Regulation of factor V by the anticoagulant protease activated protein C: Influence of the B-domain and TFPIα.

Activated protein C (APC) is an important anticoagulant protein that regulates thrombin generation through inactivation of factor V (FV) and activated factor V (FVa). The rate of APC inactivation of FV is slower compared to FVa, although proteolysis occurs at the same sites (Arg306, Arg506, and Arg679). The molecular basis for FV resistance to APC is unknown. Further, there is no information about how FV-short, a physiologically relevant isoform of FV with a shortened B-domain, is regulated by APC. Here, we identify the molecular determinants which differentially regulate APC recognition of FV versus FVa and uncover how FV-short can be protected from this anticoagulant pathway. Using recombinant FV derivatives and B-domain fragments, we show that the conserved basic region (BR; 963-1008) within the central portion of the B-domain plays a major role in limiting APC cleavage at Arg506. Derivatives of FV lacking the BR, including FV-short, were subject to rapid cleavage at Arg506 and were inactivated like FVa. The addition of a FV-BR fragment reversed this effect and delayed APC inactivation. We also found that anticoagulant glycoprotein TFPIα, which has a C-terminal BR homologous to FV-BR, protects FV-short from APC inactivation by delaying cleavage at Arg506. We conclude that the FV-BR plays a major role in protecting FV from APC inactivation. Using a similar mechanistic strategy, TFPIα also shields FV-short from APC. These findings clarify the resistance of FV to APC, advance our understanding of FV/FVa regulation, and establish a mechanistic framework for manipulating this reaction to alter coagulation.

Augmented humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 after breakthrough infection in kidney transplant recipients who received 3 doses of coronavirus disease 2019 vaccine.

Diminished immune response to coronavirus disease 2019 (COVID-19) vaccines and breakthrough infection (BI) is a major concern for solid organ transplant recipients. Humoral and cellular immune responses of kidney transplant (KT) recipients after a third COVID-19 vaccination were investigated compared to matched health care workers. Anti-severe acute respiratory syndrome coronavirus 2 spike protein antibody and severe acute respiratory syndrome coronavirus 2 specific interferon-gamma releasing assay (IGRA) were assessed. A total of 38 KT recipients, including 20 BI and 18 noninfection, were evaluated. In the KT BI group, antibody titers were significantly increased (median 5 to 724, binding antibody units/mL (P = 0.002) after the third vaccination, but IGRA responses were negligible. After BI, antibody titers increased (median 11 355 binding antibody unit/mL; P < 0.001) and there was a significant increase of IGRA responses to spike proteins (Spike1-Nil, median 0.05 to 0.41 IU/mL; P = 0.009). Antibody titers and IGRA responses were significantly higher in the BI than in the noninfection group after 6 months. Immune responses were stronger in the health care worker than in the KT cohort, but the gap became narrower after BI. In conclusion, KT recipients who experienced BI after 3 COVID-19 vaccinations acquired augmented humoral and cellular immune responses.

Clinical significance and outcomes of Clostridium tertium bacteremia: analysis of 62 cases in neutropenic and non-neutropenic patients.

The clinical significance of Clostridium tertium bacteremia is still uncertain. We evaluated the incidence, clinical characteristics, and outcomes of C. tertium bacteremia and identified differences between neutropenia and non-neutropenia. All adult patients with C. tertium bacteremia in a 2700-bed tertiary center between January 2004 and November 2021 were retrospectively enrolled. The first episode of C. tertium bacteremia in each patient was included in the analysis. Among 601 patients with Clostridium species bacteremia, 62 (10%) had C. tertium bacteremia, and of these 62 patients, 39 (63%) had had recent chemotherapy, and 31 (50%) had neutropenia or hematologic malignancy. C. tertium bacteremia originated frequently from a gastrointestinal tract infection such as enterocolitis (34%), primary bacteremia (29%), and secondary peritonitis (18%), and 34% of patients had polymicrobial bacteremia. Hematologic malignancy, prior antibiotic treatment, neutropenic enterocolitis, and primary bacteremia were significantly associated with C. tertium bacteremia in neutropenic patients, whereas solid tumor, hepatobiliary disease, secondary peritonitis, polymicrobial bacteremia, and a higher frequency of eradicable infection foci were significantly associated with C. tertium bacteremia in non-neutropenic patients. There was 15% 30-day mortality. APACHE II score (adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 1.1-2.1) and secondary peritonitis (aOR, 25.9; 95% CI, 3.0-224.7) were independent risk factors for 30-day mortality. The prevalence of C. tertium bacteremia is low, and the characteristics of C. tertium bacteremia are significantly different between neutropenic and non-neutropenic patients. Appropriate investigation for gastrointestinal mucosal injury should be performed to improve treatment outcomes in this form of bacteremia.

