Investigating the causal relationship of gut microbiota with GERD and BE: a bidirectional mendelian randomization.

BACKGROUND: Gut microbiota(GM) have been proven associated with lots of gastrointestinal diseases, but its causal relationship with Gastroesophageal reflux disease(GERD) and Barrett's esophagus(BE) hasn't been explored. We aimed to uncover the causal relation between GM and GERD/BE and potential mediators by utilizing Mendelian Randomization(MR) analysis. METHODS: Summary statistics of GM(comprising 301 bacteria taxa and 205 metabolism pathways) were extracted from MiBioGen Consortium(N = 18,340) and Dutch Microbiome Project(N = 7,738), GERD and BE from a multitrait meta-analysis(NGERD=602,604, NBE=56,429). Bidirectional two-sample MR analysis and linkage disequilibrium score regression(LDSC) were used to explore the genetic correlation between GM and GERD/BE. Mediation MR analysis was performed for the risk factors of GERD/BE, including Body mass index(BMI), weight, type 2 diabetes, major depressive disorder(MDD), smoking initiation, alcohol consumption, and dietary intake(including carbohydrate, sugar, fat, protein intake), to detect the potential mediators between GM and GERD/BE. RESULTS: 11 bacterial taxa and 13 metabolism pathways were found associated with GERD, and 18 taxa and 5 pathways exhibited causal relationship with BE. Mediation MR analysis suggested weight and BMI played a crucial role in these relationships. LDSC identified 1 taxon and 4 metabolism pathways related to GERD, and 1 taxon related to BE. Specie Faecalibacterium prausnitzii had a suggestive impact on both GERD(OR = 1.087, 95%CI = 1.01-1.17) and BE(OR = 1.388, 95%CI = 1.03-1.86) and LDSC had determined their correlation. Reverse MR indicated that BE impacted 10 taxa and 4 pathways. CONCLUSIONS: This study established a causal link between gut microbiota and GERD/BE, and identified the probable mediators. It offers new insights into the role of gut microbiota in the development and progression of GERD and BE in the host.

Unraveling the role of C1GALT1 in abnormal glycosylation and colorectal cancer progression.

C1GALT1 plays a pivotal role in colorectal cancer (CRC) development and progression through its involvement in various molecular mechanisms. This enzyme is central to the O-glycosylation process, producing tumor-associated carbohydrate antigens (TACA) like Tn and sTn, which are linked to cancer metastasis and poor prognosis. The interaction between C1GALT1 and core 3 synthase is crucial for the synthesis of core 3 O-glycans, essential for gastrointestinal health and mucosal barrier integrity. Aberrations in this pathway can lead to CRC development. Furthermore, C1GALT1's function is significantly influenced by its molecular chaperone, Cosmc, which is necessary for the proper folding of T-synthase. Dysregulation in this complex interaction contributes to abnormal O-glycan regulation, facilitating cancer progression. Moreover, C1GALT1 affects downstream signaling pathways and cellular behaviors, such as the epithelial-mesenchymal transition (EMT), by modifying O-glycans on key receptors like FGFR2, enhancing cancer cell invasiveness and metastatic potential. Additionally, the enzyme's relationship with MUC1, a mucin protein with abnormal glycosylation in CRC, highlights its role in cancer cell immune evasion and metastasis. Given these insights, targeting C1GALT1 presents a promising therapeutic strategy for CRC, necessitating further research to develop targeted inhibitors or activators. Future efforts should also explore C1GALT1's potential as a biomarker for early diagnosis, prognosis, and treatment response monitoring in CRC, alongside investigating combination therapies to improve patient outcomes.

Three-dimensional RuCo alloy nanosheets arrays integrated pinewood-derived porous carbon for high-efficiency electrocatalytic nitrate reduction to ammonia.

