Type 1 diabetes mellitus and non-alcoholic fatty liver disease: a two-sample Mendelian randomization study.

Background: NAFLD (Nonalcoholic fatty liver disease) is becoming an increasingly common cause of chronic liver disease. Metabolic dysfunction, overweight/obesity, and diabetes are thought to be closely associated with increased NAFLD risk. However, few studies have focused on the mechanisms of NAFLD occurrence in T1DM. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal association between T1DM and NAFLD with/without complications, such as coma, renal complications, ketoacidosis, neurological complications, and ophthalmic complications. Multiple Mendelian randomization methods, such as the inverse variance weighted (IVW) method, weighted median method, and MR-Egger test were performed to evaluate the causal association of T1DM and NAFLD using genome-wide association study summary data from different consortia, such as Finngen and UK biobank. Results: We selected 37 SNPs strongly associated with NAFLD/LFC (at a significance level of p < 5 × 10-8) as instrumental variables from the Finnish database based on the T1DM phenotype (8,967 cases and 308,373 controls). We also selected 14/16 SNPs based on with or without complications. The results suggest that the genetic susceptibility of T1DM does not increase the risk of NAFLD (OR=1.005 [0.99, 1.02], IVW p=0.516, MR Egger p=0.344, Weighted median p=0.959, Weighted mode p=0.791), regardless of whether complications are present. A slight causal effect of T1DM without complications on LFC was observed (OR=1.025 [1.00, 1.03], MR Egger p=0.045). However, none of the causal relationships were significant in the IVW (p=0.317), Weighted median (p=0.076), and Weighted mode (p=0.163) methods. Conclusion: Our study did not find conclusive evidence for a causal association between T1DM and NAFLD, although clinical observations indicate increasing abnormal transaminase prevalence and NAFLD progression in T1DM patients.

Identification of Piperazinyl-Difluoro-indene Derivatives Containing Pyridyl Groups as Potent FGFR Inhibitors against FGFR Mutant Tumor: Design, Synthesis, and Biological Evaluation.

The fibroblast growth factor receptor (FGFR) signaling pathway plays important roles in cellular processes such as proliferation, differentiation, and migration. In this study, we highlighted the potential of FGFR inhibitors bearing the (S)-3,3-difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene scaffold containing a crucial 3-pyridyl group for the treatment of FGFR mutant cancers. The representative compound (S)-23, which was identified through comprehensive evaluation, exhibited potent antiproliferative activity with GI50 in the range of 6.4-10.4 nM against FGFR1 fusion protein-carrying, FGFR2-amplified, and FGFR2 mutant cancer cell lines and good antiproliferative activity against FGFR3 translocation and mutant FGFR4 cancer cell lines, as well as potency assessment against FGFR1-4 kinases. Moreover, compound (S)-23 exhibited favorable pharmacokinetic properties, low potential for drug-drug interactions, and very potent antitumor activity in MFE-296 xenograft mouse models with a TGI of 99.1% at the dose of 10 mg/kg. These findings demonstrate that compound (S)-23 is a potential therapeutic agent for FGFR mutant tumors.

The distribution of heterophilic antigens and their relationship with autoimmune diseases.

Introduction: Microbial infections are associated with the occurrence of autoimmune diseases, but the mechanisms of microbial infection inducing autoimmune diseases are not fully understood. The existence of heterophilic antigens between microorganisms and human tissues may explain part of the pathogenesis of autoimmune diseases. Here, we investigate the distribution of heterophilic antigens and its relationship with autoimmune diseases. Methods: Monoclonal antibodies against a variety of microorganisms were prepared. The titer, subclass and reactivity of antibodies with microorganisms were identified, and heterophilic antibodies that cross-reacted with human tissues were screened by human tissue microarray. The reactivity of these heterophilic antibodies with different individuals and different species was further examined by immunohistochemistry. Results: In this study, 21 strains of heterophilic antibodies were screened. The results showed that these heterophilic antibodies were produced due to the existence of heterophilic antigens between microorganism and human body and the distribution of heterophilic antigens had individual, tissue and species differences. Conclusion: Our study showed that heterophilic antigens exist widely between microorganisms and human body, and the heterophilic antigens carried by microorganisms may break the immune tolerance of the body through carrier effect and initiate immune response, which may be one of the important mechanisms of infection inducing autoimmune diseases.

