Association between admission albumin levels and 30-day readmission after hip fracture surgery in geriatric patients: a propensity score-matched study.

PURPOSE: This study aimed to evaluate the correlation admission albumin levels and 30-day readmission after hip fracture surgery in geriatric patients. METHODS: In this retrospective cohort study, 1270 geriatric patients admitted for hip fractures to a level I trauma center were included. Patients were stratified by clinical thresholds and albumin level quartiles. The association between admission albumin levels and 30-day readmission risk was assessed using multivariate logistic regression and propensity score-matched analyses. The predictive accuracy of albumin levels for readmission was evaluated by ROC curves. The dose-response relationship between albumin levels and readmission risk was examined. RESULTS: The incidence of 30-day readmission was significantly higher among hypoalbuminemia patients than those with normal albumin levels (OR = 2.090, 95%CI:1.296-3.370, p = 0.003). Furthermore, propensity score-matched analyses demonstrated that patients in the Q2(35.0-37.9 g/L) (OR 0.621, 95%CI 0.370-1.041, p = 0.070), Q3(38.0-40.9 g/L) (OR 0.378, 95%CI 0.199-0.717, p < 0.001) and Q4 (≥ 41 g/L) (OR 0.465, 95%CI 0.211-0.859, p = 0.047) quartiles had a significantly lower risk of 30-day readmission compared to those in the Q1(< 35 g/L) quartile. These associations remained significant after propensity score matching (PSM) and subgroup analyses. Dose-response relationships between albumin levels and 30-day readmission were observed. CONCLUSIONS: Lower admission albumin levels were independently associated with higher 30-day readmission rates in elderly hip fracture patients. Our findings indicate that serum albumin may assist perioperative risk assessment, and prompt correction of hypoalbuminemia and malnutrition could reduce short-term readmissions after hip fracture surgery in this high-risk population.

Long-read sequencing and de novo genome assembly of marine medaka (Oryzias melastigma).

BACKGROUND: Marine medaka (Oryzias melastigma) is considered as an important ecotoxicological indicator to study the biochemical, physiological and molecular responses of marine organisms towards increasing amount of pollutants in marine and estuarine waters. RESULTS: In this study, we reported a high-quality and accurate de novo genome assembly of marine medaka through the integration of single-molecule sequencing, Illumina paired-end sequencing, and 10X Genomics linked-reads. The 844.17 Mb assembly is estimated to cover more than 98% of the genome and is more continuous with fewer gaps and errors than the previous genome assembly. Comparison of O. melastigma with closely related species showed significant expansion of gene families associated with DNA repair and ATP-binding cassette (ABC) transporter pathways. We identified 274 genes that appear to be under significant positive selection and are involved in DNA repair, cellular transportation processes, conservation and stability of the genome. The positive selection of genes and the considerable expansion in gene numbers, especially related to stimulus responses provide strong supports for adaptations of O. melastigma under varying environmental stresses. CONCLUSIONS: The highly contiguous marine medaka genome and comparative genomic analyses will increase our understanding of the underlying mechanisms related to its extraordinary adaptation capability, leading towards acceleration in the ongoing and future investigations in marine ecotoxicology.

Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics.

Hepatocyte nuclear factor 4α (HNF4α) is a ligand-sensing transcription factor and presents as a potential drug target in metabolic diseases and cancer. In humans, mutations in the HNF4α gene cause maturity-onset diabetes of the young (MODY), and the elevated activity of this protein has been associated with gastrointestinal cancers. Despite the high therapeutic potential, available ligands and structure-activity relationship knowledge for this nuclear receptor are scarce. Here, we disclose a chemically diverse collection of orthogonally validated fragment-like activators as well as inverse agonists, which modulate HNF4α activity in a low micromolar range. These compounds demonstrate the druggability of HNF4α and thus provide a starting point for medicinal chemistry as well as an early tool for chemogenomics.

Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms.