Electricity-driven nitrate (NO3-) to ammonia (NH3) conversion presents a unique opportunity to simultaneously eliminate nitrate from sewage while capturing ammonia. However, the Faradaic efficiency and ammonia yield in this eight-electron process remain unsatisfactory, underscoring the critical need for more effective electrocatalysts. In this study, a RuCo alloy nanosheets electrodeposited on pinewood-derived three-dimensional porous carbon (RuCo@TDC) is introduced as a highly-efficient electrocatalyst for the nitrate reduction reaction. The RuCo@TDC catalyst exhibits superior electrocatalytic performance, achieving the highest NH3 yield of 2.02 ± 0.11 mmol h-1 cm-2 at -0.6 V versus the reversible hydrogen electrode (vs. RHE) and the highest Faradaic efficiency of 95.7 ± 0.8 % at -0.2 V vs. RHE in an electrolyte mixture of 0.1 M KOH and 0.1 M KNO3. Furthermore, the Zn-NO3- battery using RuCo@TDC as the cathode provides a maximum power density of 2.46 mW cm-2 and a satisfactory NH3 yield of 1110 µg h-1 cm-2.

Mapping QTLs for blight resistance and morpho-phenological traits in inter-species hybrid families of chestnut (Castanea spp.).

Chestnut blight (caused by Cryphonectria parasitica), together with Phytophthora root rot (caused by Phytophthora cinnamomi), has nearly extirpated American chestnut (Castanea dentata) from its native range. In contrast to the susceptibility of American chestnut, many Chinese chestnut (C. mollissima) genotypes are resistant to blight. In this research, we performed a series of genome-wide association studies for blight resistance originating from three unrelated Chinese chestnut trees (Mahogany, Nanking and M16) and a Quantitative Trait Locus (QTL) study on a Mahogany-derived inter-species F2 family. We evaluated trees for resistance to blight after artificial inoculation with two fungal strains and scored nine morpho-phenological traits that are the hallmarks of species differentiation between American and Chinese chestnuts. Results support a moderately complex genetic architecture for blight resistance, as 31 QTLs were found on 12 chromosomes across all studies. Additionally, although most morpho-phenological trait QTLs overlap or are adjacent to blight resistance QTLs, they tend to aggregate in a few genomic regions. Finally, comparison between QTL intervals for blight resistance and those previously published for Phytophthora root rot resistance, revealed five common disease resistance regions on chromosomes 1, 5, and 11. Our results suggest that it will be difficult, but still possible to eliminate Chinese chestnut alleles for the morpho-phenological traits while achieving relatively high blight resistance in a backcross hybrid tree. We see potential for a breeding scheme that utilizes marker-assisted selection early for relatively large effect QTLs followed by genome selection in later generations for smaller effect genomic regions.

Plasmodium yoelii surface-related antigen (PySRA) modulates the host pro-inflammatory responses via binding to CD68 on macrophage membrane.

Malaria, one of the major infectious diseases in the world, is caused by the Plasmodium parasite. Plasmodium antigens could modulate the inflammatory response by binding to macrophage membrane receptors. As an export protein on the infected erythrocyte membrane, Plasmodium surface-related antigen (SRA) participates in the erythrocyte invasion and regulates the immune response of the host. This study found that the F2 segment of P. yoelii SRA activated downstream MAPK and NF-κB signaling pathways by binding to CD68 on the surface of the macrophage membrane and regulating the inflammatory response. The anti-PySRA-F2 antibody can protect mice against P. yoelii, and the pro-inflammatory responses such as IL-1ß, TNF-α, and IL-6 after infection with P. yoelii are attenuated. These findings will be helpful for understanding the involvement of the pathogenic mechanism of malaria with the exported protein SRA.

Changing profiles of the burden of Alzheimer's disease and other dementias attributable to smoking in the belt and road initiative countries: A secondary analysis of global burden of disease 2019.