Reduced Graphene Oxide Modulated FeSe/C Anode Materials for High-Stable and Long-Life Potassium-Ion Batteries.

Reduced graphene oxide (rGO) has been demonstrated to effectively enhance the potassium storage performance of transition metal selenides due to its robust mechanical properties and high conductivity. However, the impact of rGO on the electrode-electrolyte interface, a crucial factor in the electrochemical performance of potassium-ion batteries (PIBs), requires further exploration. In this study, we synthesized a seamless architecture of rGO on FeSe/C nanocrystals (FeSe/C@rGO). Comparative analysis between FeSe/C and FeSe/C@rGO reveals that the rGO layer exhibits robust adsorption energies towards EC and DEC, inducing the formation of organic-rich solid-electrolyte interphase (SEI) without damage to the structural integrity. Furthermore, incorporating rGO triggers K+ -ions into the double electrode layer (EDL), markedly improving the transport of K+ -ions. As a PIB anode, FeSe/C@rGO exhibits a reversible capacity of 332 mAh g-1 at 200 mA g-1 after 300 cycles, along with excellent long-term cycling stability, showcasing an ultralow decay rate of only 0.086 % per cycle after 1900 cycles at 1000 mA g-1 .

Organizational display rules in nursing: Impacts on caring behaviors and emotional exhaustion through emotional labor.

AIM: To examine the impact of display rules on nurses' caring behaviors and emotional exhaustion and the mediating role of emotional labor (surface/deep acting). BACKGROUND: Hospitals often implement emotional display rules for nurses with the expectation of performance benefits. However, these rules may have an impact on nurses' caring behaviors and emotional exhaustion. METHODS: This cross-sectional correlational study included a sample of 746 nurses from five hospitals and used the STROBE checklist. Relationships between display rules, emotional labor, caring behaviors, and emotional exhaustion were analyzed using structural equation modeling. RESULTS: Display rules did not directly affect caring behaviors or emotional exhaustion. Emotional labor mediated the relationships. Display rules were associated more with surface acting. Deep acting increased caring behaviors and reduced emotional exhaustion; surface acting had the opposite effect. CONCLUSIONS: Findings challenge the assumption that display rules effectively promote caring behaviors. Display rules lead to emotional labor and emotional exhaustion. Reducing display rules, emotional labor, and surface acting while supporting deep acting may alleviate emotional exhaustion. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Nurse managers should review the nature and implementation of emotional display rules and explore ways to reduce emotional labor, encourage deep acting, mitigate the negative impact of surface acting, and ultimately improve nursing caring behaviors.

Carnitine palmitoyltransferase 1A promotes mitochondrial fission by enhancing MFF succinylation in ovarian cancer.

Mitochondria are dynamic organelles that are important for cell growth and proliferation. Dysregulated mitochondrial dynamics are highly associated with the initiation and progression of various cancers, including ovarian cancer. However, the regulatory mechanism underlying mitochondrial dynamics is still not fully understood. Previously, our study showed that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer cells and promotes the development of ovarian cancer. Here, we find that CPT1A regulates mitochondrial dynamics and promotes mitochondrial fission in ovarian cancer cells. Our study futher shows that CPT1A regulates mitochondrial fission and function through mitochondrial fission factor (MFF) to promote the growth and proliferation of ovarian cancer cells. Mechanistically, we show that CPT1A promotes succinylation of MFF at lysine 302 (K302), which protects against Parkin-mediated ubiquitin-proteasomal degradation of MFF. Finally, the study shows that MFF is highly expressed in ovarian cancer cells and that high MFF expression is associated with poor prognosis in patients with ovarian cancer. MFF inhibition significantly inhibits the progression of ovarian cancer in vivo. Overall, CPT1A regulates mitochondrial dynamics through MFF succinylation to promote the development of ovarian cancer. Moreover, our findings suggest that MFF is a potential therapeutic target for ovarian cancer.

Cellular and molecular insights into incomplete immune recovery in HIV/AIDS patients.

Highly active antiretroviral therapy (ART) can effectively inhibit virus replication and restore immune function in most people living with human immunodeficiency virus (HIV). However, an important proportion of patients fail to achieve a satisfactory increase in CD4+ T cell counts. This state is called incomplete immune reconstitution or immunological nonresponse (INR). Patients with INR have an increased risk of clinical progression and higher rates of mortality. Despite widespread attention to INR, the precise mechanisms remain unclear. In this review, we will discuss the alterations in the quantity and quality of CD4+ T as well as multiple immunocytes, changes in soluble molecules and cytokines, and their relationship with INR, aimed to provide cellular and molecular insights into incomplete immune reconstitution.

