Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa609 ◽

2020 ◽

Author(s):

Angela Delaney ◽

Adam B Burkholder ◽

Christopher A Lavender ◽

Lacey Plummer ◽

Veronica Mericq ◽

...

Keyword(s):

Hypogonadotropic Hypogonadism ◽

Sequence Variants ◽

Hypothalamic Amenorrhea ◽

Individual Susceptibility ◽

The Face ◽

Stress Variability ◽

And Function ◽

And Control ◽

Previous Identification ◽

Rare Sequence

Abstract Context Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. Objective We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. Design We compared patients with HA to control women. Setting The study was conducted at secondary referral centers. Patients and Other Participants Women with HA (n = 106) and control women (ClinSeq study; n = 468). Interventions We performed exome sequencing in all patients and controls. Main Outcome Measure(s) The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. Results RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). Conclusions Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.

Pathogenic Effect of GDAP1 Gene Mutations in a Yeast Model

Genes ◽

10.3390/genes11030310 ◽

2020 ◽

Vol 11 (3) ◽

pp. 310 ◽

Cited By ~ 1

Author(s):

Weronika Rzepnikowska ◽

Joanna Kaminska ◽

Dagmara Kabzińska ◽

Andrzej Kochański

Keyword(s):

Gene Mutations ◽

Causative Mutation ◽

Mitochondrial Morphology ◽

Clinical Genetics ◽

Sequence Variant ◽

Sequence Variants ◽

Pathogenic Variants ◽

Pathogenic Effect ◽

And Function ◽

Rare Sequence

The question of whether a newly identified sequence variant is truly a causative mutation is a central problem of modern clinical genetics. In the current era of massive sequencing, there is an urgent need to develop new tools for assessing the pathogenic effect of new sequence variants. In Charcot-Marie-Tooth disorders (CMT) with their extreme genetic heterogeneity and relatively homogenous clinical presentation, addressing the pathogenic effect of rare sequence variants within 80 CMT genes is extremely challenging. The presence of multiple rare sequence variants within a single CMT-affected patient makes selection for the strongest one, the truly causative mutation, a challenging issue. In the present study we propose a new yeast-based model to evaluate the pathogenic effect of rare sequence variants found within the one of the CMT-associated genes, GDAP1. In our approach, the wild-type and pathogenic variants of human GDAP1 gene were expressed in yeast. Then, a growth rate and mitochondrial morphology and function of GDAP1-expressing strains were studied. Also, the mutant GDAP1 proteins localization and functionality were assessed in yeast. We have shown, that GDAP1 was not only stably expressed but also functional in yeast cell, as it influenced morphology and function of mitochondria and altered the growth of a mutant yeast strain. What is more, the various GDAP1 pathogenic sequence variants caused the specific for them effect in the tests we performed. Thus, the proposed model is suitable for validating the pathogenic effect of known GDAP1 mutations and may be used for testing of unknown sequence variants found in CMT patients.

OR11-6 Rare Sequence Variants in GnRH-Associated Genes May Contribute to Variable Susceptibility to Environmental Stressors in Functional Hypothalamic Amenorrhea

Journal of the Endocrine Society ◽

10.1210/js.2019-or11-6 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Angela Delaney ◽

Lacey Plummer ◽

Adam Burkholder ◽

Maria Mericq ◽

Paulina Merino ◽

...

Keyword(s):

Environmental Stressors ◽

Sequence Variants ◽

Hypothalamic Amenorrhea ◽

Functional Hypothalamic Amenorrhea ◽

Variable Susceptibility ◽

Rare Sequence

An evaluation model of 2019-nCoV prevention effectiveness based on immigration data in China (Preprint)

10.2196/preprints.18533 ◽

2020 ◽

Author(s):

Qiangsheng Huang

Keyword(s):

Prevention And Control ◽

Time Window ◽

Evaluation Model ◽

Control Measures ◽

Related Data ◽

The Face ◽

Prevention And Control Measures ◽

And Control ◽

Best Fit

BACKGROUND As of the end of February 2020, 2019-nCoV is currently well controlled in China. However, the virus is now spreading globally. OBJECTIVE This study aimed to evaluate the effectiveness of outbreak prevention and control measures in a region. METHODS A model is built for find the best fit for two sets of data (the number of daily new diagnosed, and the risk value of incoming immigration population). The parameters (offset and time window) in the model can be used as the evaluation of effectiveness of outbreak prevention and control. RESULTS Through study, it is found that the parameter offset and time window in the model can accurately reflect the prevention effectiveness. Some related data and public news confirm this result. And this method has advantages over the method using R0 in two aspects. CONCLUSIONS If the epidemic situation is well controlled, the virus is not terrible. Now the daily new diagnosed patients in most regions of China is quickly reduced to zero or close to zero. Chinese can do a good job in the face of huge epidemic pressure. Therefore, if other countries can do well in prevention and control, the epidemic in those places can also pass quickly.

