPDAC was similar, AUC was 0.735 and 0.773, respectively, and the accuracy of LOOCV was 62.4% and 68.4%, respectively. CONCLUSIONS: CT-measured body composition Radiomics strategy showed good performance for predicting LNM in LPDAC, and has sexual dimorphism. It may provide a reference for individual treatment of LPDAC and related research about body composition in the future.

Co-torrefaction of corncob and waste cooking oil coupled with fast co-pyrolysis for bio-oil production.

Lignocellulosic biomass is a rich source of fixed renewable carbon and a promising alternative to fossil sources. However, low effective hydrogen to carbon ratio limits its applications. This work studied the influence of oil-bath co-torrefaction of corncob and waste cooking oil for co-pyrolysis. It was compared with dry torrefaction and hydrothermal wet torrefaction firstly. Residual of oil-bath co-torrefaction were the highest of 97.01 %. Oil-bath co-torrefaction could maximize hydrogen atoms retention in corncob, which has a positive significance for deoxygenation during pyrolysis. Oil-bath co-torrefaction could also reduce the average activation energy required for corncob decomposition, while it was increased with dry torrefaction. Oil-bath co-torrefaction coupled with co-pyrolysis was more suitable for hydrocarbon-rich bio-oil production. Oil-bath co-torrefaction temperature had the greatest influence on bio-oil composition. High pressure promoted formation of the CC double bond and degradation of lignin, which further promoted the formation of monocyclic aromatics in bio-oil.

Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation.

PURPOSE: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. EXPERIMENTAL DESIGN: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. RESULTS: We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)-thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine-cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. CONCLUSIONS: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.

pH-dependent microbial niches succession and antibiotic resistance genes distribution in an oxygen-based membrane biofilm reactor treating greywater.

System pH is found to crucially affect biofilm growth and microorganisms' activity in the biofilm-based wastewater treatment system. This study investigated the pH-dependent pollutants removal, microbial niches succession and antibiotic resistance genes (ARGs) accumulation in an oxygen-based membrane biofilm reactor treating greywater. Results indicated that neutral conditions achieved the highest biofilm concentration and living cells, which enabled the highest pollutants removal rates; multifarious functional groups in biofilm enabled pollutants adsorption, which favored its continuous bio-removal. Microbial communities under acidic condition (pH = 5.0) were significantly different with that under other conditions (p < 0.05). The neutral and alkaline niches (pH = 7.0 and 9.0) were predominant by organics biodegradation and nitrogen reduction bacteria (e.g. Sphingobacteriales, Pseudomonas, Flavobacterium and Phenylobacterium), but which were significantly dropped under acidic conditions, leading to the declined reactor performance. ARGs in biofilm (predominant by korB, intI-1, sul1 and sul2) were much higher than that in the cell-free liquid and the target ARGs accumulation (korB, intI-1, blaCTX-M, qnrS) had nearly linear positive relationships (R2 > 0.95, P < 0.01) with biofilm-attached linear alkylbenzene sulfonate (LAS). LAS stimulate ARGs proliferation in functional microorganisms (korB, sul-1 and intI-1 were significantly associated with related microbial genus) and biofilm played a key role in ARGs dissemination. The relatively low ARGs in both biofilm and effluent under neutral conditions suggested that pH controlling can be an effective strategy to inhibit ARGs dissemination and proliferation in the system.

Preservation of the fecal microbiome is associated with reduced severity of graft-versus-host disease.