Iron-Doped Metal-Zinc-Centered Organic Framework Mesoporous Carbon Derivatives for Single-Wavelength NIR-Activated Photothermal/Photodynamic Synergistic Therapy.

Recently, single-wavelength synergetic photothermal/photodynamic (PTT/PDT) therapy is beginning to make its mark in cancer treatment, and the key to it is a photosensitizer. In this work, an iron-doped metal-zinc-centered organic framework mesoporous carbon derivative (denoted as Fex-Zn-NCT) with a similar porphyrin property was successfully synthesized by a mild, simple, and green aqueous reaction. The effects of different Fe contents and pyrolysis temperatures on the morphology, structure, and PTT/PDT of Fex-Zn-NCT were investigated. Most importantly, we found that Fe50-Zn-NC900 exhibited excellent PTT/PDT performance under single-wavelength near-infrared (808 nm) light irradiation in a hydrophilic environment. The photothermal conversion efficiency (η) was counted as ∼81.3%, and the singlet oxygen (1O2) quantum yield (Φ) was compared with indocyanine green (ICG) as ∼0.0041. Furthermore, Fe50-Zn-NC900 is provided with a clear ability for generating 1O2 in living tumor cells and inducted massive necrosis/apoptosis of tumor cells with single-wavelength near-infrared laser irradiation. All of these are clear to consider that Fe50-Zn-NC900 displays great potential as an excellent photosensitizer for single-wavelength dual-mode PTT/PDT therapy.

Stress-Dispersed Superstructure of Sn3 (PO4 )2 @PC Derived from Programmable Assembly of Metal-Organic Framework as Long-Life Potassium/Sodium-Ion Batteries Anodes.

The structures of anode materials significantly affect their properties in rechargeable batteries. Material nanosizing and electrode integrity are both beneficial for performance enhancement of batteries, but it is challenging to guarantee optimized nanosizing particles and high structural integrity simultaneously. Herein, a programmable assembly strategy of metal-organic frameworks (MOFs) is used to construct a Sn-based MOF superstructure precursor. After calcination under inert atmosphere, the as-fabricated Sn3 (PO4 )2 @phosphorus doped carbon (Sn3 (PO4 )2 @PC-48) well inherited the morphology of Sn-MOF superstructure precursor. The resultant new material exhibits appreciable reversible capacity and low capacity degradation for K+ storage (144.0 mAh g-1 at 5 A g-1 with 90.1% capacity retained after 10000 cycles) and Na+ storage (202.5 mAh g-1 at 5 A g-1 with 96.0% capacity retained after 8000 cycles). Detailed characterizations, density functional theory calculations, and finite element analysis simulations reveal that the optimized electronic structure and the stress-dispersed superstructure morphology of Sn3 (PO4 )2 @PC promote the electronic conductivity, enhance K+ / Na+ binding ability and improve the structure stabilization efficiently. This strategy to optimize the structure of anode materials by controlling the MOF growth process offer new dimension to regulate the materials precisely in the energy field.

Identification of Heterophilic Epitopes of H1N1 Influenza Virus Hemagglutinin.

Our previous studies found that the H1-50 monoclonal antibody (mAb) of influenza A virus hemagglutinin (HA) cross-reacted with pancreatic tissue and islet ß-cells, and further studies showed that H1-50 mAb binds to prohibitin (PHB) protein of islet ß-cells. These suggest that there are heterophilic epitopes between influenza virus HA and pancreatic tissue, which may be involved in the pathogenesis of type 1 diabetes. To further investigate these heterophilic epitopes, we screened binding epitopes of H1-50 mAb using a phage 12-peptide library. DNA sequencing and comparative analysis were performed on specific positive phage clones, and the sequence of 12-peptide binding to H1-50 mAb was obtained. The binding epitopes of H1-50 mAb in influenza virus HA were determined by sequence analysis and experimental verification, and their distribution within the three-dimensional structure was assessed by PyMOL. The results showed that H1-50 mAb specifically binds to polypeptides (306-SLPFQNIHPITIGK-319) of influenza A virus HA, located in the stem of the HA protein. However, there is no specific binding sequence between H1-50 mAb and the PHB protein of islet ß-cells in the primary structure, and we speculate that the binding of H1-50 mAb to islet ß-cells may depend on the spatial conformation. The identification of the heterophilic epitopes of H1N1 influenza virus hemagglutinin provides a new perspective on type 1 diabetes that may be caused by influenza virus infection, which may contribute to the prevention and control of influenza.

