Facile formation of van der Waals metal contact with III-nitride semiconductors.

Metal-semiconductor contacts play a pivotal role in controlling carrier transport in the fabrication of modern electronic devices. The exploration of van der Waals (vdW) metal contacts in semiconductor devices can potentially mitigate Fermi-level pinning at the metal-semiconductor interface, with particular success in two-dimensional layered semiconductors, triggering unprecedented electrical and optical characteristics. In this work, for the first time, we report the direct integration of vdW metal contacts with bulk wide bandgap gallium nitride (GaN) by employing a dry transfer technique. High-angle annular dark-field scanning transmission electron microscopy explicitly illustrates the existence of a vdW gap between the metal electrode and GaN. Strikingly, compared with devices fabricated with electron beam-evaporated metal contacts, the vdW contact device exhibits a responsivity two orders of magnitude higher with a significantly suppressed dark current in the nanoampere range. Furthermore, by leveraging the high responsivity and persistent photoconductivity obtained from vdW contact devices, we demonstrate imaging, wireless optical communication, and neuromorphic computing functionality. The integration of vdW contacts with bulk semiconductors offers a promising architecture to overcome device fabrication challenges, forming nearly ideal metal-semiconductor contacts for future integrated electronics and optoelectronics.

BRD3308 suppresses macrophage oxidative stress and pyroptosis via upregulating acetylation of H3K27 in sepsis-induced acute lung injury.

Background: Sepsis-induced acute lung injury (ALI) leads to severe hypoxemia and respiratory failure, contributing to poor prognosis in septic patients. Endotoxin dissemination triggers oxidative stress and the release of inflammatory cytokines in macrophages, initiating diffuse alveolar damage. The role of epigenetic histone modifications in organ injury is increasingly recognized. The present study aimed to investigate the use of a histone modification inhibitor to alleviate sepsis-induced ALI, revealing a new strategy for improving sepsis patient survival. Methods: In vivo models of ALI were established through the intraperitoneal injection of lipopolysaccharide and cecal ligation and puncture surgery. Furthermore, the disease process was simulated in vitro by stimulating Tamm-Horsfall protein-1 (THP-1) cells with lipopolysaccharide. Hematoxylin and eosin staining, blood gas analysis and pulmonary function tests were utilized to assess the extent of lung tissue damage. Western blot analysis, real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence were used to measure the levels and distribution of the indicated indicators within cells and tissues. Reactive oxygen species and autophagic flux alterations were detected using specific probes. Results: BRD3308, which is a inhibitor of histone deacetylase 3, improved lung tissue damage, inflammatory infiltration and edema in ALI by inhibiting Nod-like receptor protein3-mediated pyroptosis in macrophages. By upregulating autophagy, BRD3308 improved the disruption of redox balance in macrophages and reduced the accumulation of reactive oxygen species. Mechanistically, BRD3308 inhibited histone deacetylase 3 activity by binding to it and altering its conformation. Following histone deacetylase 3 inhibition, acetylation of H3K27 was significantly increased. Moreover, the increase in H3K27Ac led to the upregulation of autophagy-related gene 5, a key component of autophagosomes, thereby activating autophagy. Conclusions: BRD3308 inhibits oxidative stress and pyroptosis in macrophages by modulating histone acetylation, thereby preventing sepsis-induced ALI. The present study provides a potential strategy and theoretical basis for the clinical treatment of sepsis-induced ALI.

Multifaceted paternal exposures before conception and their epigenetic impact on offspring.

As scientific research progresses, there is an increasing understanding of the importance of paternal epigenetics in influencing the health and developmental path of offspring. Prior to conception, the environmental exposures and lifestyle choices of fathers can significantly influence the epigenetic state of sperm, including DNA methylation and histone changes, among other factors. These alterations in epigenetic patterns have the potential for transgenerational transmission potential and may exert profound effects on the biological characteristics of descendants. Paternal epigenetic changes not only affect the regulation of gene expression patterns in offspring but also increase the risk to certain diseases. It is crucial to comprehend the conditions that fathers are exposed to before conception and the potential outcomes of these conditions. This understanding is essential for assessing personal reproductive decisions and anticipating health risks for future generations. This review article systematically summarizes and analyzes current research findings regarding how paternal pre-pregnancy exposures influence offspring as well as elucidates underlying mechanisms, aiming to provide a comprehensive perspective for an enhanced understanding of the impact that paternal factors have on offspring health.

