Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response.

Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host's innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection.

A causal relationship between gut microbiota and subcortical brain structures contributes to the microbiota-gut-brain axis: a Mendelian randomization study.

A correlation between gut microbiota and brain structure, referring to as a component of the gut-brain axis, has been observed in observational studies. However, the causality of this relationship and its specific bacterial taxa remains uncertain. To reveal the causal effects of gut microbiota on subcortical brain volume, we applied Mendelian randomization (MR) studies in this study. Genome-wide association study data were obtained from the MiBioGen Consortium (n = 18,340) and the Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium (n = 13,170). The primary estimate was obtained utilizing the inverse-variance weighted, while heterogeneity and pleiotropy were assessed using the Cochrane Q statistic, MR Pleiotropy RESidual Sum and Outlier, and MR-Egger intercept. Our findings provide strong evidence that a higher abundance of the genus Parasutterella is causally correlated with a decrease in intracranial volume (ß = -30,921.33, 95% CI -46,671.78 to -15,170.88, P = 1.19 × 10-4), and the genus FamilyXIIIUCG001 is associated with a decrease in thalamus volume (ß = -141.96, 95% CI: -214.81 to -69.12, P = 1.0× 10-4). This MR study offers novel perspectives on the intricate interplay between the gut microbiota and subcortical brain volume, thereby lending some support to the existence of the microbiota-gut-brain axis.

Gate-tunable contact-induced Fermi-level shift in semimetal.

Low-dimensional semimetal­semiconductor (Sm-S) van der Waals (vdW) heterostructures have shown their potentials in nanoelectronics and nano-optoelectronics recently. It is an important scientific issue to study the interfacial charge transfer as well as the corresponding Fermi-level shift in Sm-S systems. Here we investigated the gate-tunable contact-induced Fermi-level shift (CIFS) behavior in a semimetal single-walled carbon nanotube (SWCNT) that formed a heterojunction with a transition-metal dichalcogenide (TMD) flake. A resistivity comparison methodology and a Fermi-level catch-up model have been developed to measure and analyze the CIFS, whose value is determined by the resistivity difference between the naked SWCNT segment and the segment in contact with the TMD. Moreover, the relative Fermi-level positions of SWCNT and two-dimensional (2D) semiconductors can be efficiently reflected by the gate-tunable resistivity difference. The work function change of the semimetal, as a result of CIFS, will naturally introduce a modified form of the Schottky­Mott rule, so that a modified Schottky barrier height can be obtained for the Sm-S junction. The methodology and physical model should be useful for low-dimensional reconfigurable nanodevices based on Sm-S building blocks.

Engineering van der Waals Contacts by Interlayer Dipoles.

Tuning the interfacial Schottky barrier with van der Waals (vdW) contacts is an important solution for two-dimensional (2D) electronics. Here we report that the interlayer dipoles of 2D vdW superlattices (vdWSLs) can be used to engineer vdW contacts to 2D semiconductors. A bipolar WSe2 with Ba6Ta11S28 (BTS) vdW contact was employed to exhibit this strategy. Strong interlayer dipoles can be formed due to charge transfer between the Ba3TaS5 and TaS2 layers. Mechanical exfoliation breaks the superlattice and produces two distinguished surfaces with TaS2 and Ba3TaS5 terminations. The surfaces thus have opposite surface dipoles and consequently different work functions. Therefore, all the devices fall into two categories in accordance with the rectifying direction, which were verified by electrical measurements and scanning photocurrent microscopy. The growing vdWSL family along with the addition surface dipoles enables prospective vdW contact designs and have practical application in nanoelectronics and nano optoelectronics.

Prediabetes is associated with increased cardiac events in patients with cancer who are prescribed anthracyclines.

BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.

1,25(OH)2 D3 inhibits Lewis lung cancer cell migration via NHE1-sensitive metabolic reprograming.

