Miracle-dz/UniFAR-FTUs huggingface dataset:
Diurnal, metabolic and thermogenic alterations in a murine model of accelerated aging

ABSTRACT Senescence-Accelerated Mouse-Prone 8 (SAMP8) mice exhibit characteristics of premature aging, including hair loss, cognitive dysfunction, reduced physical activity, impaired metabolic homeostasis, cardiac dysfunction and reduced lifespan. Interestingly, circadian disruption can induce or augment many of these same pathologies. Moreover, previous studies have reported that SAMP8 mice exhibit abnormalities in circadian wheel-running behavior, indicating possible alterations in circadian clock function. These observations led to the hypothesis that 24 h rhythms in behavior and/or circadian clock function are altered in SAMP8 mice and that these alterations may contribute to perturbations in whole-body metabolism. Here, we report that 6-month-old SAMP8 mice exhibit a more prominent biphasic pattern in daily behaviors (food intake and physical activity) and whole-body metabolism (energy expenditure, respiratory exchange ratio), relative to SAMR1 control mice. Consistent with a delayed onset of food intake at the end of the light phase, SAMP8 mice exhibit a phase delay (1.3–1.9 h) in 24 h gene expression rhythms of major circadian clock components (bmal1, rev-erbα, per2, dbp) in peripheral tissues (liver, skeletal muscle, white adipose tissue [WAT], brown adipose tissue [BAT]). Forcing mice to consume food only during the dark period improved alignment of both whole-body metabolism and oscillations in expression of clock genes in peripheral tissues between SAMP8 and SAMR1 mice. Next, interrogation of metabolic genes revealed altered expression of thermogenesis mediators (ucp1, pgc1α, dio2) in WAT and/or BAT in SAMP8 mice. Interestingly, SAMP8 mice exhibit a decreased tolerance to an acute (5 h) cold challenge. Moreover, SAMP8 and SAMR1 mice exhibited differential responses to a chronic (1 week) decrease in ambient temperature; the greatest response in whole-body substrate selection was observed in SAMR1 mice. Collectively, these observations reveal differential behaviors (e.g. 24 h food intake patterns) in SAMP8 mice that are associated with perturbations in peripheral circadian clocks, metabolism and thermogenesis.
Respiratory illness caused by Corynebacterium diphtheriae and C. ulcerans, and use of diphtheria anti-toxin in the United States, 1996-2018.

Respiratory illness caused by Corynebacterium diphtheriae and C. ulcerans, and use of diphtheria anti-toxin in the United States, 1996-2018. BACKGROUND Respiratory diphtheria is a toxin-mediated disease caused by Corynebacterium diphtheriae. Diphtheria-like illness, clinically indistinguishable from diphtheria, is caused by C. ulcerans, a zoonotic bacterium that can also produce diphtheria toxin. In the United States, respiratory diphtheria is nationally notifiable: specimens from suspected cases are submitted to the Centers for Disease Control (CDC) for species and toxin confirmation, and diphtheria antitoxin (DAT) is obtained from CDC for treatment. We summarize the epidemiology of respiratory diphtheria and diphtheria-like illness and describe DAT use during 1996-2018 in the United States. METHODS We described respiratory diphtheria cases reported to the National Notifiable Diseases Surveillance System (NNDSS) and C. ulcerans-related diphtheria-like illness identified through specimen submissions to CDC during 1996-2018. We reviewed DAT requests from 1997-2018. RESULTS From 1996-2018, 14 respiratory diphtheria cases were reported to NNDSS. Among these 14 cases, 1 was toxigenic and 3 were non-toxigenic C. diphtheriae by culture and Elek, 6 were culture-negative but PCR-positive for diphtheria toxin gene, 1 was culture-positive without further testing, and the remaining 3 were either not tested or tested negative. Five cases of respiratory diphtheria-like illness caused by toxigenic C. ulcerans were identified. DAT was requested by healthcare providers for 151 suspected diphtheria cases between 1997-2018, with an average of 11 requests per year from 1997-2007, and 3 per year from 2008-2018. CONCLUSIONS Respiratory diphtheria remains rare in the United States, and requests for DAT have declined. Incidental identification of C. ulcerans-related diphtheria-like illness suggests surveillance of this condition might be warranted.
Home Care Nursing Visits and Same-Day Emergency Department Use: Which Patients Are Most at Risk?