Functional Characterization of 11 Tentative Microneme Proteins in Type I RH Strain of Toxoplasma gondii Using the CRISPR-Cas9 System.

Toxoplasma gondii, a pathogenic apicomplexan parasite, infects approximately one third of the world's population and poses a serious threat to global public health. Microneme proteins (MICs) secreted by the microneme, an apical secretory organelle of T. gondii, play important roles in the invasion, motility, and intracellular survival of T. gondii. In this study, we selected 11 genes of interest (GOIs) of T. gondii, tentative MICs predicted to be localized in micronemes, and we used the CRISPR-Cas9 system to construct epitope tagging strains and gene knockout strains to explore the localization and function of these 11 tentative MICs. Immunofluorescence assay showed that nine tentative MICs (TGME49_243930, TGME49_200270, TGME49_273320, TGME49_287040, TGME49_261710, TGME49_205680, TGME49_304490, TGME49_245485, and TGME49_224620) were localized or partially localized in the microneme, consistent with the prediction. However, TGME49_272380 and TGME49_243790 showed different localizations from the prediction, being localized in the endoplasmic reticulum and the dense granule, respectively. Further functional characterization of the 11 RHΔGOI strains revealed that deletion of these 11 GOIs had no significant effect on plaque formation, intracellular replication, egress, invasion ability, and virulence of T. gondii. Although these 11 GOIs are not essential genes for the growth and virulence of tachyzoites of type I RH strain, they may have potential roles in other developmental stages or other genotypes of T. gondii. Thus, further research should be performed to explore the possible role of the nine mics and the other two GOIs in other life cycle stages and other genotypes of T. gondii.

A Tandem Catalysis for Isoindolinone Synthesis over Single-atom Pd/TiO2 Catalyst.

Developing an efficient strategy to replace the conventional synthesis method for producing isoindolinone (IIO) scaffold, a crucial structural motif for constructing pharmaceutical molecules, remains to be a great challenge. Herein, a single-atom Pd/TiO2 tandem catalysis has been developed for the IIO scaffold synthesis by using readily available phthalic anhydride (PA), ammonia, and H2. The single-atom Pd/TiO2 catalyst demonstrates superior catalytic performance, achieving a PA conversion of 99%, an IIO selectivity of 91%, and a turnover frequency (TOF) up to 4807 h-1. This exceptional performance can be attributed to the tandem catalysis between TiO2 support and single-atom Pd. The TiO2 efficiently catalyzes the conversion of PA with ammonia to form phthalimide (PAM), subsequently transformed into IIO over TiO2 through the reaction of PAM with NH3 and the spillover hydrogen species derived from single-atom Pd. Notably, NH3 functions not only as a reactant but also as a promoter to accelerate the reduction of amides combined with the Pd/TiO2 catalyst. This tandem catalysis of a single-atom Pd/TiO2 catalyst provides a promising strategy for the synthesis of the crucial IIO platform molecules.

Clinical Characteristics and the Prognostic Impact of Acute Kidney Injury in Critically Ill Patients with Invasive Pulmonary Aspergillosis in the Intensive Care Unit: A Retrospective, Single-Center Study.

Introduction: The incidence and impact of acute kidney injury (AKI) in patients with invasive pulmonary aspergillosis (IPA) admitted to the intensive care unit (ICU) are unknown. Methods: This retrospective study included 140 patients who were diagnosed with IPA and admitted to the medical ICU of China-Japan Friendship Hospital in Beijing, China. AKI was defined according to the Kidney Disease: Improving Global Outcomes guidelines. Data on demographic characteristics, comorbidities, laboratory tests, treatments, and prognosis at ICU admission were collected. Results: The rate of AKI was 71.4% (n = 100), and approximately 30% of the patients had preadmission acute kidney dysfunction. Of the 100 patients with AKI, 19, 8, and 73 patients had stage I, II, and III AKI, respectively, and 64 (87.6%) patients required continuous renal replacement therapy. Overall ICU mortality rate was 52.1%. Irreversible AKI was a strong independent risk factor for ICU mortality (odds ratio 13.36, 95% confidence interval 4.52-39.48, p < 0.001), followed by chronic lung disease, use of intermittent positive-pressure ventilation, and long-term corticosteroid treatment within 1 year prior to ICU admission. Higher cardiac troponin I levels at admission and worse volume control during the first 7 days of ICU stay were potential predictive factors of irreversible kidney dysfunction. Patients with irreversible AKI and those who died during the ICU stay had greater volume overload during the first 14 days of ICU stay. Patients who survived received earlier renal replacement therapy support after ICU admission compared to those who died (median, 2 vs. 5 days; p = 0.026). Conclusion: Compared to the patients with IPA in the absence of AKI, those with AKI presented with more volume overload, worse disease burden, and required stronger respiratory support, while experiencing worse prognosis. Irreversible AKI was a strong predictor of mortality in patients with critical IPA. Better volume control and earlier CRRT initiation should be considered key points in AKI management and prognostic improvement.

