Miracle-dz/UniFAR-FTUs huggingface dataset:
The association of exaggerated hypertensive response to exercise and beta-blockers use in hypertensives

ABSTRACT Purpose An elevation in blood pressure (BP) during exercise is the normal physiological response, however an abnormally exaggerated rise in BP, in terms of hypertensive response to exercise (HRE), is seen as a prognostic factor for end-organ damage and mortality. HRE is more common in hypertensive (HT) patients and data are lacking on the effect of antihypertensive medication on HRE. In this study, we evaluated patients who underwent treadmill exercise testing (TET) to reveal the effect of antihypertensive medication on HRE. Materials and Methods A cohort of 2970 individuals underwent TET and data were evaluated for HRE development. HRE has been defined as a systolic BP>210 mmHg in males and >190 mmHg in females throughout the TET. To reveal the effects of antihypertensive medication on HRE, 992 HT patients were analyzed. Results HRE was observed in 11.4% (n = 113) of HT patients and 5.9% (n = 107) of non-HT individuals(p < .001). HRE was observed significantly more in males (57.6% vs. 67.3%;p = .033), and in patients with higher body mass index BMI (29.1 ± 4.5 vs. 30.3 ± 5.2;0.033). There was no significant association between medication and HRE development apart from beta-blockers. Also, gender (odds ratio:1.787; 95%CI:1.160–2.751;p = .008), BMI (odds ratio:1.070;95%CI:1.025–1.116;p = .002) and being under beta-blocker treatment (odds ratio:0.637;95%CI:0.428–0.949;p = .026) were found to be independent predictors of HRE in multivariate logistic regression analysis. Conclusion HRE was associated with gender, BMI and beta-blocker use in hypertensive with male gender and higher BMI associated with higher HRE, while beta-blocker-based treatment, either mono- or combination therapy, associated with lower HRE.
Patterning the Drosophila embryo: A paradigm for RNA‐based developmental genetic regulation

Embryonic anterior–posterior patterning is established in Drosophila melanogaster by maternally expressed genes. The mRNAs of several of these genes accumulate at either the anterior or posterior pole of the oocyte via a number of mechanisms. Many of these mRNAs are also under elaborate translational regulation. Asymmetric RNA localization coupled with spatially restricted translation ensures that their proteins are restricted to the position necessary for the developmental process that they drive. Bicoid (Bcd), the anterior determinant, and Oskar (Osk), the determinant for primordial germ cells and posterior patterning, have been studied particularly closely. In early embryos an anterior–posterior gradient of Bcd is established, activating transcription of different sets of zygotic genes depending on local Bcd concentration. At the posterior pole, Osk seeds formation of polar granules, ribonucleoprotein complexes that accumulate further mRNAs and proteins involved in posterior patterning and germ cell specification. After fertilization, polar granules associate with posterior nuclei and mature into nuclear germ granules. Osk accumulates in these granules, and either by itself or as part of the granules, stimulates germ cell division.
Intranasal Corticosteroid Therapy: Systematic Review and Meta-analysis of Reported Safety and Adverse Effects in Adults

Objectives To address concerns related to the safety profile of both Food and Drug Administration (FDA)–approved and non–FDA-approved intranasal corticosteroid (INCS) use in the adult population. Data Source Systematic review of MEDLINE, PubMed, and EMBASE databases using a comprehensive search strategy including all INCS formulations and adverse events. The study design was developed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Additional sources were identified from study references of relevant articles. Review Methods A structured literature search was conducted. Each study was graded for level of evidence using the Oxford Centre for Evidence-Based Medicine. Extracted data included population size, study design, drug (dosage, route, and frequency), presence of hypothalamus pituitary axis suppression, ocular symptoms, and treatment-related adverse events. Results A total of 60 studies met inclusion criteria. The studies included use of INCS as metered nasal sprays, drops, injections, aerosols, and irrigations. There were no persistent abnormalities in cortisol level or intraocular pressure change. Meta-analysis of epistaxis showed a significantly increased risk in the FDA-approved treatment group in comparison with control (risk ratio 1.56; 95% confidence interval, 1.13-2.14; P = .007). Conclusions Overall, it appears that the use of both FDA and published non-FDA application of INCS are safe in the adult population. Meta-analysis demonstrated an increased risk of epistaxis in patients using INCS compared with placebo. Otherwise, there was no significant difference between in adults in the treatment group and placebo group. As an important caveat, the interpretation of safety of nonstandard INCS is restricted to delivery methods and dosages published in the literature.
Impact of Serum Calcium Levels on Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND Altered calcium homeostasis is hypothesized to underlie Alzheimer's disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. OBJECTIVE To develop effective therapies, we should establish the causal link between serum calcium levels and AD. METHODS Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. RESULTS IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35-0.95, p = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. CONCLUSION In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.
Tissue specific requirement of Drosophila Rcd4 for centriole duplication and ciliogenesis