Controllable Exfoliation of MOF-Derived Van Der Waals Superstructure into Ultrathin 2D B/N Co-Doped Porous Carbon Nanosheets: A Superior Catalyst for Ambient Ammonia Electrosynthesis.

The electrocatalytic nitrogen reduction reaction (NRR) to synthesize NH3 under ambient conditions is a promising alternative route to the conventional Haber-Bosch process, but it is still a great challenge to develop electrocatalysts' high Faraday efficiency and ammonia yield. Herein, a facile and efficient exfoliation strategy to synthesize ultrathin 2D boron and nitrogen co-doped porous carbon nanosheets (B/NC NS) via a metal-organic framework (MOF)-derived van der Waals superstructure, is reported. The results of experiments and theoretical calculations show that the doping of boron and nitrogen can modulate the electronic structure of the adjacent carbon atoms; which thus, promotes the competitive adsorption of nitrogen and reduces the energy required for ammonia synthesis. The B/NC NS exhibits excellent catalytic performance and stability in electrocatalytic NRR, with a yield rate of 153.4 µg·h-1 ·mg-1 cat and a Faraday efficiency of 33.1%, which is better than most of the reported NRR electrocatalysts. The ammonia yield of B/NC NS can maintain 92.7% of the initial NRR activity after 48 h stability test. The authors' controllable exfoliation strategy using MOF-derived van der Waals superstructure can provide a new insight for the synthesis of other 2D materials.

Metal-Organic Framework Derived Ni2P/FeP@NPC Heterojunction as Stability Bifunctional Electrocatalysts for Large Current Density Water Splitting.

The construction of heterojunction has been widely accepted as a prospective strategy for the exploration of non-precious metal-based catalysts that possess high-performance to achieve electrochemical water splitting. Herein, we design and prepare a metal-organic framework derived N, P-doped-carbon-encapsulated Ni2P/FeP nanorod with heterojunction (Ni2P/FeP@NPC) for accelerating the water splitting and working stably at industrially relevant high current densities. Electrochemical results confirmed that Ni2P/FeP@NPC could both accelerate the hydrogen and oxygen evolution reactions. It could substantially expedite the overall water splitting (1.94 V for 100 mA cm-2) which is close to the performance of RuO2 and the Pt/C couple (1.92 V for 100 mA cm-2). In particular, the durability test exhibited that Ni2P/FeP@NPC delivers 500 mA cm-2 without decay after 200 h, demonstrating the great potential for large-scale applications. Furthermore, the density functional theory simulations demonstrated that the heterojunction interface could give rise to the redistribution of electrons, which could not only optimize the adsorption energy of H-containing intermediates to achieve the optimal ΔGH* in a hydrogen evolution reaction, but also reduce the ΔG value in the rate-determining step of an oxygen evolution reaction, thus improving the HER/OER performance.

Self-Terminating Surface Reconstruction Induced by High-Index Facets of Delafossite for Accelerating Ammonia Oxidation Reaction Involving Lattice Oxygen.

Ammonia (NH3 ) is a promising hydrogen (H2 ) carrier for future carbon-free energy systems, due to its high hydrogen content and easiness to be liquefied. Inexpensive and efficient catalysts for ammonia electro-oxidation reaction (AOR) are desired in whole ammonia-based energy systems. In this work, ultrasmall delafossite (CuFeO2 ) polyhedrons with exposed high-index facets are prepared by a one-step NH3 -assisted hydrothermal method, serving as AOR pre-catalysts. The high-index CuFeO2 facet is revealed to facilitate surface reconstruction into active Cu-doped FeOOH nanolayers during AOR processes in ammonia alkaline solutions, which is driven by the favorable Cu leaching and terminates as the 2p levels of internal lattice oxygen change. The reconstructed heterostructures of CuFeO2 and Cu-doped FeOOH effectively activate the dehydrogenation steps of NH3 and exhibit a potential improvement of 260 mV for electrocatalytic AOR at 10 mA cm-2 compared to the pre-restructured phase. Further, density functional theory (DFT) calculations confirm that a lower energy barrier of the rate-determining step (*NH3 to *NH2 ) is presented on high-index CuFeO2 facets covered with Cu-doped FeOOH nanolayers. Innovatively, lattice oxygen atoms in Fe-based oxides and oxyhydroxide are involved in the dehydrogenation steps of AOR as a proton acceptor, broadening the horizons for rational designs of AOR catalysts.