High prevalence and metastasis rates are characteristics of lung cancer. Glycolysis provides energy for the development and metastasis of cancer cells. The 1,25-dihydroxy vitamin D3 (1,25(OH)2 D3 ) has been linked to reducing cancer risk and regulates various physiological functions. We hypothesized that 1,25(OH)2 D3 could be associated with the expression and activity of Na+ /H+ exchanger isoform 1 (NHE1) of Lewis lung cancer cells, thus regulating glycolysis as well as migration by actin reorganization. Followed by online public data analysis, Vitamin D3 receptor, the receptor of 1,25(OH)2 D3 has been proved to be abundant in lung cancers. We demonstrated that 1,25(OH)2 D3 treatment suppressed transcript levels, protein levels, and activity of NHE1 in LLC cells. Furthermore, 1,25(OH)2 D3 treatment resets the metabolic balance between glycolysis and OXPHOS, mainly including reducing glycolytic enzymes expression and lactate production. In vivo experiments showed the inhibition effects on tumor growth as well. Therefore, we concluded that 1,25(OH)2 D3 could amend the NHE1 function, which leads to metabolic reprogramming and cytoskeleton reconstruction, finally inhibits the cell migration.

Sanitization of hydroponic farming facilities in Singapore: what, why, and how.

This study performed microbial analysis of nutrient film technique (NFT) hydroponic systems on three indoor farms in Singapore (the "what"). To justify the necessity of sanitizing hydroponic systems, strong biofilm-forming bacteria were isolated from the facility and investigated for their influence on Salmonella colonization on polyvinyl chloride (PVC) coupons in hydroponic nutrient solutions (the "why"). Finally, sanitization solutions were evaluated with both laboratory-scale and field-scale tests (the "how"). As a result, the microbiome composition in NFT systems was found to be highly farm specific. The strong biofilm formers Corynebacterium tuberculostearicum C2 and Pseudoxanthomonas mexicana C3 were found to facilitate the attachment and colonization of Salmonella on PVC coupons. When forming dual-species biofilms, the presence of C2 and C3 also significantly promoted the growth of Salmonella (P < 0.05). Compared with hydrogen peroxide (H2O2) and sodium percarbonate (SPC), sodium hypochlorite (NaOCl) exhibited superior efficacy in biofilm removal. At 50 ppm, NaOCl reduced the Salmonella Typhimurium, C2, and C3 counts to <1 log CFU/cm2 within 12 h, whereas neither 3% H2O2 nor 1% SPC achieved this effect. In operational hydroponic systems, the concentration of NaOCl needed to achieve biofilm elimination increased to 500 ppm, likely due to the presence of organic matter accumulated during crop cultivation and the greater persistence of naturally formed multispecies biofilms. Sanitization using 500 ppm NaOCl for 12 h did not impede subsequent plant growth, but chlorination byproduct chlorate was detected at high levels in the hydroponic solution and in plants in the sanitized systems without rinsing. IMPORTANCE: This study's significance lies first in its elucidation of the necessity of sanitizing hydroponic farming systems. The microbiome in hydroponic systems, although mostly nonpathogenic, might serve as a hotbed for pathogen colonization and thus pose a risk for food safety. We thus explored sanitization solutions with both laboratory-scale and field-scale tests. Of the three tested sanitizers, NaOCl was the most effective and economical option, whereas one must note the vital importance of rinsing the hydroponic systems after sanitization with NaOCl.

Production of recombinant HPV11/16 E6/E7-MBP-His6 fusion proteins and their potential to induce cytokine secretion by immune cells in peripheral blood.

Human papillomavirus (HPV) infection poses a significant threat to public health worldwide. Targeting the function of HPV E6 and E7 proteins and activating the host immune response against these proteins represent promising therapeutic strategies for combating HPV-related diseases. Consequently, the efficient production of soluble, high-purity E6 and E7 proteins is crucial for function and host immune response studies. In this context, we selected the pMCSG19 protein expression vector for Escherichia coli to produce soluble MBP-His6 tagged HPV11/16 E6/E7 proteins, achieving relatively high purity and yield. Notably, these proteins exhibited low toxicity to peripheral blood mononuclear cells (PBMCs) and did not compromise their viability. Additionally, the recombinant proteins were capable of inducing the secretion of multiple cytokines by immune cells in peripheral blood, indicating their potential to elicit immune responses. In conclusion, our study offers a novel approach for the production of HPV11/16 E6/E7 fusion proteins with relatively high purity and yield. The fusing HPV11/16 E6/E7 proteins to MBP-His6 tag may serve as a valuable method for large-scale protein production in future research endeavors.

Species delimitation in Amana (Liliaceae): transcriptomes battle with evolutionary complexity.