Panda et al. find that Rcd4 is required for centriole duplication and ciliogenesis in neurosensory organs but dispensable for spermatogenesis, indicating tissue specific requirements for centriole formation. Loading of Rcd4 and its binding partner Ana3 onto daughter centrioles is a prerequisite for the mitotic conversion of centrioles into centrosomes.
Alveolar mimics with periodic strain and its effect on the cell layer formation.

We report on the development of a new model of alveolar air-tissue interface on a chip. The model consists of an array of suspended hexagonal monolayers of gelatin nanofibers supported by microframes and a microfluidic device for the patch integration. The suspended monolayers are deformed to a central displacement of 40 - 80 µm at the air-liquid interface by application of air pressure in the range of 200 - 1000 Pa. With respect to the diameter of the monolayers that is 500 µm, this displacement corresponds to a linear strain of 2 - 10% in agreement with the physiological strain range in the lung alveoli. The culture of A549 cells on the monolayers for an incubation time 1 - 3 days showed viability in the model. We exerted a periodic strain of 5% at a frequency of 0.2 Hz during 1 hour to the cells. We found that the cells were strongly coupled to the nanofibers, but the strain reduced the coupling and induced remodeling of the actin cytoskeleton, which led to a better tissue formation. Our model can serve as a versatile tool in lung investigations such as in inhalation toxicology and therapy. This article is protected by copyright. All rights reserved.
Dibenzocyclooctadiene lignans from the stems of Schisandra sphaerandra

Abstract Chemical investigation into the stems of the medicinal plant Schisandra sphaerandra led to the isolation and identification of a new dibenzocyclooctadiene lignan sphaerandrin A (1) and 11 known ones gomisin B (2), schirubrisin B (3), kadsuphilin B (4), schizandrin (5), benzoylgomisin Q (6), angeloylgomisin Q (7), gomisin G (8), schisanwilsonin O (9), isogomisin O (10), schisantherin D (11), and wuweizisu C (12). The structure of the new compound was elucidated by comprehensive spectroscopic methods including 1 D/2D NMR, HRESIMS, and CD spectrometry. To the best of our knowledge, compounds 2 – 11 were obtained from this species for the first time. All the compounds were evaluated for the cytotoxic activity against the triple-negative breast cancer cell lines MDA-MB-231 and HCC-1937.
Bone defect reconstruction with autologous bone inactivated with liquid nitrogen after resection of primary limb malignant tumors