The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application of currently available RXR ligands. The three human RXR isoforms exhibit different expression patterns; however, they share high sequence similarity, presenting a major obstacle toward the development of subtype-selective ligands. Here, we report the discovery of the saturated fatty acid, palmitic acid, as an RXR ligand and disclose a uniform set of crystal structures of all three RXR isoforms in an active conformation induced by palmitic acid. A structural comparison revealed subtle differences among the RXR subtypes. We also observed an ability of palmitic acid as well as myristic acid and stearic acid to induce recruitment of steroid receptor co-activator 1 to the RXR ligand-binding domain with low micromolar potencies. With the high, millimolar endogenous concentrations of these highly abundant lipids, our results suggest their potential involvement in RXR signaling.

The correlation between admission hyperglycemia and 30-day readmission after hip fracture surgery in geriatric patients: a propensity score-matched study.

Purpose: This study aimed to investigate the association between admission hyperglycemia and 30-day readmission after hip fracture surgery in geriatric patients. Methods: This retrospective study included 1253 geriatric hip fracture patients. Patients were categorized into normoglycemia(<6.10 mmol/L) and hyperglycemia groups(≥6.10 mmol/L) based on admission blood glucose. We performed multivariable logistic regression analyses and propensity score matching (PSM) to estimate adjusted odds ratios and 95% confidence intervals for 30-day readmission, controlling for potential confounding factors. An analysis of the dose-dependent association between admission blood glucose and the probability of 30-day readmission was performed. Additional subgroup analysis was conducted to examine the impact of other factors on the relationship between admission blood glucose and 30-day readmission. Results: Patients with hyperglycemia had higher 30-day readmission rates than normoglycemic patients before (19.1% vs 9.7%, p<0.001) and after PSM (18.1% vs 12.3%, p=0.035). Admission hyperglycemia was an independent predictor of increased 30-day readmission risk, with an adjusted odds ratio of 1.57 (95% CI 1.08-2.29, p=0.019) after multivariable regression and 1.57 (95% CI 1.03-2.39, p=0.036) after PSM. A dose-response relationship was observed between higher glucose levels and increased readmission risk. Conclusion: Admission hyperglycemia is an independent risk factor for 30-day readmission after hip fracture surgery in the elderly. Routine glucose testing upon admission and perioperative glycemic control may help reduce short-term readmissions in this vulnerable population.

Crystallographic fragment screening delivers diverse chemical scaffolds for Zika virus NS2B-NS3 protease inhibitor development.

Zika virus (ZIKV) infections cause microcephaly in new-borns and Guillain-Barre syndrome in adults raising a significant global public health concern, yet no vaccines or antiviral drugs have been developed to prevent or treat ZIKV infections. The viral protease NS3 and its co-factor NS2B are essential for the cleavage of the Zika polyprotein precursor into individual structural and non-structural proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 48 binders with diverse chemical scaffolds were identified in the active site of the protease, with another 6 fragment hits observed in a potential allosteric binding site. Our work provides potential starting points for the development of potent NS2B-NS3 protease inhibitors. Furthermore, we have structurally characterized a potential allosteric binding pocket, identifying opportunities for allosteric inhibitor development.

Crystallographic Fragment Screen of Coxsackievirus A16 2A Protease identifies new opportunities for the development of broad-spectrum anti-enterovirals.

Enteroviruses are the causative agents of paediatric hand-foot-and-mouth disease, and a target for pandemic preparedness due to the risk of higher order complications in a large-scale outbreak. The 2A protease of these viruses is responsible for the self-cleavage of the poly protein, allowing for correct folding and assembly of capsid proteins in the final stages of viral replication. These 2A proteases are highly conserved between Enterovirus species, such as Enterovirus A71 and Coxsackievirus A16 . Inhibition of the 2A protease deranges capsid folding and assembly, preventing formation of mature virions in host cells and making the protease a valuable target for antiviral activity. Herein, we describe a crystallographic fragment screening campaign that identified 75 fragments which bind to the 2A protease including 38 unique compounds shown to bind within the active site. These fragments reveal a path for the development of non-peptidomimetic inhibitors of the 2A protease with broad-spectrum anti-enteroviral activity.

High-throughput crystallographic fragment screening of Zika virus NS3 Helicase.

