Miracle-dz/UniFAR-FTUs huggingface dataset:
Lipid Annotator: Towards Accurate Annotation in Non-Targeted Liquid Chromatography High-Resolution Tandem Mass Spectrometry (LC-HRMS/MS) Lipidomics Using a Rapid and User-Friendly Software

Lipidomics has great promise in various applications; however, a major bottleneck in lipidomics is the accurate and comprehensive annotation of high-resolution tandem mass spectral data. While the number of available lipidomics software has drastically increased over the past five years, the reduction of false positives and the realization of obtaining structurally accurate annotations remains a significant challenge. We introduce Lipid Annotator, which is a user-friendly software for lipidomic analysis of data collected by liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). We validate annotation accuracy against lipid standards and other lipidomics software. Lipid Annotator was integrated into a workflow applying an iterative exclusion MS/MS acquisition strategy to National Institute of Standards and Technology (NIST) SRM 1950 Metabolites in Frozen Human Plasma using reverse phase LC-HRMS/MS. Lipid Annotator, LipidMatch, and MS-DIAL produced consensus annotations at the level of lipid class for 98% and 96% of features detected in positive and negative mode, respectively. Lipid Annotator provides percentages of fatty acyl constituent species and employs scoring algorithms based on probability theory, which is less subjective than the tolerance and weighted match scores commonly used by available software. Lipid Annotator enables analysis of large sample cohorts and improves data-processing throughput as compared to previous lipidomics software.
Engineering a Highly Active Sucrose Isomerase for Enhanced Product Specificity by Using a “Battleship” Strategy

The sucrose isomerase SmuA from Serratia plymuthica efficiently catalyses the isomerisation of sucrose into isomaltulose, an artificial sweetener used in the food industry. However, the formation of a hygroscopic by‐product, trehalulose, necessitates additional separation to obtain a crystalline product. Therefore, we have improved the product specificity of SmuA by first introducing a few exploratory amino acid exchanges around the active site and investigating their influence. Then, we devised a second set of mutations, either at promising positions from the preceding cycle, but with a different side chain, or at alternative positions in the vicinity. After seven iterative cycles involving just 55 point mutations, we obtained the triple mutant Y219L/D398G/V465E which showed 2.3 times less trehalulose production but still had high catalytic efficiency (kcat/KM=11.8 mM−1 s−1). Not only does this mutant SmuA appear attractive as an industrial biocatalyst, but our semirational protein‐engineering strategy, which resembles the battleship board game, should be of interest for other challenging enzyme optimization endeavours.
ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.
Optimization in continuous phase‐transition extraction of crude flavonoids from finger citron fruit and evaluation on their antiaging activities

Abstract The development of antiaging functional products is a hot topic in the field of functional foods. However, the efficient extraction of functional ingredients is the limiting step for the functional food industry. Continuous phase‐transition extraction (CPE) is a new extraction technique that combines the advantages of Soxhlet extraction and supercritical extraction, which may have a distinct advantage over traditional methods in the extraction of flavonoids. In our study, the Box–Behnken design combined with response surface methodology was used to optimize CPE of crude flavonoids from finger citron fruit. The antiaging activities of finger citron crude flavonoids (FCCF) were evaluated by Caenorhabditis elegans (C. elegans) model. The optimal extraction conditions for CPE were as follows: ethanol concentration 85%, temperature 90°C, time 120 min, and pressure 0.2 MPa. Compared with the heat reflux extraction, the extraction rate and content of FCCF extracted by CPE increased by 24.28% and 33.22% (p < .05), respectively. FCCF extended the lifespan of C. elegans by 14.94% without causing adverse effects on their reproduction and locomotion ability. A further analysis suggested that FCCF prolonged the lifespan of nematodes under normal and oxidative stress by increasing the activity of major enzymes in endogenous antioxidant defense system and reducing the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA). The results confirmed the effectiveness of CPE in extracting crude flavonoids from finger citron fruit, and the extracted FCCF exhibited strong antiaging activities.
Mental health disorders and utilization of mental healthcare services in United Nations personnel