Clinical Utility of Sero-Immunological Responses Against SARS-CoV-2 Nucleocapsid Protein During Subsequent Prevalence of Wild-Type, Delta Variant, and Omicron Variant.

As nucleocapsid protein of severe acute respiratory syndrome coronavirus 2 is immunogenic but not targeted in vaccines, it could be useful in distinguishing natural infection from vaccination. We aimed to investigate the clinical utility of sero-immunological responses against the nucleocapsid protein. Nucleocapsid antibody immunoassay study with 302 coronavirus disease 2019 (COVID-19) patients showed lower titers in immunocompromised patients (P < 0.001), higher titers in higher severity (P = 0.031), and different seroconversion rates and titers according to variants of concern. Longitudinal evaluation of nucleocapsid antibodies using 513 samples from 291 COVID-19 patients revealed that it could persist up to 556 days from symptom onset. Interferon gamma release assay against the nucleocapsid protein showed poor response, precluding the deduction of a cut-off for the nucleocapsid protein. In conclusion, nucleocapsid antibody provides instructive clues about the immunogenicity of nucleocapsid proteins by different seroconversion rates and titers according to the severity of infection, host immune status, and different variants of concern.

Bedside risk prediction for positive follow-up blood culture in Gram-negative bacilli bacteremia: for whom is follow-up blood culture useful?

PURPOSE: The value of follow-up blood culture (FUBC) in Gram-negative bacteremia (GNB) management is controversial. We evaluated bedside risk predictors and their probabilities of yielding positive FUBCs in GNB. METHODS: All adult patients with GNB in a 2700-bed tertiary center were retrospectively enrolled between January 2019 and December 2019. Only one initial GNB episode was included per patient. Positive FUBC was defined as isolation of the same organism in blood culture 48-72 h after the initial blood culture. RESULTS: A total of 2216 patients with GNB were identified, of whom 34.4% underwent FUBC. Of the 645 patients with FUBCs analyzed in the study, 89 (13.8%) had positive FUBCs. In multivariate analysis, hemodialysis [adjusted odds ratio (aOR), 2.6], fever on the day of FUBCs (aOR 3.6), intravascular device (aOR 2.4), no use of in vitro active antibiotic within 24 h (aOR 2.5), non-fermenting bacteria (aOR 4.7), and multidrug resistance (aOR 5.4) were independent risk factors for positive FUBCs. If microbiological results were excluded in multivariate analysis, hemodialysis, immunosuppressive treatment, fever on the day of FUBCs, and intravascular device were independent bedside risk predictors for positive FUBCs. The yield of FUBCs increased from 3.0% (95% CI 1.0-7.0) to 63.6% (95% CI 25.6-100) as the number of bedside risk predictors increased from 0 to 4. In addition, positive FUBCs were significantly associated with 30 day mortality. CONCLUSIONS: FUBCs may not need to be routinely used for patients with GNB bacteremia, and bedside risk predictors could be helpful in identifying patients for whom FUBC is likely to be useful.

Association of preterm birth with medications: machine learning analysis using national health insurance data.