The Zika virus (ZIKV), discovered in Africa in 1947, swiftly spread across continents, causing significant concern due to its recent association with microcephaly in newborns and Guillain-Barré syndrome in adults. Despite a decrease in prevalence, the potential for a resurgence remains, necessitating urgent therapeutic interventions. Like other flaviviruses, ZIKV presents promising drug targets within its replication machinery, notably the NS3 helicase (NS3Hel) protein, which plays critical roles in viral replication. However, a lack of structural information impedes the development of specific inhibitors targeting NS3Hel. Here we applied high-throughput crystallographic fragment screening on ZIKV NS3Hel, which yielded structures that reveal 3D binding poses of 46 fragments at multiple sites of the protein, including 11 unique fragments in the RNA-cleft site. These fragment structures provide templates for direct design of hit compounds and should thus assist the development of novel direct-acting antivirals against ZIKV and related flaviviruses, thus opening a promising avenue for combating future outbreaks.

Intention of Psychological Counseling, Attitude Toward Seeking Psychological Help, and Shame Among Vocational College Students: A Cross-Sectional Survey.

Objective: The aim of this study was to explore the psychological counseling intention of college students, the attitude of seeking psychological help, and the related factors of shame so as to promote the psychological health of college students. Methods: In 4 comprehensive colleges with sound psychological counseling centers, students of different grades were selected and divided into an active help-seeking group (n = 216) and a help-refusal group (n = 270). Students' shame behaviors were evaluated using the Self-Stigma of Seeking Help (SSOSH) scale and Self-Stigma Scale (SSS). The intention of psychological counseling was measured by the General Help-Seeking Questionnaire. The Inventory of Attitudes Toward Seeking Mental Health Services was used to evaluate the psychological status. Data from the above scales were compared through the t-test. Additionally, multiple linear regression analysis was performed to explore the impact of shame on the intention of psychological counseling. Results: The study found that the active help-seeking group scored lower on SSOSH scale compared to those in the help-refusal group (total score: 41.2 ± 9.1 vs. 37.9 ± 8.7, P = .0017). Meanwhile, the help-refusal group had higher scores on the shame dimension of the SSS (16.2 ± 3.9 vs. 5.3 ± 1.1, P = .00085). After adjusting for age, gender, and other variables, multiple linear regression analysis indicated a negative correlation between shame and intention of psychological help and counseling, revealing a significant impact of shame on professional psychological counseling (P < .05). Conclusion: Our study findings suggest that shame has a negative impact on the intention of seeking psychological help and counseling among college students, highlighting the importance of addressing shame-related factors to promote psychological health and encourage the utilization of professional psychological counseling services.

Structural insights into a regulatory mechanism of FIR RRM1-FUSE interaction.

FUBP-interacting repressor (FIR) is a suppressor of transcription of the proto-oncogene MYC. FIR binds to the far upstream element (FUSE) of the MYC promoter. Competition of FIR with FUSE-binding protein 1 (FUBP1) is a key mechanism of MYC transcriptional regulation. To gain insights into the structural mechanisms regulating FIR DNA interaction, we determined the crystal structure of two FIR RRM domains (RRM1-2) with single-stranded FUSE DNA sequences. These structures revealed an ability of the RRM domain to recognize diverse FUSE regions through distinct intermolecular interactions and binding modes. Comparative structural analyses against available RRM-ssDNA/RNA complexes showed that the nucleotide configurations in FIR were similar to those in other RRMs that harbour a tyrosine at the conserved aromatic position in the RNP2 motif (Y-type RRM), but not those with a phenylalanine (F-type RRM). Site-directed mutagenesis experiments demonstrated that a single substitution, Y115F, altered the binding affinities of oligonucleotides to FIR RRM, suggesting an important role of this conserved aromatic residue in ssDNA/RNA interactions. Our study provides the structural basis for further mechanistic studies on this important protein-DNA interaction.

Complete mitochondrial genome of Belligobio pengxianensis (Cypriniformes: Gobionidae).