Species delimitation has long been a subject of controversy, and there are many alternative concepts and approaches used to define species in plants. The genus Amana (Liliaceae), known as "East Asian tulips" has a number of cryptic species and a huge genome size (1C = 21.48-57.35 pg). It also is intriguing how such a spring ephemeral genus thrives in subtropical areas. However, phylogenetic relationships and species delimitation within Amana are challenging. Here we included all species and 84 populations of Amana, which are collected throughout its distribution range. A variety of methods were used to clarify its species relationships based on a combination of morphological, ecological, genetic, evolutionary and phylogenetic species concepts. This evidence supports the recognition of at least 12 species in Amana. Moreover, we explored the complex evolutionary history within the genus and detected several historical hybridization and introgression events based on phylogenetic trees (transcriptomic and plastid), phylonetworks, admixture and ABBA-BABA analyses. Morphological traits have undergone parallel evolution in the genus. This spring ephemeral genus might have originated from a temperate region, yet finally thrives in subtropical areas, and three hypotheses about its adaptive evolution are proposed for future testing. In addition, we propose a new species, Amana polymorpha, from eastern Zhejiang Province, China. This research also demonstrates that molecular evidence at the genome level (such as transcriptomes) has greatly improved the accuracy and reasonability of species delimitation and taxon classification.

A dual mechanism with H2S inhibition and membrane damage of morusin from Morus alba Linn. against MDR-MRSA.

It's urgent to discover new antibiotics along with the increasing emergence and dissemination of multidrug resistant (MDR) bacterial pathogens. In the present investigation, morusin exhibited rapid bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) by targeting the phospholipid of bacterial inner membrane, increasing membrane rigidity and disrupting bacterial homeostasis together with the membrane permeability, which caused fundamental metabolic disorders. Furthermore, morusin can also accumulate ROS, suppress H2S production, and aggravate oxidative damage in bacteria. Importantly, morusin also inhibited the spread of wounds and reduced the bacterial burden in the mouse model of skin infection caused by MRSA. It's a chance to meet the challenge of existing antibiotic resistance and avoid the development of bacterial resistance, given the multiple targets of morusin.

Formononetin Derivative for Osteoporosis by Simultaneous Regulating Osteoblast and Osteoclast.

Seven new formononetin derivatives (1-7) were designed and prepared from formononetin (phase II phytoestrogen). The derivatives 9-butyl-3-(4-methoxyphenyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (2) and 9-(furan-3-ylmethyl)-3-(4-methoxyphenyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (7) promoted significant osteoblast formation by modulating the BMP/Smad pathway. Compound 7 exhibited potent antiosteoclastogenesis activity in RANKL-induced RAW264.7 cells and ovariectomy (OVX)-induced osteoporosis in mice by regulation of the RANK/RANKL/OPG pathway. Compound 7 regulated osteoblast and osteoclast simultaneously and showed better effect than the well-known drug ipriflavone in vivo, suggesting 7 as a patented antiosteoporosis candidate.

Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys.

AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study.

Latent class analysis of the sleep quality of night shift nurses and impact of shift-related factors on the occupational stress and anxiety.

AIMS: The objective of this study is to explore the various latent categories within the sleep quality of night shift nurses and to investigate whether shift-related factors predispose nurses to higher levels of occupational stress and anxiety. DESIGN: This is a cross-sectional study. METHODS: From November to December 2020, registered nurses from 18 tertiary hospitals and 16 secondary hospitals in Chongqing were selected through convenience sampling for this study. Latent class analysis was used to investigate the sleep quality of nurses working night shifts. Furthermore, univariate analysis and logistic multivariate analysis were utilized to identify the contributing factors to occupational stress and anxiety. RESULTS: The four latent categories of Pittsburgh Sleep Quality Index for night shift nurses were identified as 'Low Sleep Disorder Group' (56.34%), 'Moderate Sleep Disorder Group' (37.27%), 'High Sleep Disorder Non-Reliant on Sleeping medication Group' (4.89%) and 'High Sleep Disorder Reliant on Sleeping medication Group' (1.50%). The results showed that having a night-shift frequency of 3-4 times per month, night-shift durations of 9-12 h, sleep time delay after night shift (≥2 h), total sleep time after night shift less than 4 h were shift-related factors that increased the levels of occupational stress and anxiety. CONCLUSION: The sleep quality of night shift nurses demonstrates heterogeneity and can be classified into four latent categories. Higher frequency of night shifts, extended work hours and insufficient rest time are all associated with increased levels of occupational stress and anxiety. IMPACT: By identifying the four latent categories of sleep quality among night shift nurses, this study sheds light on the relationship between sleep patterns and levels of occupational stress and anxiety. These findings have important implications for healthcare institutions in the management of nurse well-being and work schedules. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Biological Evaluation of the Antibacterial Retinoid CD437 in Cutibacterium acnes Infection.