Erbin alleviates sepsis-induced cardiomyopathy by inhibiting RIPK1-dependent necroptosis through activating PKA/CREB pathway.

Sepsis is a systemic inflammatory disease that can cause multiple organ damage. Septic patients with cardiac dysfunction have a significantly higher mortality. Based on the results of bioinformatics analysis, weighted gene co-expression network analysis (WGCNA), we found that Erbin is vital in cardiomyocyte. However, the function of Erbin in sepsis-induced cardiomyopathy (SIC) has not been explicitly studied. We discussed the role of Erbin in SIC by employing the Erbin-/- mice and HL-1 cardiomyocyte. An in vitro model of inflammation in HL-1 was used to confirm stimulation with lipopolysaccharide (LPS) and a mouse model of cecal ligation and puncture (CLP) to study the molecular mechanisms under SIC. Transmission electron microscopy (TEM) was used to characterize the morphological characteristics at the ultrastructural level. The expressions of Erbin, p-RIPK1, RIPK1, p-RIPK3, RIPK3, p-MLKL, MLKL, p-PKA, PKA, p-CREB and CREB were detected by western blot. qPCR analysis was applied to detect TNF-α, IL-1ß, IL-6, RIPK1 and MLKL mRNA expression. Cell survival was detected by CCK-8 assay and the levels of c TnI concentration were detected by ELISA kit. Our study revealed that necroptosis and inflammation were activated in cardiomyocytes during sepsis and deficiency of Erbin aggravated them. Furthermore, deficiency of Erbin exacerbated systolic dysfunction including the decline of LVEF and LVFS induced by CLP. Overexpression of Erbin alleviated necroptosis and inflammation by activating PKA/CREB pathway. Our research elucidates a noval mechanism whereby Erbin participates in SIC, providing a promising therapeutic target for myocardial dysfunction during sepsis.

Impact of corticosteroid doses on prognosis of severe and critical COVID-19 patients with Omicron variant infection: a propensity score matching study.

BACKGROUND: There is lack of research on corticosteroid use for severe and critical COVID-19 patients with Omicron variant infection. METHODS: This multi-center retrospective cohort study involved 1167 patients from 59 ICUs across the mainland of China diagnosed with severe or critical SARS-CoV-2 Omicron variant infection between November 1, 2022, and February 11, 2023. Patients were segregated into two groups based on their corticosteroid treatment-usual dose (equivalent prednisone dose 30-50 mg/day) and higher dose (equivalent prednisone dose > 50 mg/day). The primary outcome was 28-day ICU mortality. Propensity score matching was used to compare outcomes between cohorts. RESULTS: After propensity score matching, 520 patients in the usual dose corticosteroid group and 260 patients in the higher dose corticosteroid group were included in the analysis, respectively. The mortality was significantly higher in the higher dose corticosteroid group (67.3%, 175/260) compared to the usual dose group (56.0%, 291/520). Logistic regression showed that higher doses of corticosteroids were significantly associated with increased mortality at 28-day (OR = 1.62,95% CI 1.19-2.21, p = 0.002) and mortality in ICU stay (OR = 1.66,95% CI 1.21-2.28, p = 0.002). Different types of corticosteroids did not affect the effect. CONCLUSIONS: The study suggests that higher-dose corticosteroids may lead to a poorer prognosis for severe and critical COVID-19 patients with Omicron variant infection in the ICU. Further research is needed to determine the appropriate corticosteroid dosage for these patients.

Endothelial Cell-Derived Extracellular Vesicles Promote Aberrant Neutrophil Trafficking and Subsequent Remote Lung Injury.

The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis-induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single-cell RNA sequencing (scRNA-seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis-associated ARDS and is positively correlated with disease severity. Mechanically, scRNA-seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta-1 (KPNB1), promoting abluminal-to-luminal neutrophil rTEM. Additionally, EC-derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC-derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis-associated lung injury.

Shallow conductance decay along the heme array of a single tetraheme protein wire.