PURPOSE: To use machine learning and population data for testing the associations of preterm birth with socioeconomic status, gastroesophageal reflux disease (GERD) and medication history including proton pump inhibitors, sleeping pills and antidepressants. METHODS: Population-based retrospective cohort data came from Korea National Health Insurance Service claims data for all women who aged 25-40 years and gave births for the first time as singleton pregnancy during 2015-2017 (405,586 women). The dependent variable was preterm birth during 2015-2017 and 65 independent variables were included (demographic/socioeconomic determinants, disease information, medication history, obstetric information). Random forest variable importance (outcome measure) was used for identifying major determinants of preterm birth and testing its associations with socioeconomic status, GERD and medication history including proton pump inhibitors, sleeping pills and antidepressants. RESULTS: Based on random forest variable importance, major determinants of preterm birth during 2015-2017 were socioeconomic status (645.34), age (556.86), proton pump inhibitors (107.61), GERD for the years 2014, 2012 and 2013 (106.78, 105.87 and 104.96), sleeping pills (97.23), GERD for the years 2010, 2011 and 2009 (95.56, 94.84 and 93.81), and antidepressants (90.13). CONCLUSION: Preterm birth has strong associations with low socioeconomic status, GERD and medication history such as proton pump inhibitors, sleeping pills and antidepressants. For preventing preterm birth, appropriate medication would be needed alongside preventive measures for GERD and the promotion of socioeconomic status for pregnant women.

Identification of Novel Nucleocapsid Chimeric Proteins Inhibiting HIV-1 Replication.

The positive transcription elongation factor b (P-TEFb) is an essential factor that induces transcription elongation and is also negatively regulated by the cellular factor HEXIM1. Previously, the chimeric protein HEXIM1-Tat (HT) was demonstrated to inhibit human immunodeficiency virus-1 (HIV)-1 transcription. In this study, we attempted to develop an improved antiviral protein that specifically binds viral RNA (vRNA) by fusing HT to HIV-1 nucleocapsid (NC). Thus, we synthesized NC-HEXIM1-Tat (NHT) and HEXIM1-Tat-NC (HTN). NHT and HTN inhibited virus proliferation more effectively than HT, and they did not attenuate the function of HT. Notably, NHT and HTN inhibited the infectivity of the progeny virus, whereas HT had no such effect. NHT and HTN selectively and effectively interacted with vRNA and inhibited the proper packaging of the HIV-1 genome. Taken together, our results illustrated that the novel NC-fused chimeric proteins NHT and HTN display novel mechanisms of anti-HIV effects by inhibiting both HIV-1 transcription and packaging.

Validation of BMI genetic risk score and DNA methylation in a Korean population.

When DNA profiles obtained from biological evidence at a crime scene fail to match suspects or anyone in the database, forensic DNA phenotyping, which is the prediction of externally visible characteristics, can facilitate a traced search for an unknown suspect by limiting the search range. Therefore, age, trait, or lifestyle predictors, as well as the predictor for colorations, have been researched in the forensic field. In the present study, for the development of a prediction model for BMI or obesity, we investigated several previously reported BMI- or obesity-associated genetic and epigenetic markers that included four CpGs (cg06500161, cg00574958, cg12593793, and cg10505902 of the ABCG1, CPT1A, LMNA, and PDE4DIP genes, respectively), and eight SNPs (rs12463617, rs1558902, rs591166, rs11030104, rs11671664, rs6545814, rs16858082, and rs574367 near the TMEM18, FTO, MC4R, BDNF, GIPR/QPCTL, ADCY3/RBJ, GNPDA2, and SEC16B genes, respectively) in 700 Koreans within the BMI ranging from 16.1 to 40.6 (27.6 ± 4.5) kg/m2. Linear regression analysis showed that DNA methylation of the four CpG sites explained 10.9% total variance in BMI, and the model constructed using age information, genetic score from eight SNPs, and DNA methylation at four CpG sites could account for 17.4% of BMI variance. Using data mining techniques, i.e., decision tree (Entropy and Gini), random forest, and bagging, a total of eight models with BMI 31 or 32 as a cutoff value were also constructed based on the data obtained from 490 training samples with age and sex as a covariate. Among them, a random forest model with a cutoff value of 31 showed the best performance with 63.3% accuracy and the AUC value of 0.682 in 210 test set samples. In the present study, we could replicate the previous finding that DNA methylation contributes more to BMI than do genetic factors. In addition, although the accuracy for the prediction of BMI was not high, our study is meaningful in respect of the ability to use a small number of markers to achieve similar prediction accuracy to that obtained from a model composed of more than a thousand markers, which adds support to continued research to identify a small set of predictive markers for practical application in the forensic field.

Drosophila Gr64e mediates fatty acid sensing via the phospholipase C pathway.