Belligobio pengxianensis is a small fish endemic to the upper Yangtze River of China. In this study, the complete mitochondrial genome of B. pengxianensis is determined for the first time, and it should become a reference sequence to aid in species identification, biodiversity monitoring and conservation. The mitogenome has overall length of 16,610 bp and AT content of 55.23%, including 13 protein-coding genes, two ribosomal RNAs, 22 transfer RNAs, and one non-coding control region. The results of phylogenetic analyses show that B. pengxianensis is nested within the genus Hemibarbus.

Pleistocene Landscape Dynamics Drives Lineage Divergence of a Temperate Freshwater Fish Gobio rivuloides in Coastal Drainages of Northern China.

Understanding historical processes underlying lineage distribution patterns is a primary goal of phylogeography. We selected Gobio rivuloides (Cypriniformes: Gobionidae) as a model to improve our knowledge about how intraspecific genetic divergence of freshwater fishes arises in coastal drainages of northern China via statistical analysis using cytochrome b gene. The time-calibrated phylogeny of G. rivuloides showed the divergence of two major lineages (I and II) at ~0.98 Ma (million years ago). Lineage I can be divided into two sub-lineages (I-A and I-B) with a divergence time of ~0.83 Ma. Sub-lineage I-A inhabits the Amur River, and sub-lineage I-B lives in the Luan River and Liao River. Lineage II is distributed in the Yellow River and Hai River, with close genetic relationships between the two drainages, and can be split into two sub-lineages (II-C and II-D) with a divergence time of ~0.60 Ma. Our findings indicate that the splitting of lineages and sub-lineages could be attributed to geographic isolation caused by the formation of the Bohai Sea, river capture, and the episodic hydrologic closing of a paleolake during the late Lower-Middle Pleistocene. It is also the first report we know of displaying a clear phylogeographic break for freshwater fishes across coastal drainages in northern China.

Differential Brain Expression Patterns of microRNAs Related to Olfactory Performance in Honey Bees (Apis mellifera).

MicroRNAs (miRNAs) play a vital role in the nerve regulation of honey bees (Apis mellifera). This study aims to investigate the differences in expression of miRNAs in a honey bee's brain for olfactory learning tasks and to explore their potential role in a honey bee's olfactory learning and memory. In this study, 12 day old honey bees with strong and weak olfactory performances were utilized to investigate the influence of miRNAs on olfactory learning behavior. The honey bee brains were dissected, and a small RNA-seq technique was used for high-throughput sequencing. The data analysis of the miRNA sequences revealed that 14 differentially expressed miRNAs (DEmiRNAs) between the two groups, strong (S) and weak (W), for olfactory performance in honey bees were identified, which included seven up-regulated and seven down-regulated. The qPCR verification results of the 14 miRNAs showed that four miRNAs (miR-184-3p, miR-276-3p, miR-87-3p, and miR-124-3p) were significantly associated with olfactory learning and memory. The target genes of these DEmiRNAs were subjected to the GO database annotation and KEGG pathway enrichment analyses. The functional annotation and pathway analysis showed that the neuroactive ligand-receptor interaction pathway, oxidative phosphorylation, biosynthesis of amino acids, pentose phosphate pathway, carbon metabolism, and terpenoid backbone biosynthesis may be a great important pathway related to olfactory learning and memory in honey bees. Our findings together further explained the relationship between olfactory performance and the brain function of honey bees at the molecular level and provides a basis for further study on miRNAs related to olfactory learning and memory in honey bees.

Phylogeographical Analysis of the Freshwater Gudgeon Huigobio chenhsienensis (Cypriniformes: Gobionidae) in Southern China.