Objectives: This study was aimed at analyzing the burden and trend of Alzheimer's disease and other dementias attributed to smoking (SADD) in the Belt and Road Initiative (BRI) countries during 1990-2019. Methods: Data from The 2019 Global Burden of Disease Study was used to extract information on the burden of SADD in terms of the numbers and age-standardized rate of mortality (ASMR) and disability-adjusted life years (ASDALR) in the BRI countries for 1990-2019. The average annual percent change (AAPC) was used to analyze the temporal trends of ASDALR from 1990 to 2019 and in the final decade by Joinpoint regression analysis. Results: The DALYs of SADD were the highest in China, India, and the Russian Federation in 1990 and in Lebanon, Montenegro and Bosnia, and Herzegovina in 2019. From 1990 to 2019, the ASDALR in China had increased from 55.50/105 to 66.18/105, but decreased from 2010 to 2019, while that of India had declined from 32.84/105 to 29.35/105, but increased from 2010 to 2019. The ASDALR showed the fastest increase in the Russian Federation, with AAPC of 1.97% (95% confidence interval [CI]: 1.77%, 2.16%), and the fastest decline in Sri Lanka, with AAPC of -2.69% (95% CI: 2.79%, -2.59%). ASMR and ASDALR from SADD showed a substantial decline during 1990-2019 both globally and in the different socio-demographic index (SDI) regions (all P < 0.05, except for the high-middle-SDI region). Compared to the rates in males, the AAPC in ASDALR of females was significantly greater in 20 countries(all P < 0.05). In the age group of 20-54 years, the DALYs rate showed a decreasing trend only in 13 members in the low-SDI region (all P < 0.05). Conclusion: Under the premise of eliminating the differences, mobilizing resources in the country itself, the BRI organization, and globally will help reduce the global SADD burden and achieve healthy and sustainable development.

PIKfyve controls dendritic cell function and tumor immunity.

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

Coexistence of Cyclic Sequential Pattern Recognition and Associative Memory in Neural Networks by Attractor Mechanisms.

Neural networks are developed to model the behavior of the brain. One crucial question in this field pertains to when and how a neural network can memorize a given set of patterns. There are two mechanisms to store information: associative memory and sequential pattern recognition. In the case of associative memory, the neural network operates with dynamical attractors that are point attractors, each corresponding to one of the patterns to be stored within the network. In contrast, sequential pattern recognition involves the network memorizing a set of patterns and subsequently retrieving them in a specific order over time. From a dynamical perspective, this corresponds to the presence of a continuous attractor or a cyclic attractor composed of the sequence of patterns stored within the network in a given order. Evidence suggests that the brain is capable of simultaneously performing both associative memory and sequential pattern recognition. Therefore, these types of attractors coexist within the neural network, signifying that some patterns are stored as point attractors, while others are stored as continuous or cyclic attractors. This article investigates the coexistence of cyclic attractors and continuous or point attractors in certain nonlinear neural networks, enabling the simultaneous emergence of various memory mechanisms. By selectively grouping neurons, conditions are established for the existence of cyclic attractors, continuous attractors, and point attractors, respectively. Furthermore, each attractor is explicitly represented, and a competitive dynamic emerges among these coexisting attractors, primarily regulated by adjustments to external inputs.

Structural insights into histone exchange by human SRCAP complex.

Histone variant H2A.Z is found at promoters and regulates transcription. The ATP-dependent chromatin remodeler SRCAP complex (SRCAP-C) promotes the replacement of canonical histone H2A-H2B dimer with H2A.Z-H2B dimer. Here, we determined structures of human SRCAP-C bound to H2A-containing nucleosome at near-atomic resolution. The SRCAP subunit integrates a 6-subunit actin-related protein (ARP) module and an ATPase-containing motor module. The ATPase-associated ARP module encircles half of the nucleosome along the DNA and may restrain net DNA translocation, a unique feature of SRCAP-C. The motor module adopts distinct nucleosome binding modes in the apo (nucleotide-free), ADP-bound, and ADP-BeFx-bound states, suggesting that ATPase-driven movement destabilizes H2A-H2B by unwrapping the entry DNA and pulls H2A-H2B out of nucleosome through the ZNHIT1 subunit. Structure-guided chromatin immunoprecipitation sequencing analysis confirmed the requirement of H2A-contacting ZNHIT1 in maintaining H2A.Z occupancy on the genome. Our study provides structural insights into the mechanism of H2A-H2A.Z exchange mediated by SRCAP-C.