Thirteen-year viral suppression and immunologic recovery of LPV/r-based regimens in pediatric HIV treatment: a multicenter cohort study in resource-constrained settings of China.

Background: Antiretroviral Therapy (ART) in children remains challenging due to resource-constrained settings. We conducted a 13-year, prospective, multicenter cohort study on the effectiveness and safety of LPV/r-based regimens in ART-naive and ART-experienced children. Methods: From January 2008 to May 2021, children living with HIV-1 were recruited with LPV/r-based regimens from 8 clinical research sites in 6 provinces in China. Effectiveness outcomes were virologic failure (defined as at least two consecutive measurements of VL > 200 copies/mL after 6 months of ART) and immune response (defined as CD4% recovered to more than 25% after 12 months of treatment). The safety outcomes were treatment-related grade 2-4 adverse events and abnormal laboratory test results. Results: A total of 345 ART-naïve children and 113 ART-experienced children were included in this cohort study. The median follow-up time was 7.3 (IQR 5.5-10.5) years. The incidence density of virologic failure was 4.1 (95% CI 3.3-4.9) per 100 person-years in ART-naïve children and 5.0 (95% CI 3.5-6.5) per 100 person-years in ART-experienced children. Kaplan Meyer (KM) curve analysis showed children with ART experience were at a higher risk of virologic failure (p < 0.05). The risk factors of virologic failure in ART-naïve children were clinic setting in rural hospitals (aHR = 2.251, 1.108-4.575), annual missed dose times >5 days of LPV intake (aHR = 1.889, 1.004-3.554); The risk factor of virologic failure in ART-experienced children was missed dose times >5 days (aHR = 2.689, 1.299-5.604) and mother as caregivers for ART administration (aHR = 0.475, 0.238-0.948). However, during long-term treatment, viral suppression rates between ART-naïve and ART-experienced children remained similar. No significant differences were observed in the immune response, treatment-related grade 2-4 events, and abnormal laboratory test results between ART-naïve children and ART-experienced children. Conclusion: Our research underscores that with consistent, long-term treatment of LPV/r-based regimens, ART-experienced children can achieve therapeutic outcomes comparable to ART-naïve children. It provides crucial insights on LPV/r-based regimens in pediatric HIV treatment, especially in resource-limited settings where high-cost Integrase Strand Transfer Inhibitors (INSTs) are inaccessible. This evidence-based understanding provides an essential addition to the global therapeutic strategies for pediatric HIV treatment.

Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-responders.

BACKGROUND: HIV immune non-responders (INRs) are described as a failure to reestablish a pool of CD4+ T lymphocytes (CD4 cells) after antiretroviral therapy (ART), which is related to poor clinical results. Ferroptosis is a newly discovered form of cell death characterised by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). The mechanism of unrecoverable CD4 cells in INRs and whether ferroptosis plays a role are not fully understood. METHODS: Ninety-two people living with HIV (PLHIVs) who experienced four-year ART with sustained viral suppression, including 27 INRs, 34 partial responders (PRs), and 31 complete responders (CRs); and 26 uninfected control participants (UCs) were analysed for 16 immune parameters with flow cytometry. Then plasma lipid, iron and oxidation, and antioxidant indicators were detected by ELISA, and CD4 cells were sorted out and visualised under transmission electron microscopy. Finally, ferroptosis inhibitors were added, and alterations in CD4 cell phenotype and function were observed. FINDINGS: We found decreased recent thymic emigrants (RTE), over-activation and over-proliferation phenotypes, diminished killing function, decreased IL-7R and more severe inflammation; increased lipid peroxidation in the mitochondria and disruptions of the mitochondrial structure, showing typical features of ferroptosis in CD4 cells in INRs. Additionally, ferroptosis inhibitors could reduce inflammation and repair mitochondrial damage. Meanwhile, ELISA results showed increased plasma free fatty acids (FFA) and an imbalance of oxidative and antioxidant systems in INRs. Flow cytometry results displayed alterations of both transferrin receptor (CD71) and lipid transporter (CD36) expressions on the surface of CD4 cells. Mechanistically, there was a stronger correlation between CD36 expression and mitochondrial lipid peroxidation production, ferroptosis makers, and inflammation indicators; while amino acid transporter (CD98) was more related to killing functions; and CD71 was more closely related to activation status in CD4 cells. INTERPRETATION: Cellular metabolism was closely correlated with its diverse functions in INRs. Ferroptosis was observed in CD4 cells of INRs, and inhibiting ferroptosis through modulating mitochondrial disorders and inflammation may offer an alternative immunological strategy for reinvigorating CD4 cells in INRs. FUNDING: This research was supported by the 13th Five-year Plan, Ministry of Science and Technology of China (2018ZX10302-102), Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20191802), and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX202126).