Multiheme cytochromes (MHCs) are the building blocks of highly conductive micrometre-long supramolecular wires found in so-called electrical bacteria. Recent studies have revealed that these proteins possess a long supramolecular array of closely packed heme cofactors along the main molecular axis alternating between perpendicular and stacking configurations (TST = T-shaped, stacked, T-shaped). While TST arrays have been identified as the likely electron conduit, the mechanisms of outstanding long-range charge transport observed in these structures remain unknown. Here we study charge transport on individual small tetraheme cytochromes (STCs) containing a single TST heme array. Individual STCs are trapped in a controllable nanoscale tunnelling gap. By modulating the tunnelling gap separation, we are able to selectively probe four different electron pathways involving 1, 2, 3 and 4 heme cofactors, respectively, leading to the determination of the electron tunnelling decay constant along the TST heme motif. Conductance calculations of selected single-STC junctions are in excellent agreement with experiments and suggest a mechanism of electron tunnelling with shallow length decay constant through an individual STC. These results demonstrate that an individual TST motif supporting electron tunnelling might contribute to a tunnelling-assisted charge transport diffusion mechanism in larger TST associations.

Self-Floating Polydopamine/Polystyrene Composite Porous Structure via a NaCl Template Method for Solar-Driven Interfacial Water Evaporation.

Solar energy, as a clean and renewable energy source, holds significant promise for addressing water shortages. Utilizing solar energy for water evaporation is seen as an effective solution in this regard. While many existing interfacial photothermal water evaporation systems rely on nanoparticles or graphene as photothermal or support materials, this study introduced polydopamine (PDA) as a photothermal material due to its environmental friendliness and excellent photon absorption characteristics that closely match the solar spectrum. Polystyrene (PS) was also introduced as a support material for its porous structure and density similar to water, enabling it to float on water. The resulting PS-PDA composite porous structure solar evaporator exhibited a photothermal conversion efficiency comparable to nanoparticles (over 75%), yet with lower production costs and minimal environmental impact. This innovative approach offers a scalable solution for water-scarce regions, providing a cost-effective and efficient means to address water scarcity. The use of PDA and PS in this context highlights the potential for utilizing common materials in novel ways to meet pressing environmental challenges.

Jianpi Jiedu Recipe Inhibits Proliferation through Reactive Oxygen Species-Induced Incomplete Autophagy and Reduces PD-L1 Expression in Colon Cancer.

BACKGROUND: Jianpi Jiedu Recipe has been used to treat digestive tract tumors in China since ancient times, and its reliability has been proven by clinical research. Currently, the specific biological mechanism of JPJDR in treating tumors is unclear. METHODOLOGY: CCK-8 assay was used to detect cell viability. Clone formation assay and EdU assay were used to detect cell proliferation potential. DCFH-DA probe and JC-1 probe were used to detect total intracellular reactive oxygen species and mitochondrial membrane potential, respectively. Western blotting and immunofluorescence were used to detect protein expression level and subcellular localization of cells. The RFP-GFP-LC3B reporter system was used to observe the type of autophagy in cells. The xenograft tumor model was used to study the therapeutic effect of JPJDR in vivo. RESULTS: JPJDR has an excellent inhibitory effect on various colorectal cancer cells and effectively reduces the proliferation ability of HT29 cells. After treatment with JPJDR, the amount of reactive oxygen species in HT29 cells increased significantly, and the mitochondrial membrane potential decreased. JPJDR induced the accumulation of autophagosomes in HT29 cells and was shown to be incomplete autophagy. At the same time, JPJDR reduced the expression of PD-L1. Meanwhile, JPJDR can exert an excellent therapeutic effect in xenograft tumor mice. CONCLUSION: JPJDR is a low-toxicity and effective anti-tumor agent that can effectively treat colon cancer in vitro and in vivo. Its mechanism may be inducing mitochondrial dysfunction and incomplete autophagy injury to inhibit the proliferation of colon cancer cells.