Metagenomic Analysis of the Fecal Archaeome in Suckling Piglets Following Perinatal Tulathromycin Metaphylaxis

Animals ◽

10.3390/ani11061825 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1825

Author(s):

Mohamed Zeineldin ◽

Ameer Megahed ◽

Benjamin Blair ◽

Brian Aldridge ◽

James Lowe

Keyword(s):

Sequencing Analysis ◽

Metagenomic Sequencing ◽

Post Intervention ◽

Gastrointestinal Microbiome ◽

Health And Wellbeing ◽

Suckling Piglets ◽

And Function ◽

Changes Over Time ◽

And Control ◽

The Impact

The gastrointestinal microbiome plays an important role in swine health and wellbeing, but the gut archaeome structure and function in swine remain largely unexplored. To date, no metagenomics-based analysis has been done to assess the impact of an early life antimicrobials intervention on the gut archaeome. The aim of this study was to investigate the effects of perinatal tulathromycin (TUL) administration on the fecal archaeome composition and diversity in suckling piglets using metagenomic sequencing analysis. Sixteen litters were administered one of two treatments (TUL; 2.5 mg/kg IM and control (CONT); saline 1cc IM) soon after birth. Deep fecal swabs were collected from all piglets on days 0 (prior to treatment), 5, and 20 post intervention. Each piglet’s fecal archaeome was composed of rich and diverse communities that showed significant changes over time during the suckling period. At the phylum level, 98.24% of the fecal archaeome across all samples belonged to Euryarchaeota. At the genus level, the predominant archaeal genera across all samples were Methanobrevibacter (43.31%), Methanosarcina (10.84%), Methanococcus (6.51%), and Methanocorpusculum (6.01%). The composition and diversity of the fecal archaeome between the TUL and CONT groups at the same time points were statistically insignificant. Our findings indicate that perinatal TUL metaphylaxis seems to have a minimal effect on the gut archaeome composition and diversity in sucking piglets. This study improves our current understanding of the fecal archaeome structure in sucking piglets and provides a rationale for future studies to decipher its role in and impact on host robustness during this critical phase of production.

TRPC1, TRPC3, and TRPC4 in Rat Orofacial Structures

Cells Tissues Organs ◽

10.1159/000477665 ◽

2017 ◽

Vol 204 (5-6) ◽

pp. 293-303 ◽

Cited By ~ 1

Author(s):

Masatoshi Fujita ◽

Tadasu Sato ◽

Takehiro Yajima ◽

Eiji Masaki ◽

Hiroyuki Ichikawa

Keyword(s):

Transient Receptor Potential ◽

Sympathetic Neurons ◽

Receptor Potential ◽

Monovalent Cation ◽

Calcitonin Gene ◽

Cervical Ganglion ◽

Parasympathetic Neurons ◽

Transient Receptor ◽

And Function ◽

And Control

TRPC (transient receptor potential cation channel subfamily C) members are nonselective monovalent cation channels and control Ca2+ inflow. In this study, immunohistochemistry for TRPC1, TRPC3, and TRPC4 was performed on rat oral and craniofacial structures to elucidate their distribution and function in the peripheries. In the trigeminal ganglion (TG), 56.1, 84.1, and 68.3% of sensory neurons were immunoreactive (IR) for TRPC1, TRPC3, and TRPC4, respectively. A double immunofluorescence method revealed that small to medium-sized TG neurons co-expressed TRPCs and calcitonin gene-related peptide. In the superior cervical ganglion, all sympathetic neurons showed TRPC1 and TRPC3 immunoreactivity. Parasympathetic neurons in the submandibular ganglion, tongue, and parotid gland were TRPC1, TRPC3, and TRPC4 IR. Gustatory and olfactory cells were also IR for TRPC1, TRPC3, and/or TRPC4. In the musculature, motor endplates expressed TRPC1 and TRPC4 immunoreactivity. It is likely that TRPCs are associated with sensory, autonomic, and motor functions in oral and craniofacial structures.