Elucidating the Gene Signatures and Immune Cell Types in HIV-Infected Immunological Non-Responders by Bioinformatics Analyses.

Objective: Numerous studies have reported on the pathogenesis of poor immune reconstitution (PIR) after antiretroviral treatment in human immunodeficiency virus (HIV) patients. However, fewer studies focused on both immune-related genes (IRGs) and immune cells, and the correlation between IRGs and immune cells was evaluated via bioinformatics analyses. Methods: Gene expression profiling of GSE143742 from the Gene Expression Omnibus (GEO) database was analyzed to get differentially expressed immune-related genes (DEIRGs). The enrichment analysis and protein-protein interaction (PPI) networks of DEIRGs were established. The relative fractions of 22 immune cell types were detected using the "CIBERSORT". The correlation analysis between DEIRGs and immune cells was constructed to discover the potential IRGs associated with immune cells. A logistic regression diagnostic model was built, and a receiver operating characteristic (ROC) curve was performed to evaluate the model's diagnostic efficacy. The CMap database was used to find molecules with therapeutic potential. RT-qPCR was used to verify the expression of the hub DEIRGs. Results: We identified eight types of significantly changed immune cells and five hub IRGs in INRs. The DEIRGs were mainly enriched in lymphocyte activation, receptor-ligand activity, and T cell receptor signaling pathway. The correlation analysis showed that the expression of TNF, CXCR4 and TFRC correlate with CD8 cells, resting mast cells, activated NK cells, and naïve CD4 cells in INRs. Meanwhile, TFRC and IL7R relate to activated NK cells and resting memory CD4 cells respectively in IRs. A diagnostic model was constructed using multiple logistic regression and nine small molecules were identified as possible drugs. Conclusion: In this study, we suggested that the process of PIR might be related to TNF, CXCR4, TFRC, CD48, and IL7R. And these IRGs play roles in regulating immune-competent cells. And our constructed diagnostic model has excellent effectiveness. Moreover, some small-molecule drugs are screened to alleviate PIR.

A Concentration Method for HIV Drug Resistance Testing in Low-Level Viremia Samples.

Background: Drug resistance testing in HIV-1 low-level viremia (LLV) samples is challenging yet critical. Our study is aimed at assessing the performance of lentivirus concentration reagent (LCR) in combination with a validated Sanger sequencing (SS) for monitoring drug resistance mutations (DRMs) in LLV samples. Methods: A series of clinical samples were diluted and amplified for genotypic resistance testing (GRT) to prove the performance of the LCR. The Stanford HIV-1 drug resistance database (HIVdb version 8.9) was used to analyze the mutations. HIV-1 subtypes and CRFs were determined using the COMET online tool. The overall success rate of genotyping was compared with ultracentrifugation combined with SS. Furthermore, the success rates at varied VL of the two concentration methods were evaluated, and the DRMs of diluted samples were compared with those undiluted samples. Results: When LCR was used, the overall success rate was 90% (72/80) in the PR and RT regions and 60% (48/80) in the IN region. In addition, when HIV RNA was 1000 copies/ml, 400 copies/ml, 200 copies/ml, and 100 copies/ml, the success rates of PR and RT regions were 100%, 100%, 95%, and 65%, respectively, while the success rates of IN region were 85%, 60%, 45%, and 50%, respectively. We found that the sample DR-387A2 missed the E138A mutation, and mutations in other samples were consistent with undiluted samples using LCR. Conclusions: LCR will support monitoring DRMs in HIV-1 patients with LLV and can be an effective alternative for small- and medium-sized laboratories that cannot afford an ultracentrifuge.