Animals use taste to sample and ingest essential nutrients for survival. Free fatty acids (FAs) are energy-rich nutrients that contribute to various cellular functions. Recent evidence suggests FAs are detected through the gustatory system to promote feeding. In Drosophila, phospholipase C (PLC) signaling in sweet-sensing cells is required for FA detection but other signaling molecules are unknown. Here, we show Gr64e is required for the behavioral and electrophysiological responses to FAs. GR64e and TRPA1 are interchangeable when they act downstream of PLC: TRPA1 can substitute for GR64e in FA but not glycerol sensing, and GR64e can substitute for TRPA1 in aristolochic acid but not N-methylmaleimide sensing. In contrast to its role in FA sensing, GR64e functions as a ligand-gated ion channel for glycerol detection. Our results identify a novel FA transduction molecule and reveal that Drosophila Grs can act via distinct molecular mechanisms depending on context.

The First Case of Multisystem Inflammatory Syndrome in Adult after COVID-19 in Korea.

Multisystem inflammatory disease in children is a Kawasaki disease like illness occurring after severe acute respiratory syndrome coronavirus 2 infection in children. As the pandemic progresses, similar syndromes were also reported in adult with a decreased incidence. Multisystem inflammatory syndrome in adults (MIS-A) can be characterized with shock, heart failure, and gastrointestinal symptoms with elevated inflammatory markers after coronavirus disease 2019 (COVID-19) infection. Herein, we describe the first case of MIS-A in South Korea. A 38-year-old man presented to our hospital with a 5-day history of abdominal pain and fever. He had been treated with antibiotics for 5 days at the previous hospital, but symptoms had worsened and he had developed orthopnea on the day of presentation. He suffered COVID-19 six weeks ago. Laboratory data revealed elevated white blood cell counts with neutrophil dominance, C-reactive protein, and B-type natriuretic peptide. Chest X-ray showed normal lung parenchyme and echocardiography showed severe biventricular failure with normal chamber size. We diagnosed him as MIS-A and treated with intravenous immunoglobulin and steroid.

Metamaterial-Integrated High-Gain Rectenna for RF Sensing and Energy Harvesting Applications.

This paper presents a metamaterial (MTM)-integrated high-gain rectenna for RF sensing and energy harvesting applications that operates at 2.45 GHz, an industry, science, medicine (ISM) band. The novel MTM superstrate approach with a three-layered integration method is firstly introduced for rectenna applications. The integrated rectenna consists of three layers, where the first layer is an MTM superstrate consisting of four-by-four MTM unit cell arrays, the second layer a patch antenna, and the third layer a rectifier circuit. By integrating the MTM superstrate on top of the patch antenna, the gain of the antenna is enhanced, owing to its beam focusing capability of the MTM superstrate. This induces the increase of the captured RF power at the rectifier input, resulting in high-output DC power and high entire end-to-end efficiency. A parametric analysis is performed in order to optimize the near-zero property of the MTM unit cell. In addition, the effects of the number of MTM unit cells on the performance of the integrated rectenna are studied. A prototype MTM-integrated rectenna, which is designed on an RO5880 substrate, is fabricated and characterized. The measured gain of the MTM-integrated rectenna is 11.87 dB. It shows a gain improvement of 6.12 dB compared to a counterpart patch antenna without an MTM superstrate and a maximum RF-DC conversion efficiency of 78.9% at an input RF power of 9 dBm. This results in the improvement of the RF-DC efficiency from 39.2% to 78.9% and the increase of the output DC power from 0.7 mW to 6.27 mW (a factor of 8.96 improvements). The demonstrated MTM-integrated rectenna has shown outstanding performance compared to other previously reported work. We emphasize that the demonstrated MTM-integrated rectenna has a low design complexity compared with other work, as the MTM superstrate layer is integrated on top of the simple patch antenna and rectifier circuit. In addition, the number of MTM units can be determined depending on applications. It is highly envisioned that the demonstrated MTM-integrated rectenna will provide new possibilities for practical energy harvesting applications with improved antenna gain and efficiency in various IoT environments.

Small-Molecule Antibiotics Inhibiting tRNA-Regulated Gene Expression Is a Viable Strategy for Targeting Gram-Positive Bacteria.