Abstract Surgical treatment of malignant bone tumors comprises tumor resection and reconstruction. The most commonly used reconstruction method is prosthesis replacement, which achieves good early function, but has a high long-term incidence of complications. Another reconstruction option is autologous bone replantation, which has the advantages of anatomical matching and no need for large bone bank support. Few studies have evaluated reconstruction with liquid nitrogen-inactivated autogenous bone. The present study aimed to evaluate the oncological results, bone healing results, complications, and indications of reconstruction with liquid nitrogen-inactivated autogenous bone grafts. The study population comprised 21 consecutive patients. The tumor site was the tibia in 9 cases, femur in 8, and humerus in 4. There were 37 osteotomy ends in total. After freezing and rewarming, the medullary cavity of the autogenous bone was filled with antibiotic bone cement. Seventeen patients received bilateral plate fixation, 2 received intramedullary nail and distal plate fixation, and 2 received single plate fixation. The average follow-up was 31 ± 6 months. Eighteen patients survived without tumors, and the 3-year survival rate was 80.4%. All cases had adequate surgical margins, but recurrence developed in 1 patient. Metastasis occurred in 3 patients, who all died of metastasis. Intraoperative inactivated bone fracture occurred in 1 patient, and screw breakage was found in 1 patient. Nonunion occurred at 1 humeral diaphysis osteotomy site, and 1 patient was lost to follow-up; the average healing time of the other 35 ends was 13 ± 6 months, and the bone healing rate was 97.2%. The average bone healing times in the metaphysis and diaphysis were 9 ± 3 months and 15 ± 6 months (P = .003). The average bone healing times in the upper and lower limbs were 16.6 ± 7.4 months and 12.3 ± 5.8 months (P = .020). The average Muscle and Skeletal Tumor Society score was 28 ± 3 (21–30) in the 18 survivors. Liquid nitrogen-inactivated autologous bone replantation for primary malignant limb tumor was safe and effective, as shown by the relatively low complication rate, high bone healing rate, and satisfactory postoperative function. This is a reliable biological reconstruction method for malignant bone tumors with specific site and bone destruction characteristics.
Genomic Signatures of Local Adaptation in Clam Shrimp (Eulimnadia texana) from Natural Vernal Pools

Abstract Vernal pools are unique in their isolation and the strong selection acting on their resident species. Vernal pool clam shrimp (Eulimnadia texana) are a promising model due to ease of culturing, short generation time, small genomes, and obligate desiccated diapaused eggs. Clam shrimp are also androdioecious (sexes include males and hermaphrodites), and here we use population-scaled recombination rates to support the hypothesis that the heterogametic sex is recombination free in these shrimp. We collected short-read sequence data from pooled samples from different vernal pools to gain insights into local adaptation. We identify genomic regions in which some populations have allele frequencies that differ significantly from the metapopulation. BayPass (Gautier M. 2015. Genome-wide scan for adaptive divergence and association with population-specific covariates. Genetics 201(4):1555–1579. ) detected 19 such genomic regions showing an excess of population subdivision. These regions on average are 550 bp in size and had 2.5 genes within 5 kb of them. Genes located near these regions are involved in Malpighian tubule function and osmoregulation, an essential function in vernal pools. It is likely that salinity profiles vary between pools and over time, and variants at these genes are adapted to local salinity conditions.
Accelerated terrestrial ecosystem carbon turnover and its drivers

The terrestrial carbon cycle has been strongly influenced by human‐induced CO2 increase, climate change, and land use change since the industrial revolution. These changes alter the carbon balance of ecosystems through changes in vegetation productivity and ecosystem carbon turnover time (τeco). Even though numerous studies have drawn an increasingly clear picture of global vegetation productivity changes, global changes in τeco are still unknown. In this study, we analyzed the changes of τeco between the 1860s and the 2000s and their drivers, based on theory of dynamic carbon cycle in non‐steady state and process‐based ecosystem model. Results indicate that τeco has been reduced (i.e., carbon turnover has accelerated) by 13.5% from the 1860s (74 years) to the 2000s (64 years), with reductions of 1 year of carbon residence times in vegetation (rveg) and of 9 years in soil (rsoil). Additionally, the acceleration of τeco was examined at biome scale and grid scale. Among different driving processes, land use change and climate change were found to be the major drivers of turnover acceleration. These findings imply that carbon fixed by plant photosynthesis is being lost from ecosystems to the atmosphere more quickly over time, with important implications for the climate‐carbon cycle feedbacks.
E2F1 sumoylation as a protective cellular mechanism in oxidative stress response