Human biomonitoring without in-person interaction: public health engagements during the COVID-19 pandemic and future implications.

BACKGROUND: Public health initiatives, including human biomonitoring, have been impacted by unique challenges since the onset of the COVID-19 pandemic, compounding a decades-long trend of declining public participation. To combat low public participation rates, public health professionals often employ extensive engagement approaches including in-person interactions related to enrollment and sampling, success of which is an essential component of a statistically defensible study. The onset of the COVID-19 pandemic challenged public health programs to diversify engagement and sampling approaches, limiting direct interactions for the health and safety of the population. This study explores biomonitoring recruitment strategies through non-contact mechanisms and evaluate the application feasibility for population-based studies. METHODS: The Iowa Biomonitoring Program at the State Hygienic Laboratory developed a human biomonitoring study that utilized a multifaceted, distance-based approach. Traditional techniques, such as mailed recruitment invitations and phone-based discussions, were coupled with internet-based surveys and self-collected, shipped urine and water samples. Participation rates were evaluated by employing different mailing methods, and the demographics of enrolled participants were examined. RESULTS: This non-human contact approach achieved a nearly 14% participation rate among a rural population, well above our target rates. Our improved mailing strategy for targeting initially unresponsive participants yielded a significantly increase in the participation rates. The respondents were predominantly individuals with educational attainment of at least high school level. Among all the eligible participants, 83% submitted self-collected samples, a rate comparable to the National Health and Nutrition Examination Survey which involved in-person interviews. CONCLUSIONS: The practice of engaging a rural population during the COVID-19 pandemic by transitioning from face-to-face interactions to a combination of mailing and internet-based approaches resulted in higher-than-expected participant recruitment and sample collection rates. Given the declining trend in the response rates for population-based survey studies, our results suggest conducting human biomonitoring without direct human interaction is feasible, which provides further opportunity to improve response rates and the relevance and reach of public health initiatives.

[High mobility group nucleosome binding protein 1 (HMGN1) induces activation of mouse BV2 microglia and upregulates their pro-inflammatory mediator expression by activating TLR4/MyD88/NF-κB p65/IKK-ß signal pathway].

Objective To explore the effects and mechanism of high-mobility group nucleosome-binding protein 1 (HMGN1) on the inflammatory response of mouse BV2 microglia. Methods BV2 cells were incubated with recombinant HMGN1 at different concentrations (0, 100, 200, 500, 1000, 2000 ng/mL) for 6 hours, and the morphological changes were observed under a microscope. The mRNA levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and monocyte chemotactic protein 1 (MCP-1) were detected by real time quantitative PCR. Microglial cells were then randomly divided into a control group, model group, inhibitor group and antagonist group. The cells in the model group were treated with 500 ng/mL HMGN1, while the antagonist group was treated with 500 ng/mL TAK-242 (resatorvid), a Toll-like receptor 4 (TLR4) antagonist, in addition to HMGN1. Real time quantitative PCR and immunofluorescence were used to detect the expression of M1/M2 markers in the four groups, and Western blot analysis was used to measure the protein expression levels of inducible nitric-oxide synthase (iNOS), TLR4, myeloid differentiation factor88 (MyD88), nuclear factor κB p65 (NF-κB p65) and inhibitor of NF-κB(IκB)kinase ß(IKK-ß). Results After the treatment of HMGN1, the morphology of BV2 cells changed significantly, showing an amoeba-like appearance. The mRNA levels of TNF-α, IL-6, IL-1ß and MCP-1 increased with the HMGN1 concentration, with a statistically significant difference compared to the 0 ng/mL HMGN1 group. At the same time, the mRNA level of iNOS, a M1 phenotype marker, increased with the HMGN1 concentration, while the level of CD206, a M2 phenotype marker, decreased with HMGN1 concentration, showing a statistically significant difference compared to the 0 ng/mL HMGN1 group. Compared with the model group, the mRNA level of M1 phenotypic marker iNOS in the antagonist group was significantly lower, and the level of M2 phenotypic marker CD206 was significantly higher. The results of immunofluorescence cytochemistry also showed that the expression of M1 phenotypic marker iNOS in the antagonist group was lower. The results of Western blot suggested that the protein expression levels of iNOS, TLR4, MyD88, NF-κB p65 and IKK-ß decreased significantly in the antagonist group. Conclusion HMGN1 may induce the activation of BV2 microglial cells by upregulating pro-inflammatory mediators through activating the TLR4/MyD88/NF-κB p65/IKK-ß signaling pathway.

Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fcγ receptors.

Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade.

Introducing CuCo2S4 Nanoparticles on Reduced Graphene Oxide for High-Performance Supercapacitor.

In this work, a bimetallic sulfide-coupled graphene hybrid was designed and constructed for capacitive energy storage. The hybrid structure involved decorating copper-cobalt-sulfide (CuCo2S4) nanoparticles onto graphene layers, with the nanoparticles anchored within the graphene layers, forming a hybrid energy storage system. In this hybrid structure, rGO can work as the substrate and current collector to support the uniform distribution of the nanoparticles and provides efficient transportation of electrons into and out of the electrode. In the meantime, CuCo2S4-active materials are expected to offer an evident enhancement in electrochemical activities, due to the rich valence change provided by Cu and Co. Benefiting from the integrated structure of CuCo2S4 nanoparticles and highly conductive graphene substrates, the prepared CuCo2S4@rGO electrode exhibited a favorable capacitive performance in 1 M KOH. At 1 A g-1, CuCo2S4@rGO achieved a specific capacitance of 410 F g-1. The capacitance retention at 8 A g-1 was 70% of that observed at 1 A g-1, affirming the material's excellent rate capability. At the current density of 5 A g-1, the electrode underwent 10,000 charge-discharge cycles, retaining 98% of its initial capacity, which indicates minimal capacity decay and showcasing excellent cycling performance.

Shifting and state transformations-based adaptive tracking control for deferred full state-constrained uncertain nonlinear systems.

This paper concerns the tracking control problem of a class of uncertain nonlinear systems subject to deferred time-varying state constraints and external disturbances. The states of the system are free in the initial phase and are restricted by some time-varying constraints after a particular time. A class of novel shifting functions are defined, which make any initial states that beyond the constraint region move to the desired position (such as zero). Thereafter, a new state transformation is implemented for the shifted state, which transforms the state constraint problem into the boundedness of a new variable. Compared with the existing BLF method, this approach avoids feasibility test for virtual control variables. Adaptive backstepping control and dynamic surface control are used in system controller design and stability analysis, and the ideal tracking performance is achieved. Finally, simulation example and comparative studies are carried out to illustrate the effectiveness and outstanding characteristics of the proposed approach. Simulation results show that the proposed control scheme broadens the scope of application, shortens running time and improves control efficiency compared with the existing control strategies.

Bibliometric and visualized analysis of applying tumor markers in lung cancer diagnosis from 2000 to 2022.