Modelling the Human Placental Interface In Vitro—A Review

Micromachines ◽

10.3390/mi12080884 ◽

2021 ◽

Vol 12 (8) ◽

pp. 884

Author(s):

Marta Cherubini ◽

Scott Erickson ◽

Kristina Haase

Keyword(s):

Drug Testing ◽

Cell Types ◽

In Vitro Models ◽

Placental Development ◽

Scientific Challenge ◽

Induced Pluripotent ◽

And Function ◽

And Control

Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal–fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models.

Endothelium as a Source and Target of H2S to Improve Its Trophism and Function

Antioxidants ◽

10.3390/antiox10030486 ◽

2021 ◽

Vol 10 (3) ◽

pp. 486

Author(s):

Valerio Ciccone ◽

Shirley Genah ◽

Lucia Morbidelli

Keyword(s):

Endothelial Dysfunction ◽

Vessel Wall ◽

Redox Reactions ◽

Single Layer ◽

Fine Tuning ◽

Therapeutic Approaches ◽

Impaired Wound Healing ◽

Blood Fluidity ◽

And Function ◽

And Control

The vascular endothelium consists of a single layer of squamous endothelial cells (ECs) lining the inner surface of blood vessels. Nowadays, it is no longer considered as a simple barrier between the blood and vessel wall, but a central hub to control blood flow homeostasis and fulfill tissue metabolic demands by furnishing oxygen and nutrients. The endothelium regulates the proper functioning of vessels and microcirculation, in terms of tone control, blood fluidity, and fine tuning of inflammatory and redox reactions within the vessel wall and in surrounding tissues. This multiplicity of effects is due to the ability of ECs to produce, process, and release key modulators. Among these, gasotransmitters such as nitric oxide (NO) and hydrogen sulfide (H2S) are very active molecules constitutively produced by endotheliocytes for the maintenance and control of vascular physiological functions, while their impairment is responsible for endothelial dysfunction and cardiovascular disorders such as hypertension, atherosclerosis, and impaired wound healing and vascularization due to diabetes, infections, and ischemia. Upregulation of H2S producing enzymes and administration of H2S donors can be considered as innovative therapeutic approaches to improve EC biology and function, to revert endothelial dysfunction or to prevent cardiovascular disease progression. This review will focus on the beneficial autocrine/paracrine properties of H2S on ECs and the state of the art on H2S potentiating drugs and tools.

Effects of Face Mask Use on Objective and Subjective Measures of Thermoregulation During Exercise in the Heat

Sports Health A Multidisciplinary Approach ◽

10.1177/19417381211028212 ◽

2021 ◽

pp. 194173812110282

Author(s):

Ayami Yoshihara ◽

Erin E. Dierickx ◽

Gabrielle J. Brewer ◽

Yasuki Sekiguchi ◽

Rebecca L. Stearns ◽

...

Keyword(s):

Exercise Intensity ◽

Thermal Sensation ◽

Face Mask ◽

Whole Body ◽

Moderate Exercise ◽

Physically Active ◽

Time Points ◽

The Face ◽

And Control ◽

Moderate Exercise Intensity

Background: While increased face mask use has helped reduce COVID-19 transmission, there have been concerns about its influence on thermoregulation during exercise in the heat, but consistent, evidence-based recommendations are lacking. Hypothesis: No physiological differences would exist during low-to-moderate exercise intensity in the heat between trials with and without face masks, but perceptual sensations could vary. Study Design: Crossover study. Level of Evidence: Level 2. Methods: Twelve physically active participants (8 male, 4 female; age = 24 ± 3 years) completed 4 face mask trials and 1 control trial (no mask) in the heat (32.3°C ± 0.04°C; 54.4% ± 0.7% relative humidity [RH]). The protocol was 60 minutes of walking and jogging between 35% and 60% of relative VO2max. Rectal temperature (Trec), heart rate (HR), temperature and humidity inside and outside of the face mask (Tmicro_in, Tmicro_out, RHmicro_in, RHmicro_out) and perceptual variables (rating of perceived exertion (RPE), thermal sensation, thirst sensation, fatigue level, and overall breathing discomfort) were monitored throughout all trials. Results: Mean Trec and HR increased at 30- and 60-minute time points compared with 0-minute time points, but no difference existed between face mask trials and control trials ( P > 0.05). Mean Tmicro_in, RHmicro_in, and humidity difference inside and outside of the face mask (ΔRHmicro) were significantly different between face mask trials ( P < 0.05). There was no significant difference in perceptual variables between face mask trials and control trials ( P > 0.05), except overall breathing discomfort ( P < 0.01). Higher RHmicro_in, RPE, and thermal sensation significantly predicted higher overall breathing discomfort ( r2 = 0.418; P < 0.01). Conclusion: Face mask use during 60 minutes of low-to-moderate exercise intensity in the heat did not significantly affect Trec or HR. Although face mask use may affect overall breathing discomfort due to the changes in the face mask microenvironment, face mask use itself did not cause an increase in whole body thermal stress. Clinical Relevance: Face mask use is feasible and safe during exercise in the heat, at low-to-moderate exercise intensities, for physically active, healthy individuals.