Significance Cells need to cope with oxidative stress caused by oxygen free radicals from mitochondrial oxidative phosphorylation. We identify a role for E2F1 to halt cell cycle progression for cell survival upon oxidative stress. Oxidative stress induces sumoylation of E2F1, primarily at lysine 266, which specifically modulates E2F1 transcriptional activity to enhance cell cycle arrest for cell survival. Furthermore, we identify SENP3 as an E2F1-interacting partner and a desumoylating enzyme for E2F1. Oxidative stress inhibits the interaction between E2F1 and SENP3, and leads to accumulation of sumoylated E2F1. These data demonstrate that sumoylation of E2F1 is important for cell cycle arrest to provide cells the opportunity to cope with oxidative stress and survive. Oxidative stress is a ubiquitous threat to all aerobic organisms and has been implicated in numerous pathological conditions such as cancer. Here we demonstrate a pivotal role for E2F1, a cell cycle regulatory transcription factor, in cell tolerance of oxidative stress. Cells lacking E2F1 are hypersensitive to oxidative stress due to the defects in cell cycle arrest. Oxidative stress inhibits E2F1 transcriptional activity, independent of changes in association with Rb and without decreasing its DNA-binding activity. Upon oxidative insult, SUMO2 is extensively conjugated to E2F1 mainly at lysine 266 residue, which specifically modulates E2F1 transcriptional activity to enhance cell cycle arrest for cell survival. We identify SENP3, a desumoylating enzyme, as an E2F1-interacting partner. Oxidative stress inhibits the interaction between E2F1 and SENP3, which leads to accumulation of sumoylated E2F1. SENP3-deficient cells exhibit hypersumoylation of E2F1 and are resistant to oxidative insult. High levels of SENP3 in breast cancer are associated with elevated levels of E2F targets, high tumor grade, and poor survival. Given the prevalence of elevated levels of SENP3 across numerous cancer types, the SENP3-E2F1 axis may serve as an avenue for therapeutic intervention in cancer.
Uterine leiomyomas: correlation between histologic composition and stiffness via magnetic resonance elastography - a Pilot Study.

OBJECTIVES To evaluate magnetic resonance elastography as a tool for characterizing uterine leimyomas. MATERIAL AND METHODS At total of 12 women with symptomatic leiomyomas diagnosed in physical and ultrasound examinations were enrolled in this pilot study. Before surgery, all patients underwent magnetic resonance elastography of the uterus using a 1.5 T MR whole-body scanner (Optima, GE Healthcare, Milwaukee, WI, USA). Surgical specimens were forwarded for histological examination. The findings were allocated into 3 categories depending on the percentage content of connective tissue: below 15%, from 15 to 30% and more than 30%. The median stiffness of leiomyomas for each of the group was calculated. The U-Mann Whitney test was used for statistical analysis. RESULTS The stiffness of the leiomyomas ranged between 3.7-6.9 kPa (median value 4.9 kPa). The concentration of extracellular components in the leiomyomas did not exceed 40%. An increasing trend of the stiffness with the growing percentage of extracellular component was observed. Stiffness of the leiomyomas obtained by MRE varies depending on microscopic composition. CONCLUSIONS The value of stiffness shows a trend of increasing with the percentage of extracellular component of the leiomyoma. Further studies are required to assess the usefulness of MRE in diagnostics of uterine leiomyomas.
Analysis of Normal High-Frequency Intracranial Pressure Values and Treatment Threshold in Neurocritical Care Patients: Insights into Normal Values and a Potential Treatment Threshold.