Following allogeneic hematopoietic cell transplantation (allo-HCT), the gastrointestinal (GI) tract is frequently affected by acute graft-versus-host disease (aGVHD), the pathophysiology of which is associated with a dysbiotic microbiome. Since microbial composition varies along the length of the GI tract, the authors hypothesized that microbiome features correlate with the pattern of organ involvement after allo-HCT. We evaluated 266 allo-HCT recipients from whom 1303 stool samples were profiled by 16S ribosomal gene sequencing. Patients were classified according to which organs were affected by aGVHD. In the 20 days prior to disease onset, GVHD patients had lower abundances of members of the class Clostridia, lower counts of butyrate producers, and lower ratios of strict-to-facultative (S/F) anaerobic bacteria compared with allograft recipients who were free of GVHD. GI GVHD patients showed significant reduction in microbial diversity preonset. Patients with lower GI aGVHD had lower S/F anaerobe ratios compared with those with isolated upper GI aGVHD. In the 20 days after disease onset, dysbiosis was observed only in GVHD patients with GI involvement, particularly those with lower-tract disease. Importantly, Clostridial and butyrate-producer abundance as well as S/F anaerobe ratio were predictors of longer overall survival; higher abundance of butyrate producers and higher S/F anaerobe ratio were associated with decreased risk of GVHD-related death. These findings suggest that the intestinal microbiome can serve as a biomarker for outcomes of allo-HCT patients with GVHD.

MAIT and Vδ2 unconventional T cells are supported by a diverse intestinal microbiome and correlate with favorable patient outcome after allogeneic HCT.

Microbial diversity is associated with improved outcomes in recipients of allogeneic hematopoietic cell transplantation (allo-HCT), but the mechanism underlying this observation is unclear. In a cohort of 174 patients who underwent allo-HCT, we demonstrate that a diverse intestinal microbiome early after allo-HCT is associated with an increased number of innate-like mucosal-associated invariant T (MAIT) cells, which are in turn associated with improved overall survival and less acute graft-versus-host disease (aGVHD). Immune profiling of conventional and unconventional immune cell subsets revealed that the prevalence of Vδ2 cells, the major circulating subpopulation of γδ T cells, closely correlated with the frequency of MAIT cells and was associated with less aGVHD. Analysis of these populations using both single-cell transcriptomics and flow cytometry suggested a shift toward activated phenotypes and a gain of cytotoxic and effector functions after transplantation. A diverse intestinal microbiome with the capacity to produce activating ligands for MAIT and Vδ2 cells appeared to be necessary for the maintenance of these populations after allo-HCT. These data suggest an immunological link between intestinal microbial diversity, microbe-derived ligands, and maintenance of unconventional T cells.

A compilation of fecal microbiome shotgun metagenomics from hematopoietic cell transplantation patients.

Hospitalized patients receiving hematopoietic cell transplants provide a unique opportunity to study the human gut microbiome. We previously compiled a large-scale longitudinal dataset of fecal microbiota and associated metadata, but we had limited that analysis to taxonomic composition of bacteria from 16S rRNA gene sequencing. Here we augment those data with shotgun metagenomics. The compilation amounts to a nested subset of 395 samples compiled from different studies at Memorial Sloan Kettering. Shotgun metagenomics describes the microbiome at the functional level, particularly in antimicrobial resistances and virulence factors. We provide accession numbers that link each sample to the paired-end sequencing files deposited in a public repository, which can be directly accessed by the online services of PATRIC to be analyzed without the users having to download or transfer the files. Then, we show how shotgun sequencing enables the assembly of genomes from metagenomic data. The new data, combined with the metadata published previously, enables new functional studies of the microbiomes of patients with cancer receiving bone marrow transplantation.

Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.

Construction of an Interfacial Photocatalytic Mode Based on Carbonized Mushrooms to Enhance Infrared Light-Assisted Photocatalytic Water Splitting Performance.

To find a more efficient way to generate photocatalytic hydrogen, we developed the interfacial photocatalytic mode, in which the photocatalytic reaction can be transferred to a high-energy interfacial area. The new interfacial mode in this work is assembled with the help of carbonized mushrooms, which is an ideal water transporter as well as an excellent photothermal converter. The higher temperature from efficient light-to-heat conversion performance and thermal localization promote the efficiency of hydrogen evolution, and some effects peculiar to the interfacial mode can make the departure of hydrogen from the active sites of the photocatalyst smoother. As a result, the active sites can be exposed in a timely manner to allow the progress of the next cycle of the photocatalytic reaction to be smoother. The efficiency of interfacial photocatalytic hydrogen production can reach >10 times that of the corresponding sample in the traditional bulk water mode. This work has allowed further exploration of the construction of the interfacial photocatalytic mode, provided a reliable experimental basis for the development of the interfacial mode, and illuminated a new path for the development of photocatalytic water splitting.