Acne vulgaris is a complex skin disease involving infection by Cutibacterium acnes, inflammation, and hyperkeratinization. We evaluated the activity of the retinoid 6-[3-(adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and 16 other retinoid analogs as potential anti-C. acnes compounds and found that CD437 displayed the highest antimicrobial activity with an MIC against C. acnes (ATCC 6919 and HM-513) of 1 µg/mL. CD437 demonstrated an MBC of 2 µg/mL compared to up to 64 µg/mL for the retinoid adapalene and up to 16 µg/mL for tetracycline, which are commonly used clinically to treat acne. Membrane permeability assays demonstrated that exposure of C. acnes ATCC 6919 to CD437 damaged the integrity of C. acnes ATCC 6919 bacterial membranes, and this finding was confirmed with scanning electron microscopy. Additionally, CD437 downregulated the expression of C. acnes ATCC 6919 virulence factors, including the genes encoding Christie-Atkins-Munch-Petersen factor 1 (CAMP1), CAMP2, glycerol-ester hydrolase B (GehB), sialidase B, and neuraminidase. In a mouse skin infection model of C. acnes ATCC 6919, topical treatment with CD437 ameliorated skin lesions and reduced the bacterial burden in situ (P < 0.001). In human NHEK primary cells, CD437 reduced the transcriptional levels of the coding genes for inflammatory cytokines (interleukin-1α, ~10-fold; interleukin-6, ~20-fold; interleukin-8, ~30-fold; and tumor necrosis factor-alpha, ~6-fold) and downregulated the transcriptional levels of KRT10 (~10-fold), FLG (~4-fold), and TGM1 (~2-fold), indicating that CD437 can diminish inflammation and hyperkeratinization. In summary, CD437 deserves further attention for its dual function as a potential acne therapeutic that potentially acts on both the pathogen and the host.

Risk of ICU Admission and Related Mortality in Patients With Sodium-Glucose Cotransporter 2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors: A Territory-Wide Retrospective Cohort Study.

OBJECTIVES: The benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the occurrence rate of adverse cardiac and renal outcomes in patients with type 2 diabetes has been well described in randomized trials. Whether this benefit extends to patients at the most severe end of the disease spectrum requiring admission to the ICU remains to be examined. DESIGN: Retrospective observational study. SETTING: Data were obtained from a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System). PATIENTS: All adult patients (age ≥ 18 yr) with type 2 diabetes and newly prescribed SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors between January 1, 2015, and December 31, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After 1:2 propensity score matching, a total of 27,972 patients (10,308 SGLT2 inhibitors vs 17,664 DPP-4 inhibitors) were included in the final analysis. The mean age was 59 ± 11 years, and 17,416 (62.3%) were male. The median follow-up period was 2.9 years. The use of SGLT2 inhibitors was associated with decreased ICU admission (286 [2.8%] vs 645 [3.7%]; hazard ratio [HR], 0.79; 95% CI, 0.69-0.91; p = 0.001) and lower risks of all-cause mortality (315 [3.1%] vs 1,327 [7.5%]; HR, 0.44; 95% CI, 0.38-0.49; p < 0.001), compared with DPP-4 inhibitors. The severity of illness upon ICU admission by Acute Physiology and Chronic Health Evaluation IV-predicted risk of death was also lower in SGLT2 inhibitors users. Admissions and mortality due to sepsis were lower in SGLT2 inhibitor users compared with DPP-4 inhibitor users (admissions for sepsis: 45 [0.4%] vs 134 [0.8%]; p = 0.001 and mortality: 59 [0.6%] vs 414 [2.3%]; p < 0.001, respectively). CONCLUSIONS: In patients with type 2 diabetes, SGLT2 inhibitors were independently associated with lower rates of ICU admission and all-cause mortality across various disease categories.