The freshwater gudgeon Huigobio chenhsienensis (Cypriniformes: Gobionidae) is a small fish endemic to southern China. In this study, we used mitochondrial cytochrome b gene (Cytb), from wide-ranging samplings of H. chenhsienensis from the Ou River (the central of southern China) to the Yangtze River Basin (the northernmost part of southern China) to explore genetic variations and the evolutionary history of H. chenhsienensis in southern China. In total, 66 haplotypes were identified from Cytb sequences of 142 H. chenhsienensis individuals, which could be divided into lineages A, B, and C with divergence times of ~4.24 Ma and ~3.03 Ma. Lineage A was distributed in the lower reaches of the Yangtze River, the Oujiang River, and the Jiao River, lineage B was distributed in the Qiantang River and the Cao'e River, whereas lineage C was restricted to the Poyang Lake drainage from the middle reaches of the Yangtze River. Lineage A could be subdivided into sub-lineages A-I, A-II, A-III, and A-IV, with divergence times of 1.30, 0.97, and 0.44 Ma. Lineage C could be subdivided into sub-lineages C-I and C-II, with a divergence time of 0.85 Ma. Our findings indicate that climate change during the Pliocene and Pleistocene eras, as well as the limited dispersal ability of H. chenhsienensis, have been major drivers for shaping the phylogeographical patterns of H. chenhsienensis.

The complete mitochondrial genome of Mesogobio lachneri (Cypriniformes: Gobionidae) from Northeast Asia.

Although Mesogobio lachneri is the type species of the genus Mesogobio, its systematic position and status have remained unresolved to date. In this study, for the first time, we report the complete mitochondrial genome of M. lachneri using Sanger sequencing. It is a circular genome with a length of 16,602 bp, comprising 22 tRNAs, 13 protein-coding genes (PCGs), two rRNAs, and one non-coding control region. Our phylogenetic analysis reveals that M. lachneri is the close relative of the genus Gobio, indicating that Mesogobio may be a valid genus.

The role of landscape evolution in the genetic diversification of a stream fish Sarcocheilichthys parvus from Southern China.

Sarcocheilichthys parvus (Cypriniformes: Gobionidae) is a stream fish which is endemic to sub-tropical coastal drainages in southern China, thus offering a valuable model for understanding how genetic divergence arises in stream-adapting freshwater fishes in this region. Using the mitochondrial Cyt b gene, integrative analyses of phylogeny, population demography, and ancestral area and paleo-drainage reconstructions are carried out to explicitly explore the role of landscape evolution in genetic diversification of S. parvus. The time-calibrated phylogeny of S. parvus indicates the splitting of two major lineages (A and B) at ∼3.66 Ma. Lineage A inhabits the Poyang Lake sub-drainage of the middle Yangtze River, Han River and Pearl River, and can be split into two sub-lineages (A-I and A-II), where sub-lineage A-II can be further sub-divided into three infra-sub-lineages (A-IIa, A-IIb and A-IIc). Except for the infra-sub-lineage A-IIc, which is restricted to the Han River and Pearl River, the other sub-lineages and infra-sub-lineages live exclusively in the Poyang Lake sub-drainage. Lineage B lives in the lower Yangtze River, Qiantang River, Jiaojiang River and Ou River, displaying close genetic relationships among the drainages. Rapid population expansion has occurred since the Late Pleistocene. Our findings indicate that the splitting of lineages A and B could be attributed to geographic isolation due to the Zhe-Min Uplift, acting as a biogeographic barrier before the late Early Pleistocene. Furthermore, the strong genetic divergence within Lineage A could be explained by the isolation role of the Nanling Mountains and Poyang Lake acting as an ecological barrier; while the lack of phylogenetic structure within Lineage B may have been the result of paleo-drainage connections or episodic freshwater connections during the eustatic low stand of sea level in the late Middle-Late Pleistocene.

Toxoplasma gondii and Neospora caninum Infections in Stray Cats and Dogs in the Qinghai-Tibetan Plateau Area, China.