Background: Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Tumor marker (TM) detection can indicate the existence and growth of a tumor and has therefore been used extensively for diagnosing LC. Here, we conducted a bibliometric analysis to examine TM-related publications for LC diagnosis to illustrate the current state and future trends of this field, as well as to identify additional promising TMs with high sensitivity. Methods: Publications regarding TMs in LC diagnosis were downloaded from the Web of Science Core Collection. CiteSpace was applied to perform a bibliometric analysis of journals, cocitation authors, keywords, and references related to this field. VOSviewer was used to generate concise diagrams about countries, institutions, authors, and keywords. Changes in the TM research frontier were analyzed through citation burst detection. Results: A total of 990 studies were analyzed in this work. The collaboration network analysis revealed that the People's Republic of China, Yonsei University, and Molina R were the most productive country, institution, and scholar, respectively. Additionally, Molina R was the author with the most citations. The National Natural Science Foundation of China was the largest funding source. "Carcinoembryonic antigen (CEA) as tumor marker in lung cancer" was the top reference with the most citations, Lung Cancer was the core journal, and "serum tumor marker" experienced a citation burst over the past 5 years. Conclusion: This bibliometric analysis of TMs in LC diagnosis presents the current trends and frontiers in this field. We summarized the research status of this field and the methods to improve the diagnostic efficacy of traditional serum TMs, as well as provided new directions and ideas for improving the LC clinical detection rate. Priority should be given to the transformation of computer-assisted diagnostic technology for clinical applications. In addition, circulating tumor cells, exosomes, and microRNAs were the current most cutting-edge TMs.

Central administration of Dapagliflozin alleviates a hypothalamic neuroinflammatory signature and changing tubular lipid metabolism in type 2 diabetic nephropathy by upregulating MCPIP1.

BACKGROUND: Hypothalamic neuroinflammation is associated with disorders of lipid metabolism. Considering the anti-neuroinflammation effects of sodium-glucose cotransporter 2(SGLT2) inhibitors, a central administration of Dapagliflozin is postulated to provide hypothalamic protection and change lipid metabolism in kidney against diabetic kidney disease (DKD). METHODS: Blood samples of DKD patients were collected. Male Sprague-Dawley (SD) rats with 30 mg/kg streptozotocin and a high-fat diet, db/db mice and palmitic acid (PA)-stimulated BV2 microglia were used for study models. 0.28 mg/3ul dapagliflozin was injected into the lateral ventricle in db/db mice. Genes and protein expression levels were determined by qPCR, western blotting, immunofluorescence, and immunohistochemistry staining. Secreted IL-1ß and IL-6 were quantified by ELISA. Oil red O staining, lipidomic, and non-targeted metabolomics were performed to evaluate abnormal lipid metabolism in kidney. RESULTS: The decrease of serum MCPIP1 was an independent risk factor for renal progression in DKD patients (OR=1.22, 95 %CI: 1.02-1.45, P = 0.033). Higher microglia marker IBA1 and lower MCPIP1 in the hypothalamus, as well as lipid droplet deposition increasing in the kidney were observed in DKD rats. Central dapagliflozin could reduce the blood sugar, hypothalamic inflammatory cytokines, lipid droplet deposition in renal tubular. Lipidomics and metabolomics results showed that dapagliflozin changed 37 lipids and 19 metabolites considered on promoting lipolysis. These lipid metabolism changes were attributed to dapagliflozin by upregulating MCPIP1, and inhibiting cytokines in the microglia induced by PA. CONCLUSIONS: Central administrated Dapagliflozin elicits an anti-inflammatory effect by upregulating MCPIP1 levels in microglia and changes lipid metabolism in kidney of DKD.

Hearing intervention for decreasing risk of developing dementia in elders with mild cognitive impairment: study protocol of a multicenter randomized controlled trial for Chinese Hearing Solution for Improvement of Cognition in Elders (CHOICE).