Effect of Metagenomic Next-Generation Sequencing on Clinical Outcomes of Patients With Severe Community-Acquired Pneumonia in the ICU: A Multicenter, Randomized Controlled Trial.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) was previously established as a method that can increase the pathogen identification rate in patients with severe community-acquired pneumonia (SCAP). RESEARCH QUESTION: What is the impact on clinical outcomes of mNGS of BAL fluid (BALF) in patients with SCAP in the ICU? STUDY DESIGN AND METHODS: A multicenter, randomized controlled, open-label clinical trial was conducted in 10 ICUs. Patients were randomized in a 1:1 ratio to undergo BALF assessment with conventional microbiological tests (CMTs) only (ie, the CMT group) or BALF assessment with both mNGS and CMTs (ie, the mNGS group). The primary outcome was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the ICU, whichever occurred first. RESULTS: A total of 349 patients were randomized to treatment between January 1, 2021, and November 18, 2022; 170 were assigned to the CMT group and 179 to the mNGS group. In the intention-to-treat analysis, the time to clinical improvement was better in the mNGS group than in the CMT group (10 days vs 13 days; difference, -2.0 days; 95% CI, -3.0 to 0.0 days). Similar results were obtained in the per-protocol analysis. The proportion of patients with clinical improvement within 14 days was significantly higher in the mNGS group (62.0%) than in the CMT group (46.5%). There was no significant difference in other secondary outcomes. INTERPRETATION: Compared with the use of CMTs alone, mNGS combined with CMTs reduced the time to clinical improvement for patients with SCAP. CLINICAL TRIAL REGISTRATION: ChiCTR2000037894.

The deubiquitinase OTUD1 deubiquitinates TIPE2 and plays a protective role in sepsis-induced lung injury by targeting TAK1-mediated MAPK and NF-κB signaling.

Ovarian tumor domain-containing protease 1 (OTUD1) is a critical negative regulator that promotes innate immune homeostasis and is extensively involved in the pathogenesis of sepsis. In this study, we performed a powerful integration of multiomics analysis and an experimental mechanistic investigation to elucidate the immunoregulatory role of OTUD1 in sepsis at the clinical, animal and cellular levels. Our study revealed the upregulation of OTUD1 expression and the related distinctive alterations observed via multiomics profiling in clinical and experimental sepsis. Importantly, in vivo and in vitro, OTUD1 was shown to negatively regulate inflammatory responses and play a protective role in sepsis-induced pathological lung injury by mechanistically inhibiting the activation of the transforming growth factor-beta-activated kinase 1 (TAK1)-mediated mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in the present study. Subsequently, we probed the molecular mechanisms underlying OTUD1's regulation of NF-κB and MAPK pathways by pinpointing the target proteins that OTUD1 can deubiquitinate. Drawing upon prior research conducted in our laboratory, it has been demonstrated that tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) performs a protective function in septic lung injury and septic encephalopathy by suppressing the NF-κB and MAPK pathways. Hence, we hypothesized that TIPE2 might be a target protein of OTUD1. Additional experiments, including Co-IP, immunofluorescence co-localization, and Western blotting, revealed that OTUD1 indeed has the ability to deubiquitinate TIPE2. In summary, OTUD1 holds potential as an immunoregulatory and inflammatory checkpoint agent, and could serve as a promising therapeutic target for sepsis-induced lung injury.

Design, synthesis, and biological evaluation of novel highly selective non-carboxylic acid FABP1 inhibitors.

Histologic spectrum studies in patients revealed fatty acid binding proteins 1 (FABP1) as a potential new target for the treatment of metabolic associated fatty liver disease. However, there is no FABP1 inhibitor has been reported except the first-in-class FABP1 inhibitor bearing acid moiety reported by our laboratory. Herein, we firstly report the structure-activity relationship of novel non-carboxylic acid FABP1 inhibitors, which resulted in the identification of the potent and selective FABP1 inhibitor 30. The IC50 value of compound 30 for subtype FABP4 in the same family was greater than 80 µM. Moreover, compound 30 significantly alleviated the hepatic steatosis in DIO mice, which is equivalent to that of clinical drug obeticholic acid. This study might be provided a promising probe for the development of FABP1 inhibitors and thus can help to further elucidate the pharmacology of FABP1.

Functional Characterization of Six Eukaryotic Translation Initiation Factors of Toxoplasma gondii Using the CRISPR-Cas9 System.