Toxoplasma gondii and Neospora caninum belong to the Apicomplexan protozoa which is an obligate intracellular parasite, causing toxoplasmosis and neosporosis throughout the world. Cats and dogs are the definitive hosts of these two parasites. However, information on the epidemiology of toxoplasmosis and neosporosis in stray cats and dogs in the Qinghai-Tibetan Plateau Area (QTPA) is limited, and little is known about the diversity of the diseases. Therefore, the aim of this study was to perform indirect ELISA tests based on recombinant TgSAG1, TgGRA1, NcSAG1 and NcGRA7 proteins to establish a detailed record of the seroprevalence of T. gondii and N. caninum-specific IgG and IgM antibodies in serum samples and to develop qPCR amplification based on TgB1 and NcNc5 genes to conduct molecular epidemiology in feces from stray cats and dogs in the QTPA. In the current study, a total of 128 cat serum samples were analyzed through serological tests in which 53 (41.4%) and 57 (44.5%) samples were found positive for T. gondii specific-IgG and IgM antibodies, and 2 (1.6%) and 74 (57.8%) samples were confirmed positive for N. caninum specific-IgG and IgM antibodies, respectively. Out of 224 stray dog sera, 59.8% and 58.9% were recorded as positive against anti-Toxoplasma IgG and IgM antibodies, 17.9% and 64.7% were detected positive against Neospora IgG and IgM. On the other hand, 1 of 18 cat fecal samples was successfully amplified within the Ct value of 10 to 30 while no cat was positive for neosporosis. Moreover, a higher prevalence of toxoplasmosis in stray dogs (14.5%, 16/110) than of neosporosis (5.5%, 6/110) with different parasite numbers were found. Further analysis showed that no significant sex differences were found nor between the overall infection rates of T. gondii and N. caninum in this study. This study suggests that stray cats and dogs play key roles in the transmission and prevalence of T. gondii and N. caninum in the plateau area.

Transgenerational Effects of Hexavalent Chromium on Marine Medaka (Oryzias melastigma) Reveal Complex Transgenerational Adaptation in Offspring.

Hexavalent chromium [Cr(VI)] pollution is one of most serious heavy metal pollutants in the coastal area and posed serious threats to marine organisms and human beings. Many studies have been conducted on its toxicological effects on living organisms from morphological to physiological aspects. However, there are few studies about the transgenerational toxicological of Cr(VI). In this study, we exposed adult marine medaka fishes with Cr(VI) and their offspring with Cr(VI) to examine transgenerational effects of Cr(VI). We found that there were mechanisms such as changing reproduction modes in males to compensate for impacts on the reproduction. There were differences and similarities between the parental effect and the environmental effect, with the former one causing more serious adverse effects on the offspring of Cr(VI)-exposed fish. It was noteworthy that there was an interaction between the parental and offspring treatment which leads to the attenuation of the parental effects on offspring when the offspring also underwent the same treatment. In addition, physiological adaptation has also been observed in fish to improve their fitness. Overall, effects of Cr(VI) on fish and their offspring were studied to pave a way to study the of mechanisms of adaptation.

Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants.

Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers. Mutations in the YEATS domain have been recently reported as a cause of MLLT1 aberrant reader function. However, the structural basis for the reported alterations in affinity for acetylated/acylated histone has remained elusive. Here, we report the crystal structures of both insertion and substitution mutants present in cancer, revealing significant conformational changes of the YEATS-domain loop 8. Structural comparison demonstrates that not only did such alteration alter the binding interface for acetylated/acylated histones, but the sequence alterations in the loop in T1 mutant may enable dimeric assembly consistent with inducing self-association behavior. Nevertheless, we show that also the MLLT1 mutants can be targeted by developed acetyllysine mimetic inhibitors with affinities similarly to wild-type. Our report provides a structural basis for the altered behaviors and a potential strategy for targeting oncogenic MLLT1 mutants.

Structural Insights into Plasticity and Discovery of Remdesivir Metabolite GS-441524 Binding in SARS-CoV-2 Macrodomain.

The nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in the host immune response by recognizing and removing posttranslational ADP-ribosylation sites during SARS-CoV-2 infection. Thus targeting this protein domain may offer a therapeutic strategy to combat current and future virus pandemics. To assist inhibitor development efforts, we report here a comprehensive set of macrodomain crystal structures complexed with diverse naturally occurring nucleotides, small molecules, and nucleotide analogues including GS-441524 and its phosphorylated analogue, active metabolites of remdesivir. The presented data strengthen our understanding of the SARS-CoV-2 macrodomain structural plasticity and provide chemical starting points for future inhibitor development.