Plastome evolution and phylogenomics of Impatiens (Balsaminaceae).

MAIN CONCLUSION: This study reported seven new plastomes from Impatiens and observed three highly variable regions for phylogeny and DNA barcoding, which resolved the relationships among sections of subgenus Impatiens. Impatiens L. (Balsaminaceae, Ericales) is one of the largest and most diverse genera of angiosperms, widely known for its taxonomic difficulty. In this study, we reevaluated the infrageneric relationships within the genus Impatiens, using complete plastome sequence data. Seven complete plastomes of Impatiens (representing 6 species) were newly sequenced and characterized along with 20 previously published plastomes of other Impatiens species, plus 2 plastomes of outgroups (Hydrocera triflora, Balsaminaceae; Marcgravia coriacea, Marcgraviaceae). The total size of these 29 plastomes ranged from 151,538 bp to 152,917 bp, except 2 samples of Impatiens morsei, which exhibited a shorter length and lost some genes encoding NADH dehydrogenase subunits. Moreover, the number of simple sequence repeats (SSRs) ranged from 51 to 113, and the number of long repeats from 17 to 26. In addition, three highly variable regions were identified (trnG-GCC (The previous one), ndhF-rpl32-trnL-UGA-ccsA, and ycf1). Our phylogenomic analysis based on 80 plastome-derived protein-coding genes strongly supported the monophyly of Impatiens and its two subgenera (Clavicarpa and Impatiens), and fully resolved relationships among the six (out of seven) sampled sections of subgenus Impatiens. Overall, the plastome DNA markers and phylogenetic results reported in this study will facilitate future identification, taxonomic and DNA barcoding studies in Impatiens as well as evolutionary studies in Balsaminaceae.

Autophagy benefits the in vitro and in vivo clearance of Talaromyces marneffei.

Talaromycosis, namely Talaromyces marneffei infection, is increasing gradually and has a high mortality rate even under antifungal therapy. Although autophagy acts differently on different pathogens, it is a promising therapeutic strategy. However, information on autophagy in macrophages and animals upon infection by T. marneffei is still limited. Therefore, several models were employed here to investigate the role of autophagy in host defense against T. marneffei, including RAW264.7 macrophages as in vitro models, different types of Caenorhabditis elegans and BALB/c mice as in vivo models. We applied the clinical T. marneffei isolate SUMS0152 in this study. T. marneffei-infected macrophages exhibit increased formation of autophagosomes. Further, macrophage autophagy promoted by rapamycin or Earle's balanced salt solution (EBSS) inhibited the viability of intracellular T. marneffei. In vivo, compared with uninfected Caenorhabditis elegans, the wild-type nematodes upregulated the expression of the autophagy-related gene lgg-1 and atg-18, and nematodes carrying GFP reporter were induced to form autophagosomes (GFP::LGG-1) after T. marneffei infection. Furthermore, the knockdown of lgg-1 significantly reduced the survival rate of T. marneffei-infected nematodes. Likewise, the autophagy activator rapamycin reduced the fungal burden and suppressed lung inflammation in a mouse model of infection. In conclusion, autophagy is essential for host defense against T. marneffei in vitro and in vivo. Therefore, autophagy may be an attractive target for developing new therapeutics to treat talaromycosis.

Important Correlates of Purpose in Life in a Diverse Population-Based Cohort: A Machine Learning Approach.

BACKGROUND: Purpose-in-life (PiL) refers to the tendency to derive meaning and purpose from daily life experiences. Individuals with higher PiL were more likely to have better physical, mental, and cognitive health in prospective studies. Here, we aimed to identify important correlates of PiL among people of diverse backgrounds. METHODS: Participants were recruited by the population-based Health and Retirement Study and provided information on 34 different sociodemographic and psychosocial factors through psychometrically validated measures. To identify important correlates of PiL, we employed regularized regression implemented by Elastic Net on the entire cohort as well as among self-identified black participants only and white participants only, respectively. RESULTS: A total of 6,620 participants were included in this study, among whom 913 were black and 5,707 were white. We identified 12 and 23 important sociodemographic and psychosocial correlates of PiL among black and white participants, respectively. Notably, all the 12 correlates in black participants were also correlates among white participants. Interestingly, when we examined both black and white participants together, being black was associated with having higher PiL. The correlates with the largest effect on PiL that were shared among black and white participants were hopelessness, perceived constraint on personal control, and self-mastery. CONCLUSION: Several sociodemographic and psychosocial factors most strongly associated with PiL were shared among black and white participants. Future studies should investigate whether interventions targeting correlates of PiL can lead to higher sense of life purpose in participants of diverse backgrounds.