Bacterial infections and the rise of antibiotic resistance, especially multidrug resistance, have generated a clear need for discovery of novel therapeutics. We demonstrated that a small-molecule drug, PKZ18, targets the T-box mechanism and inhibits bacterial growth. The T-box is a structurally conserved riboswitch-like gene regulator in the 5' untranslated region (UTR) of numerous essential genes of Gram-positive bacteria. T-boxes are stabilized by cognate, unacylated tRNA ligands, allowing the formation of an antiterminator hairpin in the mRNA that enables transcription of the gene. In the absence of an unacylated cognate tRNA, transcription is halted due to the formation of a thermodynamically more stable terminator hairpin. PKZ18 targets the site of the codon-anticodon interaction of the conserved stem I and reduces T-box-controlled gene expression. Here, we show that novel analogs of PKZ18 have improved MICs, bactericidal effects against methicillin-resistant Staphylococcus aureus (MRSA), and increased efficacy in nutrient-limiting conditions. The analogs have reduced cytotoxicity against eukaryotic cells compared to PKZ18. The PKZ18 analogs acted synergistically with aminoglycosides to significantly enhance the efficacy of the analogs and aminoglycosides, further increasing their therapeutic windows. RNA sequencing showed that the analog PKZ18-22 affects expression of 8 of 12 T-box controlled genes in a statistically significant manner, but not other 5'-UTR regulated genes in MRSA. Very low levels of resistance further support the existence of multiple T-box targets for PKZ18 analogs in the cell. Together, the multiple targets, low resistance, and synergy make PKZ18 analogs promising drugs for development and future clinical applications.

Decreased Incidence of Methicillin-Resistant Staphylococcus aureus Bacteremia in Intensive Care Units: a 10-Year Clinical, Microbiological, and Genotypic Analysis in a Tertiary Hospital.

There are limited long-term data on the trends in incidence and characteristics of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (MRSAB) in intensive care units (ICUs) in which infection control measures have been adopted. We evaluated the trend of incidence and changes in characteristics of MRSA bacteremia in ICUs at a tertiary-care hospital over 10 years using prospective cohort data. ICU-acquired bacteremia was defined as S. aureus bacteremia (SAB) that occurred 48 h or more after ICU admission. MRSA isolates were collected and subjected to microbiological and genotypic analyses. A total of 529 SAB episodes were identified among 367,175 ICU patients. Of these episodes, 288 (54.4%) were ICU acquired, 238 (82.6%) of which were MRSAB. The incidence density of ICU-acquired MRSAB decreased from 1.32 per 1,000 patient-days to 0.19 per 1,000 patient-days (a decrease of 20% annually; P < 0.001 for trend), whereas that of non-ICU-acquired MRSAB fluctuated and did not decrease significantly. The decline in ICU-acquired MRSAB was due to lower catheter-related infection and less pneumonia. Rates of persistent bacteremia and 12-week mortality also fell significantly. A total of 183 isolates were collected from 238 ICU-acquired MRSAB cases. There were no significant changes in the geometric means of vancomycin MICs, vancomycin heteroresistance, or the sequence types of MRSA isolates over time. Chlorhexidine MICs decreased (P < 0.001 for trend) in association with a decline in frequency of the qacA or qacB gene that was related to reductions in specific spa types. The incidence of MRSAB in ICUs has decreased dramatically over time, but most of the microbiological and genotypic characteristics of MRSA isolates have not changed.

MMP11 and CD2 as novel prognostic factors in hormone receptor-negative, HER2-positive breast cancer.

PURPOSE: More accurate prediction of patient outcome based on molecular subtype is required to identify patients who will benefit from specific treatments. METHODS: We selected novel 16 candidate prognostic genes, including 10 proliferation-related genes (p-genes) and 6 immune response-related genes (i-genes), from the gene list identified in our previous study. We then analyzed the association between their expression, measured by quantitative real-time reverse transcription-PCR in formalin-fixed, paraffin-embedded tissues, and clinical outcome in 819 breast cancer patients according to molecular subtype. RESULTS: The prognostic significance of clinical and gene variables varied according to the molecular subtype. Univariate analysis showed that positive lymph node status was significantly correlated with the increased risk of distant metastasis in all subtypes except the hormone receptor-negative, HER2-positive (HR-/HER2+) subtype. Most p-genes were significantly associated with poor prognosis in patients with the HR+/HER2- subtype, whereas i-genes correlated with a favorable outcome in patients with HR-/HER2+ breast cancer. In HR-/HER2+ breast cancer, four genes (three i-genes BTN3A2, CD2, and TRBC1 and the p-gene MMP11) were significantly associated with distant metastasis-free survival (DMFS). A new prognostic model for HR-/HER2+ breast cancer based on the expression of MMP11 and CD2 was developed and the DMFS for patients in the high-risk group according to our model was significantly lower than that for those in the low-risk group. Multivariate analyses revealed that our risk score is an independent prognostic factor for DMFS. Moreover, C-index showed that our risk score has a superior prognostic performance to traditional clinicopathological factors. CONCLUSIONS: Our new prognostic model for HR-/HER2+ breast cancer provides more accurate information on the risk of distant metastasis than traditional clinical prognostic factors and may be used to identify patients with a good prognosis in this aggressive subtype of breast cancer.