Abstract Background United Nations (UN) personnel address a diverse range of political, social, and cultural crises throughout the world. Compared with other occupations routinely exposed to traumatic stress, there remains a paucity of research on mental health disorders and access to mental healthcare in this population. To fill this gap, personnel from UN agencies were surveyed for mental health disorders and mental healthcare utilization. Methods UN personnel (N = 17 363) from 11 UN entities completed online measures of generalized anxiety disorder (GAD), major depressive disorder (MDD), posttraumatic stress disorder (PTSD), trauma exposure, mental healthcare usage, and socio-demographic information. Results Exposure to one or more traumatic events was reported by 36.2% of survey responders. Additionally, 17.9% screened positive for GAD, 22.8% for MDD, and 19.9% for PTSD. Employing multivariable logistic regressions, low job satisfaction, younger age (<35 years of age), greater length of employment, and trauma exposure on or off-duty was significantly associated with all the three disorders. Among individuals screening positive for a mental health disorder, 2.05% sought mental health treatment within and 10.01% outside the UN in the past year. Conclusions UN personnel appear to be at high risk for trauma exposure and screening positive for a mental health disorder, yet a small percentage screening positive for mental health disorders sought treatment. Despite the mental health gaps observed in this study, additional research is needed, as these data reflect a large sample of convenience and it cannot be determined if the findings are representative of the UN.
Morphological Carotid Plaque Area Is Associated With Glomerular Filtration Rate: A Study of South Asian Indian Patients With Diabetes and Chronic Kidney Disease

We evaluated the association between automatically measured carotid total plaque area (TPA) and the estimated glomerular filtration rate (eGFR), a biomarker of chronic kidney disease (CKD). Automated average carotid intima–media thickness (cIMTave) and TPA measurements in carotid ultrasound (CUS) were performed using AtheroEdge (AtheroPoint). Pearson correlation coefficient (CC) was then computed between the TPA and eGFR for (1) males versus females, (2) diabetic versus nondiabetic patients, and (3) between the left and right carotid artery. Overall, 339 South Asian Indian patients with either type 2 diabetes mellitus (T2DM) or CKD, or hypertension (stage 1 or stage 2) were retrospectively analyzed by acquiring cIMTave and TPA measurements of their left and right common carotid arteries (CCA; total CUS: 678, mean age: 54.2 ± 9.8 years; 75.2% males; 93.5% with T2DM). The CC between TPA and eGFR for different scenarios were (1) for males and females −0.25 (P < .001) and −0.35 (P < .001), respectively; (2) for T2DM and non-T2DM −0.26 (P < .001) and −0.49 (P = .02), respectively, and (3) for left and right CCA −0.25 (P < .001) and −0.23 (P < .001), respectively. Automated TPA is an equally reliable biomarker compared with cIMTave for patients with CKD (with or without T2DM) with subclinical atherosclerosis.
Dyspareunia as a chronic pain syndrome : a comparative study

The diagnosis of Dyspareunia relies on a woman's self-report of pain associated with sexual intercourse, and is reported to be a common and distressing condition. Considered within psychiatric classifications as primarily a sexual dysfunction, there has been little research on dyspareunia as a pain syndrome. In this study 11 women with dyspareunia were compared with 13 women with more generalised chronic pelvic pain, and a comparison group of 11 women with other recognised chronic pain syndromes. The groups were compared on various psychosocial measures including sexual functioning, relationship adjustment, anxiety, depression, beliefs about pain and pain intensity. It was hypothesised that women with dyspareunia would share many psychosocial characteristics with women experiencing other chronic pain syndromes. The data were analysed using nonparametric analysis of variance and correlational statistics. The study found many similarities between women with dyspareunia, chronic pelvic pain and other chronic pain syndromes on the measures of psychosocial functioning. In addition, significant relationships were found between the frequent experience of catastrophising self-statements and anxiety, with self-reports of pain ratings. The results suggest that impairments in sexual and relationship functioning may not be specific to women with dyspareunia. The findings provide support for the view, expressed recently in the literature, that dyspareunia may be more usefully considered as a chronic pain syndrome resulting in sexual difficulties. The findings highlight the role of cognitive factors that may promote or hinder attempts to cope with pain, and have important implications for possible psychological interventions. An integrative model of investigation and management is proposed, drawing on current biopsychosocial pain theories for women with dyspareunia and chronic pelvic pain.
Antimicrobial susceptibility profiling of milk samples from bovine clinical mastitis

Mastitis is one of the most important diseases of milch animals leading to heavy economic losses due to reduced milk yield, discard of milk because of compromised quality and premature culling of animals. Early and specific use of antimicrobials significantly limits the severity of the disease and in many cases prevent the appearance of any visible sign of infection. However, the indiscriminate use of antimicrobial is leading to development of resistance in microbes. Thus the regular screening for the selection of suitable and effective antimicrobial is need of the day. With this objective, in present study primary antimicrobial drugs susceptibility test was performed on fifty clinical mastitis milk samples of cattle and buffaloes against eight commonly used drugs and their combinations to know the status of drug susceptibility to select the most effective drug for an early treatment. Drug susceptibility test revealed resistance towards multiple antimicrobials. Overall, the highest resistance was observed against cefotaxime, ampicillin-sulbactam, cefixime and ceftriaxone while majority of the culture showed susceptibility to amikacin, chloramphenicol and gentamicin. The higher resistance against third generation cephalosporin and better susceptibility for amikacin, available only in injectable preparations is suggestive of indiscriminate use of oral therapy of cephalosporins as the first choice for treatment because of their broad spectrum of action and easy mode of administration. Therefore, the present study recommends regular use of antimicrobial susceptibility testing of mastitis bacterial pathogens to decide the appropriate antimicrobial drug for treatment and to limiting the indiscriminate use of antimicrobial drugs to avoid the development of resistance among microbes.
Developing and Validating the Functional, Communicative, and Critical Health Literacy Questionnaire among the Iranian General Population