Background Home care patients are a growing group of community-dwelling older adults with complex care needs and high health service use. Adult home care patients are at high risk for emergency department (ED) visits, which is greater on the same day as a nursing visit. Purpose The purpose of this study was to examine whether common nursing indicators modified the association between nursing visits and same-day ED visits. Methods A case-crossover design within a retrospective cohort of adult home care patients in Ontario. Results A total of 11,840 home care nursing patients were analyzed. Home care patients who received a home nursing visit were more likely to go the ED afterhours on the same day with a stronger association for visits not admitted to the hospital. Having a urinary catheter increased the risk of a same-day ED visit (OR: 1.78 (95% CI 1.15–1.60) vs. 1.21 (95% CI 1.15–1.28)). No other clinical indicator modified the association. Conclusions The findings of this study can be used to inform care policies and practices for home care nurses in the management of indwelling urinary catheter complications. Further examination of system factors such as capacity and resources available to respond to catheter related complications in the community setting are recommended.
Patient Perspectives about Mild Cognitive Impairment: A Systematic Review

ABSTRACT Objectives Mild cognitive impairment (MCI) is a concept that is steeped in controversy not limited to prognostic uncertainty; it is unclear how patients interpret or attribute meaning to the label, and whether they perceive that being made aware is beneficial. Methods A systematic review was conducted, searching ISI Web of Science, PubMed and PsycINFO in accordance with PRISMA guidelines. Search terms were developed to include articles concerning perceptions regarding MCI and experiences and impact of being informed. Thematic synthesis was applied to the findings. Results Fourteen papers met criteria. Three themes emerged regarding the MCI label: 1) Individual differences relating to living circumstances, personal perceptions and experiences, and coping style affect how patients adjust to the MCI label; 2) Patients’ reactions to the MCI label and their perceptions about how useful it was to receive are affected by the nebulous nature of the construct and information available regarding MCI; 3) Care partners are uncertain about what MCI means and how to address and cope with the patient’s cognitive difficulties. Conclusions Patient and care partner perspectives were affected by the quality of information and support provided, possibly influenced by clinicians’ understanding of the concept. Personal perceptions and experiences, living circumstance and coping styles also shaped experiences of being informed. Clinical Implications Clinicians should develop their understanding of MCI to deliver clear information to patients and consider the necessity of applying the label. Offering support tailored to patients’ specific needs may improve perceptions about the label’s utility, whilst aiding coping and adjustment.
Effective range of non-cell autonomous activator and inhibitor peptides specifying plant stomatal patterning

ABSTRACT Stomata are epidermal valves that facilitate gas exchange between plants and their environment. Stomatal patterning is regulated by the EPIDERMAL PATTERING FACTOR (EPF) family of secreted peptides: EPF1 enforces stomatal spacing, whereas EPIDERMAL PATTERNING FACTOR-LIKE9 (EPFL9), also known as Stomagen, promotes stomatal development. It remains unknown, however, how far these signaling peptides act. Utilizing Cre-lox recombination-based mosaic sectors that overexpress either EPF1 or Stomagen in Arabidopsis cotyledons, we reveal a range within the epidermis and across the cell layers in which these peptides influence patterns. To determine their effective ranges quantitatively, we developed a computational pipeline, SPACE (stomata patterning autocorrelation on epidermis), that describes probabilistic two-dimensional stomatal distributions based upon spatial autocorrelation statistics used in astrophysics. The SPACE analysis shows that, whereas both peptides act locally, the inhibitor EPF1 exerts longer range effects than the activator Stomagen. Furthermore, local perturbation of stomatal development has little influence on global two-dimensional stomatal patterning. Our findings conclusively demonstrate the nature and extent of EPF peptides as non-cell autonomous local signals and provide a means for quantitative characterization of complex spatial patterns in development. This article has an associated ‘The people behind the papers’ interview. Highlighted Article: Non-cell autonomous effects of activator and inhibitor peptides on 2D spatial patterning of stomata were quantitatively characterized using chimeric sectors and a SPACE computational pipeline.
Simultaneous quantitation of four androgens and 17‐hydroxyprogesterone in polycystic ovarian syndrome patients by LC‐MS/MS