Alterations in circulating markers in HIV/AIDS patients with poor immune reconstitution: Novel insights from microbial translocation and innate immunity.

After long-term anti-retroviral therapy (ART) treatment, most human immunodeficiency virus (HIV)/Acquired Immure Deficiency Syndrome (AIDS) patients can achieve virological suppression and gradual recovery of CD4+ T-lymphocyte (CD4+ T cell) counts. However, some patients still fail to attain normal CD4+ T cell counts; this group of patients are called immune non-responders (INRs), and these patients show severe immune dysfunction. The potential mechanism of poor immune reconstitution (PIR) remains unclear and the identification of uniform biomarkers to predict the occurrence of PIR is particularly vital. But limited information is available on the relationship between circulating markers of INRs and immune recovery. Hence, this review summarises alterations in the intestine microbiota and associated markers in the setting of PIR to better understand host-microbiota-metabolite interactions in HIV immune reconstitution and to identify biomarkers that can predict recovery of CD4+ T cell counts in INRs.

Efficacy and Safety of a Simplified Lamivudine Plus Dolutegravir Dual Therapy in HIV-1-Infected Patients: A Multicenter Cohort Study in China.

BACKGROUND: Results from both clinical trials and real-world observational studies suggest that lamivudine plus dolutegravir (3TC + DTG) dual therapy has excellent virological efficacy and safety in HIV-1-infected patients. However, there is still no relevant study related to this dual therapy reported in China. METHODS: In this multicenter, retrospective, observational study that included HIV-1-infected patients in China, baseline and follow-up data were collected to analyze the virological suppression rate, immune restoration, and adverse events during follow-up in HIV-1-infected patients who switched to the 3TC + DTG dual therapy. RESULTS: This study recruited 112 HIV-1-infected patients, including 101 men (90.2%), with a median age of 44.0 years (IQR: 33.00-57.75) and median CD4+ T-cell count of 432.13 cells/µL (IQR: 237.75-578.50). The overall virological suppression rate was 94.5% at the 24-week follow-up. However, the virological suppression rates of men who have sex with men patients and patients with CD4+ T-cell count of <350 cells/µL were higher than the baseline value (P < 0.05) at week 24. The results of Cox regression analysis showed that the baseline CD4+ T-cell count was an independent determinant of immune restoration in patients, and patients with baseline CD4+ T-cell count of 350-500 cells/µL outperformed patients with baseline CD4+ T-cell count of <350 cells/µL in immune restoration (hazard ratio: 4.469, 95% confidence interval: 1.801 to 11.091, P = 0.001). Adverse events were reported in 5 patients (incidence rate of 4.5%); among them, 3 patients developed neuropsychiatric symptoms. Results from the laboratory data analysis showed that patients with grade 1 and 2 adverse events had elevated levels of low-density lipoprotein cholesterol and total bilirubin. Furthermore, grade 3 and 4 adverse events were associated with the elevation of blood glucose level in 4 patients. CONCLUSIONS: Thus, the 3TC + DTG dual therapy displayed an excellent virological efficacy against HIV-1 infections and had an acceptable safety profile, with predominantly mild adverse events in HIV-1-infected patients in China.

Adsorption in Reversed Order of C2 Hydrocarbons on an Ultramicroporous Fluorinated Metal-Organic Framework.

Metal-organic frameworks have been widely studied in the separation of C2 hydrocarbons, which usually preferentially bind unsaturated hydrocarbons with the order of acetylene (C2 H2 )>ethylene (C2 H4 )>ethane (C2 H6 ). Herein, we report an ultramicroporous fluorinated metal-organic framework Zn-FBA (H2 FBA=4,4'-(hexafluoroisopropylidene)bis(benzoic acid)), shows a reversed adsorption order characteristic for C2 hydrocarbons, that the uptake for C2 hydrocarbons of the framework and the binding affinity between the guest molecule and the framework follows the order C2 H6 >C2 H4 >C2 H2 . Density-functional theory calculations confirm that the completely reversed adsorption order behavior is attributed to the close van der Waals interactions and multiple cooperative C-H⋅⋅⋅F hydrogen bonds between the framework and C2 H6 . Moreover, Zn-FBA exhibits a high selectivity of about 2.9 for C2 H6 over C2 H4 at 298 K and 1 bar. The experimental breakthrough studies show that the high-purity C2 H4 can be obtained from C2 H6 and C2 H4 mixtures in one step.