Objectives Many scales have been developed to assess health literacy. These scales have been developed extensively in clinical populations in developed countries. Our study describes the process of development and validation of the Health Literacy Questionnaire to measure health literacy in the general Iranian population. Methods We followed the scale development process outlined by Schwab in 1980. After a comprehensive review of the research published on Nutbeam’s definition of health literacy and its measurement, two focus groups were considered to generate a pool of items. We then assessed the face validity and content validity of the items. The final version of the questionnaire was subject to independent exploratory and confirmatory factor analysis. The internal consistency of the questionnaire was evaluated using Cronbach’s alpha. Finally, construct validity was assessed using bivariate analysis between the total scores on the scale and theoretically relevant variables. Results The results of exploratory factor analysis revealed a three-factor 14-item structure for the scale. Confirmatory factor analysis provided a good statistical and conceptual fit for the data. The analysis of the internal consistency of the scale was satisfactory (α = 0.798). Further, health literacy was significantly associated with participants’ age, educational level, self-rated household income, smoking history, self-rated health, and self-rated health literacy. Conclusions The results we obtained indicate that this newly constructed health literacy tool is highly valid and reliable. Prospective studies are required to evaluate the predictive validity of the scale with regard to health outcomes.
Fe‐Doped Polyoxometalate as Acid‐Aggregated Nanoplatform for NIR‐II Photothermal‐Enhanced Chemodynamic Therapy

The combination of reactive oxygen species‐involved chemodynamic therapy (CDT) and photothermal therapy (PTT) holds great promise in enhancing anticancer effects. Herein, a multifunctional Fe‐doped polyoxometalate (Fe‐POM) cluster is fabricated via a simple method. The Fe‐POM can not only be utilized as PTT agents to generate a hyperthermia effect for cancer cell killing under near‐infrared (NIR) II laser (1060 nm) irradiation, but also can be used as CDT agents to convert endogenous less‐reactive H2O2 into harmful ·OH and simultaneously deplete glutathione for an amplified CDT effect. Notably, the hyperthermia induced by PTT can further enhance the CDT effect, achieving a synergistic PTT/CDT effect. Owing to the self‐assembling properties at lowered pH values, the Fe‐POM exhibits high tumor accumulation as revealed by photoacoustic imaging. More importantly, Fe‐POM enables effective destruction of tumors without inducing noticeable damage to normal tissues under 1060 nm laser irradiation. The work presents a new type of multifunctional agent with high PTT/CDT efficacy, providing promising methods for PTT‐enhanced CDT in a NIR‐II biowindow.
In vitro insulin treatment reverses changes elicited by nutrients in cellular metabolic processes that regulate food intake in fish

ABSTRACT This research assessed the direct effects of insulin on nutrient-sensing mechanisms in the brain of rainbow trout (Oncorhynchus mykiss) using an in vitro approach. Cultured hypothalamus and hindbrain were exposed to 1 µmol l−1 insulin for 3 h, and signals involved in appetite regulation and nutrient-sensing mechanisms were measured. Additionally, the involvement of the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in the actions of insulin was studied by using the inhibitor wortmannin. Treatment with insulin alone did not elicit many changes in the appetite regulators and nutrient-sensing-related genes and enzymes tested in the hypothalamus and hindbrain. However, we found that, when insulin and nutrients were added together, insulin reversed most of the effects exerted by nutrients alone, suggesting that insulin changes responsiveness to nutrients at the central level. Effects reversed by insulin included expression levels of genes related to the sensing of both glucose (slc2a2, slc5a1, gck, pck1, pklr, g6pcb, gys1, tas1r3 and nr1h3 in the hindbrain, and slc2a2, pklr and pck1 in the hypothalamus) and fatty acid (cd36 in the hindbrain, and cd36 and acly in the hypothalamus). Nutrient-induced changes in the activity of Acly and Cpt-1 in the hindbrain and of Pepck, Acly, Fas and Hoad in the hypothalamus were also reversed by insulin. Most of the insulin effects disappeared in the presence of wortmannin, suggesting the PI3K/Akt pathway is a mediator of the effects of insulin reported here. This study adds new information to our knowledge of the mechanisms regulating nutrient sensing in fish. Summary: Insulin does not directly modulate glucose- and fatty acid-sensing systems in the rainbow trout hypothalamus and hindbrain, but counteracts the changes elicited by nutrients.
Rabies Vaccination of 6-Week-Old Puppies Born to Immunized Mothers: A Randomized Controlled Trial in a High-Mortality Population of Owned, Free-Roaming Dogs