Due to the low concentration of androgens in women and the limitation of immunoassays, it remains a challenge to accurately determine the levels of serum androgens in polycystic ovary syndrome (PCOS) patients for clinical laboratories. In this report, a liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method was developed and validated for simultaneous quantitation of testosterone (T), androstenedione (A4), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), and 17‐hydroxyprogesterone (17‐OHP) that are associated with PCOS.
Assessing the trophic niche of South American Terns integrating conventional and isotopie methods

Abstract Conventional dietary studies combined with stable isotope analysis allowed the characterisation of the trophic niche of South American Terns (Sterna hirundinacea) breeding in Argentina. Direct observation of prey deliveries during mate-and chick-provisioning showed that the diet of South American Terns comprised at least 18 prey items, mainly pelagic schooling fish with smaller proportions of marine invertebrates. Argentine Anchovy (Engraulis anchoita) was the main fish prey. Adults delivered a higher proportion of fish and smaller prey to their chicks than to their mates. Analysis of stable isotope ratios in blood samples, using Bayesian stable isotope mixing models, indicated that adult Terns used a higher proportion of marine invertebrates for self-feeding than for mate-or chick-provisioning. Analyses of stable isotopes ratios in blood samples from chicks were consistent with the determination of diet from direct observation, and indicated differences from adults in both the proportion of different prey in the diet and trophic niche. In addition, isotopic niche analysis showed that chicks had a significantly higher trophic position compared with self-feeding adults during both mate-provisioning and chick stages. The results highlight the importance of combining stable isotope and conventional methods to adequately assess the food requirements of a population during the breeding season.
Decreased Threshold of Fasting Serum Glucose for Cardiovascular Events: MASHAD Cohort Study.

Background Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally, and specifically in Iran. Generally, diabetes mellitus is the result of impaired glucose tolerance which together with dyslipidemia are considered as important risk factors of CVD. The aim of this study was to determine the relationship between fasting serum glucose (FSG), lipid profile and CVD endpoints, and to establish an optimal FSG cut-off in the MASHAD cohort study after nearly 6 years of follow-up. Methods All the participants of MASHAD study were followed up for 6 years to determine their cardiovascular status. FSG, fasting lipids, and physical examinations were all recorded. To identify the optimal cut- off point of FSG, we carried out receiver operating curve (ROC) analysis. Results We determined MASHAD cutoff point of blood glucose as 90 mg/dl predicting the CVD outcome. The sensitivity and speciﬁcity of the FSG criterion were 54.34% and 71.68%, respectively. The AUC was 0.665 (95% CI 0.656-0.675, P< 0.0001). The adjusted hazard ratio show that FSG is associated with 2.34 increase in CVD risk using MASHAD cutoff point (HR 2.34, 95% 1.73-3.17, P< 0.001). Conclusion These findings suggest that not only FSG and lipid profile are related to CVD outcome in the MASHAD study, but also elevated fasting glucose levels is strongly associated with cardiovascular events in this population. Besides, the fasting glucose at a threshold of 90 mg/dl can be used for screening cardiovascular events among the Iranian population.
Target search and recognition mechanisms of glycosylase AlkD revealed by scanning FRET-FCS and Markov state models