Kif18a is specifically required for mitotic progression during germ line development.

Genome integrity in the developing germ line is strictly required for fecundity. In proliferating somatic cells and in germ cells, there are mitotic checkpoint mechanisms that ensure accurate chromosome segregation and euploidy. There is growing evidence of mitotic cell cycle components that are uniquely required in the germ line to ensure genome integrity. We previously showed that the primary phenotype of germ cell deficient 2 (gcd2) mutant mice is infertility due to germ cell depletion during embryogenesis. Here we show that the underlying mutation is a mis-sense mutation, R308K, in the motor domain of the kinesin-8 family member, KIF18A, a protein that is expressed in a variety of proliferative tissues and is a key regulator of chromosome alignment during mitosis. Despite the conservative nature of the mutation, we show that its functional consequences are equivalent to KIF18A deficiency in HeLa cells. We also show that somatic cells progress through mitosis, despite having chromosome alignment defects, while germ cells with similar chromosome alignment defects undergo mitotic arrest and apoptosis. Our data provide evidence for differential requirements for chromosome alignment in germ and somatic cells and show that Kif18a is one of a growing number of genes that are specifically required for cell cycle progression in proliferating germ cells.

Behavioral Analysis of Bitter Taste Perception in Drosophila Larvae.

Insect larvae, which recognize food sources through chemosensory cues, are a major source of global agricultural loss. Gustation is an important factor that determines feeding behavior, and the gustatory receptors (Grs) act as molecular receptors that recognize diverse chemicals in gustatory receptor neurons (GRNs). The behavior of Drosophila larvae is relatively simpler than the adult fly, and a gustatory receptor-to-neuron map was established in a previous study of the major external larval head sensory organs. Here, we extensively study the bitter taste responses of larvae using 2-choice behavioral assays. First, we tested a panel of 23 candidate bitter compounds to compare the behavioral responses of larvae and adults. We define 9 bitter compounds which elicit aversive behavior in a dose-dependent manner. A functional map of the larval GRNs was constructed with the use of Gr-GAL4 lines that drive expression of UAS-tetanus toxin and UAS-VR1 in specific gustatory neurons to identify bitter tastants-GRN combinations by suppressing and activating discrete subsets of taste neurons, respectively. Our results suggest that many gustatory neurons act cooperatively in larval bitter sensing, and that these neurons have different degrees of responsiveness to different bitter compounds.

Ethanolic Extract of Acanthopanax koreanum Nakai Alleviates Alcoholic Liver Damage Combined with a High-Fat Diet in C57BL/6J Mice.

Alcoholic and nonalcoholic liver steatosis have an indistinguishable spectrum of histological features and liver enzyme elevations. In this study, we investigated the potential of the ethanolic extract of Acanthopanax koreanum Nakai (AK) to protect against experimental alcoholic liver disease in a mouse model that couples diet and daily ethanol bolus gavage. Fifty-six C57BL/6J mice were randomly divided into seven groups: normal control (NC), alcohol control (AC), alcohol/HFD control (AH), low-dose (1%) AK in alcohol group (ACL), high-dose (3%) AK in alcohol group (ACH), low-dose AK in alcohol/HFD group (AHL), and high-dose AK in alcohol/HFD group (AHH). The AH group showed more severe damage than the AC group in terms of biochemical and molecular data that were observed in this study. The administration of AK exerted remarkable effects in: plasma ALT (p < 0.0001), total lipid (p = 0.014), TG (p = 0.0037) levels; CPT-1α (p = 0.0197), TLR4 (p < 0.0001), CD14 (p = 0.0002), IL-6 (p = 0.0264) and MCP-1 (p = 0.0045) gene expressions; and ALDH (p < 0.0001) and CAT (p = 0.0076) activities. The data suggested that at least the high dose AK might confer protection against alcoholic liver damage combined with an HFD by accelerating lipid oxidation and alcohol metabolism and by suppressing the inflammatory response, including the TLR pathway.