To achieve global elimination of human rabies from dogs by 2030, evidence-based strategies for effective dog vaccination are needed. Current guidelines recommend inclusion of dogs younger than 3 months in mass rabies vaccination campaigns, although available vaccines are only recommended for use by manufacturers in older dogs, ostensibly due to concerns over interference of maternally-acquired immunity with immune response to the vaccine. Adverse effects of vaccination in this age group of dogs have also not been adequately assessed under field conditions. In a single-site, owner-blinded, randomized, placebo-controlled trial in puppies born to mothers vaccinated within the previous 18 months in a high-mortality population of owned, free-roaming dogs in South Africa, we assessed immunogenicity and effect on survival to all causes of mortality of a single dose of rabies vaccine administered at 6 weeks of age. We found that puppies did not have appreciable levels of maternally-derived antibodies at 6 weeks of age (geometric mean titer 0.065 IU/mL, 95% CI 0.061–0.069; n = 346), and that 88% (95% CI 80.7–93.3) of puppies vaccinated at 6 weeks had titers ≥0.5 IU/mL 21 days later (n = 117). Although the average effect of vaccination on survival was not statistically significant (hazard ratio [HR] 1.35, 95% CI 0.83–2.18), this effect was modified by sex (p = 0.02), with the HR in females 3.09 (95% CI 1.24–7.69) and the HR in males 0.79 (95% CI 0.41–1.53). We speculate that this effect is related to the observed survival advantage that females had over males in the unvaccinated group (HR 0.27; 95% CI 0.11–0.70), with vaccination eroding this advantage through as-yet-unknown mechanisms.
Accelerate development of topical cream drug product using a common platform base formulation

Abstract The aim of this work was to identify stable topical platform cream formulations (placebo creams without active drug substance) using the quality attributes of cream consistency, droplet size distribution (<1 μm), and separation or instability index of <0.1 to accelerate the development of topical cream drug product. The formulations were developed with six emulsifier systems that were screened in three different solvent systems across a range of emulsifier ratios. Each formulation was characterized by microscopy, separation index, and consistency. The results showed that there are three emulsifier combination (PEG 40 stearate:GMS, S21:S2, and PEG 40 stearate:Span 60) that works well with the solvent systems. Platform cream formulations F4, F15, F33, F40, F52, F69, F77, F87, and F106 were found to meet the three criteria for a long-term stable platform cream formulation. Formulation development for topical administered drug product can be very time consuming, expensive, and resourceful in identifying a chemically and physically stable product. In early development, where it can take 1–2 years to develop a first time in human (FTIH) formulation for a new chemical entity. The use of the platform base cream formulations will expedite the early development timeline for new chemical entity by 3–6 months.
Human transport of thirdhand tobacco smoke: A prominent source of hazardous air pollutants into indoor nonsmoking environments

Tobacco smoke off-gassing from prior exposure releases contaminants that are equivalent to several cigarettes of secondhand smoke. The contamination of indoor nonsmoking environments with thirdhand smoke (THS) is an important, poorly understood public health concern. Real-time THS off-gassing from smokers into a nonsmoking movie theater was observed with online and offline high-resolution mass spectrometry. Prominent emission events of THS tracers (e.g., 2,5-dimethylfuran, 2-methylfuran, and acetonitrile) and other tobacco-related volatile organic compounds (VOCs) coincided with the arrival of certain moviegoers and left residual contamination. These VOC emission events exposed occupants to the equivalent of 1 to 10 cigarettes of secondhand smoke, including multiple hazardous air pollutants (e.g., benzene and formaldehyde) at parts-per-billion concentrations. Nicotine and related intermediate-volatility nitrogen-containing compounds, which vaporized from clothes/bodies and recondensed onto aerosol, comprised 34% of observed functionalized organic aerosol abundance. Exposure to THS VOC emission events will be considerably enhanced in poorly ventilated or smaller spaces in contrast with a large, well-ventilated theater—amplifying concentrations and potential impacts on health and indoor chemistry.