Chronic kidney disease begets heart failure and vice versa: temporal associations between heart failure events in relation to incident chronic kidney disease in type 2 diabetes.

AIM: To investigate the interplay of incident chronic kidney disease (CKD) and/or heart failure (HF) and their associations with prognosis in a large, population-based cohort with type 2 diabetes (T2DM). METHODS: Patients aged ≥18 years with new-onset T2DM, without renal disease or HF at baseline, were identified from the territory-wide Clinical Data Analysis Reporting System between 2000 and 2015. Patients were followed up until December 31, 2020 for incident CKD and/or HF and all-cause mortality. RESULTS: Among 102 488 patients (median age 66 years, 45.7% women, median follow-up 7.5 years), new-onset CKD occurred in 14 798 patients (14.4%), in whom 21.7% had HF. In contrast, among 9258 patients (9.0%) with new-onset HF, 34.6% had CKD. The median time from baseline to incident CKD or HF (4.4 vs. 4.1 years) did not differ. However, the median (interquartile range) time until incident HF after CKD diagnosis was 1.7 (0.5-3.6) years and was 1.2 (0.2-3.4) years for incident CKD after HF diagnosis (P < 0.001). The crude incidence of CKD was higher than that of HF: 17.6 (95% confidence interval [CI] 17.3-17.9) vs. 10.6 (95% CI 10.4-10.9)/1000 person-years, respectively, but incident HF was associated with a higher adjusted-mortality than incident CKD. The presence of either condition (vs. CKD/HF-free status) was associated with a three-fold hazard of death, whereas concomitant HF and CKD conferred a six to seven-fold adjusted hazard of mortality. CONCLUSION: Cardiorenal complications are common and are associated with high mortality risk among patients with new-onset T2DM. Close surveillance of these dual complications is crucial to reduce the burden of disease.

Effect of Multicomponent Home-Based Training on Gait and Muscle Strength in Older Adults After Hip Fracture Surgery: A Single Site Randomized Trial.

OBJECTIVE: To investigate the effect of 16-week home-based physical therapy interventions on gait and muscle strength. DESIGN: A single-blinded randomized controlled trial. SETTING: General community. PARTICIPANTS: Thirty-four older adults (N=34) post hip fracture were randomly assigned to either experimental group (a specific multi-component intervention group [PUSH], n=17, 10 women, age=78.6±7.3 years, 112.1±39.8 days post-fracture) or active control (a non-specific multi-component intervention group [PULSE], n=17, 11 women, age=77.8±7.8 years, 118.2±37.5 days post-fracture). INTERVENTION: PUSH and PULSE groups received 32-40 sessions of specific or non-specific multi-component home-based physical therapy, respectively. Training in the PUSH group focused on lower extremity strength, endurance, balance, and function for community ambulation, while the PULSE group received active movement and transcutaneous electrical nerve stimulation on extremities. MAIN OUTCOME MEASURES: Gait characteristics, and ankle and knee muscle strength were measured at baseline and 16 weeks. Cognitive testing of Trail Making Test (Part A: TMT-A; Part-B: TMT-B) was measured at baseline. RESULTS: At 16 weeks, both groups demonstrated significant increases in usual (P<.05) and fast (P<.05) walking speed, while there was no significant difference in increases between the groups. There was only 1 significant change in lower limb muscle strength over time (non-fractured side) between the groups, such that PUSH did better (mean: 4.33%, 95% confidence interval:1.43%-7.23%). The increase in usual and fast walking speed correlated with the baseline Trail-making Test-B score (r=-0.371, P=.037) and improved muscle strength in the fractured limb (r=0.446, P=.001), respectively. CONCLUSION: Gait speed improved in both home-based multicomponent physical therapy programs in older adults after hip fracture surgery. Muscle strength of the non-fractured limb improved in the group receiving specific physical therapy training. Specific interventions targeting modifiable factors such as muscle strength and cognitive performance may assist gait recovery after hip fracture surgery.