Role of attitude in nurses’ responses to requests for assisted dying

Nursing Ethics ◽

10.1177/0969733020966777 ◽

2020 ◽

pp. 096973302096677

Author(s):

Michael Wilson ◽

Marie Wilson ◽

Suzanne Edwards ◽

Lynette Cusack ◽

Richard Wiechula

Keyword(s):

Online Survey ◽

Rare Event ◽

Control Beliefs ◽

Assisted Dying ◽

Cross Sectional ◽

Assisted Death ◽

Institutional Ethics ◽

The Face ◽

Generalised Linear Modelling ◽

And Control

Background: Legal assisted dying is a rare event, but as legalisation expands, requests for it will likely increase, and the nurse most often receives the informal, initial request. Objectives: To assess the effects of attitude in interaction with normative and control beliefs on an intention to respond to a request for legal assisted dying. Ethical considerations: The study had the lead author’s institutional ethics approval, and participants were informed that participation was both anonymous and voluntary. Methodology: This was a cross-sectional correlational study of 377 Australian registered nurses who completed an online survey. Generalised linear modelling assessed the effects of independent variables against intended responses to requests for legal assisted dying. Results: Compared to nurses who did not support legal assisted dying, nurses who did had stronger beliefs in patient rights, perceived social expectations to refer the request and stronger control in that intention. Nurses who did not support legal assisted dying had stronger beliefs in ethics of duty to the patient and often held dual intentions to discuss the request with the patient but also held an intention to deflect the request to consideration of alternatives. Discussion: This study advances the international literature by developing quantified models explaining the complexity of nurses’ experiences with requests for an assisted death. Attitude was operationalised in interaction with other beliefs and was identified as the strongest influence on intentions, but significantly moderated by ethical norms. Conclusion: The complex of determinants of those intentions to respond to requests for an assisted death suggests they are not isolated from each other. Nurses might have distinct intentions, but they can also hold multiple intentions even when they prioritise one. These findings present opportunities to prepare nurses in a way that enhances moral resilience in the face of complex moral encounters.

Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

Oncogene ◽

10.1038/s41388-021-01886-3 ◽

2021 ◽

Author(s):

Rósula García-Navas ◽

Pilar Liceras-Boillos ◽

Carmela Gómez ◽

Fernando C. Baltanás ◽

Nuria Calzada ◽

...

Keyword(s):

Mitochondrial Dynamics ◽

Redox Homeostasis ◽

Atp Production ◽

Oxidative Energy Metabolism ◽

Ras Activation ◽

Mitochondrial Defects ◽

Critical Requirement ◽

Dynamics And Function ◽

And Function ◽

And Control

AbstractSOS1 ablation causes specific defective phenotypes in MEFs including increased levels of intracellular ROS. We showed that the mitochondria-targeted antioxidant MitoTEMPO restores normal endogenous ROS levels, suggesting predominant involvement of mitochondria in generation of this defective SOS1-dependent phenotype. The absence of SOS1 caused specific alterations of mitochondrial shape, mass, and dynamics accompanied by higher percentage of dysfunctional mitochondria and lower rates of electron transport in comparison to WT or SOS2-KO counterparts. SOS1-deficient MEFs also exhibited specific alterations of respiratory complexes and their assembly into mitochondrial supercomplexes and consistently reduced rates of respiration, glycolysis, and ATP production, together with distinctive patterns of substrate preference for oxidative energy metabolism and dependence on glucose for survival. RASless cells showed defective respiratory/metabolic phenotypes reminiscent of those of SOS1-deficient MEFs, suggesting that the mitochondrial defects of these cells are mechanistically linked to the absence of SOS1-GEF activity on cellular RAS targets. Our observations provide a direct mechanistic link between SOS1 and control of cellular oxidative stress and suggest that SOS1-mediated RAS activation is required for correct mitochondrial dynamics and function.