Significance DNA glycosylase repairs DNA damage to maintain the genome integrity, and thus it is essential for the survival of all organisms. However, it remains a long-standing puzzle how glycosylase diffuses along the genomic DNA to locate the sparse and aberrant lesion sites efficiently and accurately in the genome containing numerous base pairs. Previously, only the high-speed–low-accuracy search mode has been characterized experimentally, while the low-speed–high-accuracy mode is undetectable. Here, we observed the low-speed mode of glycosylase AlkD translocating, and further dissected its molecular mechanisms. To achieve this, we developed an integrated platform by combining scanning FRET-FCS with Markov state model. We expect that this platform can be widely applied to investigate other glycosylases and DNA-binding proteins. DNA glycosylase is responsible for repairing DNA damage to maintain the genome stability and integrity. However, how glycosylase can efficiently and accurately recognize DNA lesions across the enormous DNA genome remains elusive. It has been hypothesized that glycosylase translocates along the DNA by alternating between a fast but low-accuracy diffusion mode and a slow but high-accuracy mode when searching for DNA lesions. However, the slow mode has not been successfully characterized due to the limitation in the spatial and temporal resolutions of current experimental techniques. Using a newly developed scanning fluorescence resonance energy transfer (FRET)–fluorescence correlation spectroscopy (FCS) platform, we were able to observe both slow and fast modes of glycosylase AlkD translocating on double-stranded DNA (dsDNA), reaching the temporal resolution of microsecond and spatial resolution of subnanometer. The underlying molecular mechanism of the slow mode was further elucidated by Markov state model built from extensive all-atom molecular dynamics simulations. We found that in the slow mode, AlkD follows an asymmetric diffusion pathway, i.e., rotation followed by translation. Furthermore, the essential role of Y27 in AlkD diffusion dynamics was identified both experimentally and computationally. Our results provided mechanistic insights on how conformational dynamics of AlkD–dsDNA complex coordinate different diffusion modes to accomplish the search for DNA lesions with high efficiency and accuracy. We anticipate that the mechanism adopted by AlkD to search for DNA lesions could be a general one utilized by other glycosylases and DNA binding proteins.
Novel Mechanism of Microvesicle Regulation by the Antiviral Protein Tetherin During HIV Infection

Background Microvesicles are cell membrane–derived vesicles that have been shown to augment inflammation. Specifically, monocyte‐derived microvesicles (MDMVs), which can express the coagulation protein tissue factor, contribute to thrombus formation and cardiovascular disease. People living with HIV experience higher prevalence of cardiovascular disease and also exhibit increased levels of plasma microvesicles. The process of microvesicle release has striking similarity to budding of enveloped viruses. The surface protein tetherin inhibits viral budding by physically tethering budding virus particles to cells. Hence, we investigated the role of tetherin in regulating the release of MDMVs during HIV infection. Methods and Results The plasma of aviremic HIV‐infected individuals had increased levels of tissue factor + MDMVs, as measured by flow cytometry, and correlated to reduced tetherin expression on monocytes. Superresolution confocal and electron microscopy showed that tetherin localized at the site of budding MDMVs. Mechanistic studies revealed that the exposure of monocytes to HIV‐encoded Tat triggered tetherin loss and subsequent rise in MDMV production. Overexpression of tetherin in monocytes led to morphologic changes in the pseudopodia directly underneath the MDMVs. Further, tetherin knockout mice demonstrated a higher number of circulating MDMVs and less time to bleeding cessation. Conclusions Our studies define a novel regulatory mechanism of MDMV release through tetherin and explore its contribution to the procoagulatory state that is frequently observed in people with HIV. Such insights could lead to improved therapies for individuals infected with HIV and also for those with cardiovascular disease.
A comparison of aquaporin expression in mosquito larvae (Aedes aegypti) that develop in hypo-osmotic freshwater and iso-osmotic brackish water