Importance Intracranial pressure (ICP) elevation is a compartment syndrome that impairs blood flow to the brain. Despite the importance of ICP values in neurocritical care, normal ICP values and the precise ICP threshold at which treatment should be initiated remain uncertain. Objective To refine our understanding of normal ICP values and determine the ICP threshold most strongly associated with outcome. Design, Setting, and Participants Prospective observational study (2004-2010), with outcomes determined at hospital discharge. The study included neurocritical care patients from a single level I trauma center, San Francisco General Hospital. Three hundred eighty-three patients had a traumatic brain injury with or without craniectomy; 140 patients had another indication for ICP monitoring. Consecutive patients were studied. Data analyses were completed between March 2015 and December 2019. Exposures Five hundred twenty-three ICP-monitored patients. Main Outcomes and Measures A computer system prospectively and automatically collected 1-minute physiologic data from patients in the intensive care unit during a 6-year period. Mean ICP was calculated, as was the proportion of ICP values greater than thresholds from 1 to 80 mm Hg in 1-mm Hg increments. The association between these measures and outcome was explored for various epochs up to 30 days from the time of injury. A principal component analysis was used to explore physiologic changes at various ICP thresholds, and elastic net regression was used to identify ICP thresholds most strongly associated with Glasgow Outcome Scale score at discharge. Results Of the 523 studied patients, 70.7% of studied patients were men (n = 370) and 72.1% had a traumatic brain injury (n = 377). A total of 4 090 964 1-minute ICP measurements were recorded for the included patients (7.78 years of recordings). Intracranial pressure values of 8 to 9 mm Hg were most commonly recorded and could possibly reflect normal values. The principal component analysis suggested state shifts in the physiome occurred at ICPs greater than 19 mm Hg and 24 mm Hg. Elastic net regression identified an ICP threshold of 19 mm Hg as most robustly associated with outcome when considering all neurocritical care patients, patients with TBI, and patients with TBI who underwent craniectomy. Intracranial pressure values greater than 19 mm Hg were associated with mortality, while lower values were associated with outcome in surviving patients. Conclusions and Relevance This study provides insight into what normal ICP values could be. An ICP threshold of 19 mm Hg was robustly associated with outcome in studied patients, although lower ICP values were associated with outcome in surviving patients.
In utero inflammatory challenge induces an early activation of the hepatic innate immune response in late gestation fetal sheep

Chorioamnionitis is associated with inflammatory end-organ damage in the fetus. Tissues in direct contact with amniotic fluid drive a pro-inflammatory response and contribute to this injury. However, due to a lack of direct contact with the amniotic fluid, the liver contribution to this response has not been fully characterized. Given its role as an immunologic organ, we hypothesized that the fetal liver would demonstrate an early innate immune response to an in utero inflammatory challenge. Fetal sheep (131 ± 1 d gestation) demonstrated metabolic acidosis and high cortisol and norepinephrine values within 5 h of exposure to intra-amniotic LPS. Likewise, expression of pro-inflammatory cytokines increased significantly at 1 and 5 h of exposure. This was associated with NF-κB activation, by inhibitory protein IκBα degradation, and nuclear translocation of NF-κB subunits (p65/p50). Corroborating these findings, LPS exposure significantly increased pro-inflammatory innate immune gene expression in fetal sheep hepatic macrophages in vitro. Thus, an in utero inflammatory challenge induces an early hepatic innate immune response with systemic metabolic and stress responses. Within the fetal liver, hepatic macrophages respond robustly to LPS exposure. Our results demonstrate that the fetal hepatic innate immune response must be considered when developing therapeutic approaches to attenuate end-organ injury associated with in utero inflammation.
Paved With Good Intentions: Hospital Visitation Restrictions in the Age of Coronavirus Disease 2019*

Hospital visitation restrictions have been widely implemented during the coronavirus disease 2019 pandemic as a means of decreasing the transmission of coronavirus. While decreasing transmission is an important goal, it is not the only goal that quality healthcare must aim to achieve. Severely restricted visitation policies undermine our ability to provide humane, family-centered care, particularly during critical illness and at the end of life. The enforcement of these policies consequently increases the risk of moral distress and injury for providers. Using our experience in a PICU, we survey the shortcomings of current visitation restrictions. We argue that hospital visitation restrictions can be implemented in ways that are nonmaleficent, but this requires unwavering acknowledgment of the value of social and familial support during illness and death. We advocate that visitation restriction policies be implemented by independent, medically knowledgeable decision-making bodies, with the informed participation of patients and their families.