Eukaryotic translation initiation factors (eIFs) are crucial for initiating protein translation and ensuring the correct assembly of mRNA-ribosomal subunit complexes. In this study, we investigated the effects of deleting six eIFs in the apicomplexan parasite Toxoplasma gondii using the CRISPR-Cas9 system. We determined the subcellular localization of these eIFs using C-terminal endogenous tagging and immunofluorescence analysis. Four eIFs (RH::315150-6HA, RH::286090-6HA, RH::249370-6HA, and RH::211410-6HA) were localized in the cytoplasm, while RH::224235-6HA was localized in the apicoplast. Additionally, RH::272640-6HA was found in both the basal complex and the cytoplasm of T. gondii. Functional characterization of the six RHΔeIFs strains was conducted using plaque assay, cell invasion assay, intracellular growth assay and egress assay in vitro, and virulence assay in mice. Disruption of five eIF genes (RHΔ315150, RHΔ272640, RHΔ249370, RHΔ211410, and RHΔ224235) did not affect the ability of the T. gondii RH strain to invade, replicate, form plaques and egress in vitro, or virulence in Kunming mice (p > 0.05). However, the RHΔ286090 strain showed slightly reduced invasion efficiency and virulence (p < 0.01) compared to the other five RHΔeIFs strains and the wild-type strain. The disruption of the TGGT1_286090 gene significantly impaired the ability of tachyzoites to differentiate into bradyzoites in both type I RH and type II Pru strains. These findings reveal that the eukaryotic translation initiation factor TGGT1_286090 is crucial for T. gondii bradyzoite differentiation and may serve as a potential target for drug development and an attenuated vaccine against T. gondii.

Correlation between geriatric nutritional risk index and intradialytic hypotension in elderly patients undergoing maintenance hemodialysis: a case-control study.

BACKGROUND: There is a correlation between nutritional status and treatment outcomes and long-term survival in MHD patients but there is limited research on the relationship between GNRI and IDH. This case-control study aimed to investigate the correlation between Geriatric Nutritional Risk Index (GNRI) and intradialytic hypotension (IDH) in elderly patients undergoing maintenance hemodialysis (MHD). METHODS: This study was carried out on 129 cases of MHD patients with IDH and 258 non-IDH-controls in Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China, between June 2020 and May 2022. Professional researchers collected patients' general information on gender, primary disease, dialysis-related indicators, anthropometric measures, laboratory biochemicals, and GNRI. Logistic regression analysis was used to evaluate the correlation between GNRI and IDH. RESULTS: A total of 385 elderly MHD patients were included. Compared with GNRI Q4 group, the odds ratios for the risk of IDH in GNRI Q3 group, GNRI Q2 group, and GNRI Q1 group of elderly MHD patients were 1.227, 2.196, and 8.350, respectively, showing a significant downward trend (P-trend < 0.05). The area under the curve of GNRI for predicting IDH was 0.839 (95% CI: 0.799-0.879). Between different genders, a decrease in GNRI was closely related to an increase in IDH risk (P for trend < 0.05). CONCLUSIONS: This research shows a significant association between GNRI and the incidence of IDH among elderly MHD patients and has an important warning effect. Encouraging the incorporation of GNRI assessment into the clinical assessment protocols of older patients with MHD may help to improve the nutritional status of those suffering from it and reduce the risk of IDH.

GRA47 is important for the morphology and permeability of the parasitophorous vacuole in Toxoplasma gondii.

Establishing an intact intracellular parasitophorous vacuole (PV) that enables efficient nutrient uptake and protein trafficking is essential for the survival and proliferation of Toxoplasma gondii. Although the PV membrane (PVM)-localized dense granule protein 17 (GRA17) and GRA23 mediate the permeability of the PVM to small molecules, including nutrient uptake and excretion of metabolic by-products, the molecular mechanism by which T. gondii acquires nutrients remains unclear. In this study, we showed that the secreted protein GRA47 contributed to normal PV morphology, PVM permeability to small molecules, growth, and virulence in T. gondii. Co-immunoprecipitation analysis demonstrated potential interaction of GRA47 with GRA72, and the loss of GRA72 affected PV morphology, parasite growth and infectivity. To investigate the biological relationship among GRA47, GRA72, GRA17 and GRA23, attempts were made to construct strains with double gene deletion and overexpressing strains. Only Δgra23Δgra72 was successfully constructed. This strain exhibited a significant increase in the proportion of aberrant PVs compared with the Δgra23 strain. Overexpressing one of the three related GRAs partially rescued PVs with aberrant morphology in Δgra47, Δgra72 and Δgra17, while the expression of the Plasmodium falciparum PVM protein PfExp2, an ortholog of GRA17 and GRA23, fully rescued the PV morphological defect in all three Δgra strains. These results suggest that these GRA proteins may not be functionally redundant but rather work in different ways to regulate nutrient acquisition. These findings highlight the versatility of the nutrient uptake mechanisms in T. gondii, which may contribute to the parasite's remarkable ability to grow in different cellular niches in a very broad range of hosts.