BACKGROUND: Age-related hearing loss (ARHL) signifies the bilateral, symmetrical, sensorineural hearing loss that commonly occurs in elderly individuals. Several studies have suggested a higher risk of dementia among patients diagnosed with ARHL. Although the precise causal association between ARHL and cognitive decline remains unclear, ARHL has been recognized as one of the most significant factors that can be modified to reduce the risk of developing dementia potentially. Mild cognitive impairment (MCI) typically serves as the initial stage in the transition from normal cognitive function to dementia. Consequently, the objective of our randomized controlled trial (RCT) is to further investigate whether the use of hearing aids can enhance cognitive function in older adults diagnosed with ARHL and MCI. METHODS AND DESIGN: This study is a parallel-arm, randomized controlled trial conducted at multiple centers in Shanghai, China. We aim to enlist a total of 688 older adults (age ≥ 60) diagnosed with moderate-to-severe ARHL and MCI from our four research centers. Participants will be assigned randomly to either the hearing aid fitting group or the health education group using block randomization with varying block sizes. Audiometry, cognitive function assessments, and other relevant data will be collected at baseline, as well as at 6, 12, and 24 months post-intervention by audiologists and trained researchers. The primary outcome of our study is the rate of progression to dementia among the two groups of participants. Additionally, various evaluations will be conducted to measure hearing improvement and changes in cognitive function. Apart from the final study results, we also plan to conduct an interim analysis using data from 12-month follow-up. DISCUSSION: In recent years, there has been a notable lack of randomized controlled trials (RCTs) investigating the possible causal relationship between hearing fitting and the improvement of cognitive function. Our findings may demonstrate that hearing rehabilitation can be a valuable tool in managing ARHL and preventing cognitive decline, which will contribute to the development of a comprehensive framework for the prevention and control of cognitive decline. TRIAL REGISTRATION: Chinese Clinical Trial Registry chictr.org.cn ChiCTR2000036139. Registered on 21 August 2020.

Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy.

Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8+ T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion were CD8+ T cell- and MHC-I-dependent, as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.

A study on the path of governance in health insurance fraud considering moral hazard.

Combating health insurance fraud is of utmost importance to physicians, patients, and health insurers. To delve into the mechanisms of health insurance fraud between doctors and patients, this study employed evolutionary game theory to construct a model that comprehensively considers moral hazard, fraud cost, reward, punishment, bribes from patients, and other factors. Through theoretical analysis and numerical simulation of the model, the study discovered that the evolution of governance behavior in health insurance fraud is closely linked to its initial construction of the payment matrix and the initial selection of parameters for the payment matrix. Additionally, increasing penalties for fraudulent behavior, increasing the cost of fraud for both doctors and patients, and reducing moral hazard for both can effectively drive the final strategy of the system toward a non-fraudulent state. The study aims to provide valuable insights and recommendations to doctors, patients, and medical insurance institutions in establishing a sound governance environment for managing fraud behavior in health insurance.

Reverse Micellar Dyeing of Cotton Fabric with Reactive Dye Using Biodegradable Non-Ionic Surfactant as Nanoscale Carrier: An Optimisation Study by One-Factor-at-One-Time Approach.

This study investigates the feasibility of using biodegradable secondary alcohol ethoxylate (SAE) non-ionic surfactant as a building block for the formation of reverse micelles, functioning as reactive dye carriers for the dyeing of cotton fabric in non-aqueous octane medium. Ten dyeing parameters were optimised, by a one-factor-at-a-time approach, namely: (i) effect of colour fixation agent; (ii) surfactant-to-water mole ratio; (iii) surfactant-to-co-surfactant mole ratio; (iv) volume of soda ash; (v) volume of dye; (vi) solvent-to-cotton ratio; (vii) dyeing temperature; (viii) dyeing time; (ix) fixation time; (x) soda-ash-to-cotton ratio. The colour properties, fastness properties and physical properties of SAE-dyed samples were experimentally compared with the conventional water-dyed samples. The optimised condition was found when SAE samples were dyed as follows: (a) 1:20 surfactant-to-water ratio; (b) 1:8 surfactant-to-co-surfactant ratio; (c) 10:1 solvent ratio; (d) 40 min dyeing time; (e) 60 min fixation time; and (f) 70 °C dyeing and fixation temperature. The results showed that SAE-dyed samples have better colour strength, lower reflectance percentage and comparable levelness, fastness and physical properties than that of water-dyed samples. SEM images revealed that the dyed cotton fibres had no severe surface damage caused by an SAE-based reverse micellar dyeing system. The TEM image depicts that the reverse micelle was of nanoscale, spherical-shaped and had a core-shell structure, validating the presence of reverse micelle as a reactive dye carrier and the potential of an SAE-based reverse micellar system for dyeing of cotton fabrics.