The mosquito Aedes aegypti vectors the arboviral diseases yellow fever, dengue, Zika and chikungunya. Larvae are usually found developing in freshwater; however, more recently they have been increasingly found in brackish water, potential habitats which are traditionally ignored by mosquito control programs. Aedes aegypti larvae are osmo-regulators maintaining their hemolymph osmolarity in a range of ~ 250 to 300 mOsmol l-1. In freshwater, the larvae must excrete excess water while conserving ions while in brackish water, they must alleviate an accumulation of salts. The compensatory physiological mechanisms must involve the transport of ions and water but little is known about the water transport mechanisms in the osmoregulatory organs of these larvae. Water traverses cellular membranes predominantly through transmembrane proteins named aquaporins (AQPs) and Aedes aegypti possesses 6 AQP homologues (AaAQP1 to 6). The objective of this study was to determine if larvae that develop in freshwater or brackish water have differential aquaporin expression in osmoregulatory organs, which could inform us about the relative importance and function of aquaporins to mosquito survival under these different osmotic conditions. We found that AaAQP transcript abundance was similar in organs of freshwater and brackish water mosquito larvae. Furthermore, in the Malpighian tubules and hindgut AaAQP protein abundance was unaffected by the rearing conditions, but in the gastric caeca the protein level of one aquaporin, AaAQP1 was elevated in brackish water. We found that AaAQP1 was expressed apically while AaAQP4 and AaAQP5 were found to be apical and/or basal in the epithelia of osmoregulatory organs. Overall, the results suggest that aquaporin expression in the osmoregulatory organs is mostly consistent between larvae that are developing in freshwater and brackish water. This suggests that aquaporins may not have major roles in adapting to longterm survival in brackish water or that aquaporin function may be regulated by other mechanisms like post-translational modifications.
Determination of PAR4 numbers on the surface of human platelets: no effect of the single nucleotide polymorphism rs773902

Abstract The thrombin receptor, protease-activated receptor 4 (PAR4), is important for platelet activation and is the target of emerging anti-thrombotic drugs. A frequently occurring single nucleotide polymorphism (SNP; rs773902) causes a function-altering PAR4 sequence variant (NC_000019.10:p.Ala120Thr), whereby platelets from Thr120-expressing individuals are hyper-responsive to PAR4 agonists and hypo-responsive to some PAR4 antagonists than platelets from Ala120-expressing individuals. This altered pharmacology may impact PAR4 inhibitor development, yet the underlying mechanism(s) remain unknown. We tested whether PAR4 surface expression contributes to the altered receptor function. Quantitative flow cytometry was used to determine the absolute number of PAR4 on platelets from individuals subsequently genotyped at rs773902. We detected 539 ± 311 PAR4 per platelet (mean ± SD, n = 84). This number was not different across rs773902 genotypes. This first determination of cellular PAR4 numbers indicates variations in platelet surface expression do not explain the altered pharmacology of the rs773902 PAR4 sequence variant.
Muscle fiber typology is associated with the incidence of overreaching in response to overload training.

The aim of this study was to identify markers of training stress and characteristics of middle-distance runners related to the incidence of overreaching following overload training. Twenty-four highly-trained runners (n=16 male; VO2peak=73.3(4.3) mL·kg·min-1; n=8 female, VO2peak=63.2(3.4) mL·kg·min-1) completed 3 weeks of normal training (NormTr), 3 weeks of high-volume training (HVTr; a 10, 20 and 30% increase in training volume each successive week from NormTr), and a 1-week taper (TapTr; 55% exponential reduction in training volume from HVTr week 3). Before, and immediately after each training period, an incremental treadmill-running test was performed, while resting metabolic rate (RMR), subjective fatigue responses and various resting blood biomarkers were assessed. Muscle fiber typology of the gastrocnemius was estimated by quantification of muscle carnosine using proton magnetic resonance spectroscopy and expressed as a z-score relative to a non-athlete control group. Twelve runners were classified as functionally overreached (FOR) following HVTr (decreased running TTE), whereas the other twelve were classified as acutely fatigued (AF; no decrease in running TTE). The FOR group did not demonstrate systematic alterations in RMR, resting blood biomarkers or submaximal exercise responses compared to the AF group. Gastrocnemius carnosine z-score was significantly higher in FOR (-0.44 ± 0.57) compared to AF (-1.25 ± 0.49, p = 0.004, d = 1.53) and was also associated with changes in running TTE from pre- to post-HVTr (r=-0.55, p=0.005) and pre-HVTr to post-TapTr (r=-0.64, p=0.008). Muscle fiber typology is related to the incidence of overreaching and performance super-compensation following increased training volume and a taper.