HisCl1 regulates gustatory habituation in sweet taste neurons and mediates sugar ingestion in Drosophila.

Similar to other animals, the fly, Drosophila melanogaster, reduces its responsiveness to tastants with repeated exposure, a phenomenon called gustatory habituation. Previous studies have focused on the circuit basis of gustatory habituation in the fly chemosensory system1,2. However, gustatory neurons reduce their firing rate during repeated stimulation3, suggesting that cell-autonomous mechanisms also contribute to habituation. Here, we used deep learning-based pose estimation and optogenetic stimulation to demonstrate that continuous activation of sweet taste neurons causes gustatory habituation in flies. We conducted a transgenic RNAi screen to identify genes involved in this process and found that knocking down Histamine-gated chloride channel subunit 1 (HisCl1) in the sweet taste neurons significantly reduced gustatory habituation. Anatomical analysis showed that HisCl1 is expressed in the sweet taste neurons of various chemosensory organs. Using single sensilla electrophysiology, we showed that sweet taste neurons reduced their firing rate with prolonged exposure to sucrose. Knocking down HisCl1 in sweet taste neurons suppressed gustatory habituation by reducing the spike frequency adaptation observed in these neurons during high-concentration sucrose stimulation. Finally, we showed that flies lacking HisCl1 in sweet taste neurons increased their consumption of high-concentration sucrose solution at their first meal bout compared to control flies. Together, our results demonstrate that HisCl1 tunes spike frequency adaptation in sweet taste neurons and contributes to gustatory habituation and food intake regulation in flies. Since HisCl1 is highly conserved across many dipteran and hymenopteran species, our findings open a new direction in studying insect gustatory habituation.

Stability of Zr-Based UiO-66 Metal-Organic Frameworks in Basic Solutions.

Although Zr-based metal-organic frameworks (MOFs) exhibit robust chemical and physical stability in the presence of moisture and acidic conditions, their susceptibility to nucleophilic attacks from bases poses a critical challenge to their overall stability. Herein, we systematically investigate the stability of Zr-based UiO-66 (UiO = University of Oslo) MOFs in basic solutions. The impact of 11 standard bases, including inorganic salts and organic bases, on the stability of these MOFs is examined. The destruction of the framework is confirmed through powder X-ray diffraction (PXRD) patterns, and the monitored dissolution of ligands from the framework is assessed using nuclear magnetic resonance (NMR) spectroscopy. Our key findings reveal a direct correlation between the strength and concentration of the base and the destruction of the MOFs. The summarized data provide valuable insights that can guide the practical application of Zr-based UiO-66 MOFs under basic conditions, offering essential information for their optimal utilization in various settings.

Physical Therapy Assessment Tool Threshold Values to Identify Sarcopenia and Locomotive Syndrome in the Elderly.

This study aimed to evaluate sarcopenia and locomotive syndrome in Korean elderly patients, analyze the closely related factors, and determine the threshold for distinguishing participants with sarcopenia, locomotive syndrome, and non-disease. To this end, we enrolled 210 subjects aged 65 years or more and classified them into the sarcopenia (n = 36) and locomotive syndrome (n = 164) groups; a control group was also included (n = 10). We evaluated the characteristics of these patients using the Timed Up and Go (TUG) test and Berg Balance Scale (BBS) and performed statistical analysis. Our findings showed statistically significant differences between the groups, leading to the derivation of a significant threshold value. The threshold value of the TUG test between the control and locomotive syndrome groups was 9.47 s; the threshold value of the BBS was 54 points, respectively. The threshold value of the TUG test between the locomotive syndrome and sarcopenia groups was 10.27 s, and the threshold value of the BBS was 50 points, respectively. These findings suggest that sarcopenia is closely related to locomotive syndrome, and that sarcopenia and locomotive syndrome can be identified using a physical therapy diagnostic evaluation tool.