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Introduction: Foot-borne soldiers sometimes carry out nighttime operations. It has previously been reported an elevated metabolic demand and impaired walking economy during outdoor walking on a gravel road in darkness wearing night vision goggles (NVG), compared with wearing a headlamp. The aim of the present study was to evaluate the effect of wearing NVG while walking in a hilly forest terrain and compare the results between experienced and inexperienced NVG users., Materials and Methods: At nighttime, two different groups, inexperienced (five men and six women) and experienced (nine men) NVG users, walked 1.1 km at a self-selected comfortable pace in a hilly forest. Part I was mainly uphill, and Part II was mainly downhill. Walks were performed wearing a headlamp (light), monocular NVG (mono), binocular NVG (bino), or mono with a 25 kg extra weight (backpack). Walking economy calculated from oxygen uptake in relation to body mass and covered distance (V̇O2 (mL/[kg · km])), heart rate, gait, and walking speed were measured., Results: In both groups, walking economy was deteriorated in all three conditions with limited vision (mono, bino, and backpack) compared to the light condition, both during Part I (mono/bino, experienced: +26/+25%, inexperienced: +34/+28%) and Part II (mono/bino, experienced: +44/+46%, inexperienced: +63/+49%). In the backpack condition, the relative change of walking economy was greater for the inexperienced group than the experienced group: Part I (experienced: +46%, inexperienced: +70%), Part II (experienced: +71%, inexperienced: +111%). Concurrently, the step length was shorter in all three conditions with limited vision during Part I (mono/bino/backpack, experienced: -7/-7/-15%, inexperienced: -12/-12/-19%) and Part II (mono/bino/backpack; experienced: -8/-8/-14%, inexperienced: -17/-15/-24%) than in the light condition. The experienced NVG users walked faster during all conditions, but there was no difference in heart rate between groups., Conclusions: Despite that foveal vision using NVG is adequate, it appears that the mechanical efficiency during nighttime walking in hilly terrain was markedly lower while wearing NVG than with full vision, regardless of whether the soldier was an experienced or inexperienced NVG user. Moreover, the walking economy was even more affected when adding the 25-kg extra weight. It is probable that the deteriorated mechanical efficiency was partly due to the shorter step length in all three conditions with limited vision., (© The Association of Military Surgeons of the United States 2024.)

Introduction: For tactical reasons, the foot-borne soldiers sometimes undertake nighttime operations. However, the metabolic demand during walking in complete darkness may be markedly increased. The purpose of this study was to investigate if metabolic demand and kinematics would change while walking on a gravel road and a slightly hilly trail in darkness with or without visual aid., Materials and Methods: Fourteen cadets (11 men and 3 women, age: 25 ± 7 years, height: 178 ± 8 cm, and weight: 78 ± 13 kg) walked at 4 km/h on a straight gravel road and on a slightly hilly forest trail (n = 9). Both trials were performed at nighttime under four different conditions, wearing a headlamp (Light), blindfold (Dark), monocular (Mono), or binocular (Bino) night vision goggles. During the 10-minute walks, oxygen uptake, heart rate, and kinematic data were assessed. Ratings of perceived exertion, discomfort, and mental stress were evaluated after each condition using a category ratio scale. Physiologic and kinematic variables were evaluated using repeated-measures analysis of variance, whereas ratings were evaluated using non-parametric Friedman analysis of variance., Results: Oxygen uptake was higher in all three conditions with no or limited vision (Dark, Mono, and Bino) than in the Light condition (P ≤ 0.02) when walking on both the gravel road (+5-8%) and the forest trail (+6-14%). Heart rate was higher during the Dark than during the Light condition when walking on the forest trail, whereas there was no difference between conditions on the gravel road. During both trials, gait frequency was higher during the Dark than during the Light, Mono, and Bino conditions. Ratings were generally low during all conditions., Conclusions: Walking on a gravel road or a forest trail wearing a blindfold or visual aid increased the metabolic demand. Thus, it appears that the metabolic demand is higher during overground walking with night vision goggles than with full vision, which may influence the performance of nighttime operations., (© The Association of Military Surgeons of the United States 2023.)

Static apneas performed after an overnight fast as opposed to postprandially have been evinced to improve apneic performance. However, no study has explored the effect of dietary intake on apneic performance, cardiovascular or splenic responses over a series of repeated apneas. Ten healthy adults attended the laboratory on three separate occasions (≥48-h apart): after a 14-h fast (F14), 1 h postconsumption of a high-calorie, high-carbohydrate (HCHC) meal, or 1 h postconsumption of a low-calorie, low-carbohydrate (LCLC)-based meal. During each visit, the subjects performed a hyperoxic rebreathing trial and a series of three repeated maximal static apneas. Heart rate, peripheral oxyhemoglobin saturation ([Formula: see text]), and gas exchange were monitored continuously, whereas splenic volume (SV) and hematology were assessed after the rebreathing and apneas. At rest, after HCHC, the respiratory exchange ratio (0.87 ± 0.17, P ≤ 0.043), expired minute volume of carbon dioxide (CO 2 ; HCHC, 0.35 ± 0.09 L/min, P ≤ 0.014), and SV (227 ± 45 mL, P ≤ 0.031) were higher compared with F14 (0.71 ± 0.08; 0.23 ± 0.04 L/min; 204 ± 49 mL) and LCLC (0.72 ± 0.07; 0.25 ± 0.03 L/min; 199 ± 49 mL). A faster CO 2 accumulation was recorded during the HCHC (96 ± 35 s) rebreathing trial (F14, 162 ± 42 s, P = 0.001; LCLC, 151 ± 23 s, P = 0.002). Longer apneas were reported in F14 compared with HCHC (apneas 1-3, P ≤ 0.046) and LCLC (apneas 2-3, P ≤ 0.006). After the first apnea, SV was lower in F14 (141 ± 43 mL, P = 0.015) compared with HCHC (180 ± 34 mL). Moreover, after the third apnea, end-tidal partial pressure of oxygen and nadir [Formula: see text] were lower in F14 (8.6 ± 2.2 kPa, P = 0.028; 77 ± 13%, P = 0.009) compared with HCHC (10.1 ± 1.7 kPa; 84 ± 9%). No differences were measured in end-apneic end-tidal partial pressure of CO 2 , heart rate nor hematology across diets. Fasting improved apneic performance with apneas being terminated at lower oxygen levels through altering the rate of CO 2 accumulation but without affecting the cardiovascular responses.

Drug discovery for diseases such as Parkinson's disease are impeded by the lack of screenable cellular phenotypes. We present an unbiased phenotypic profiling platform that combines automated cell culture, high-content imaging, Cell Painting, and deep learning. We applied this platform to primary fibroblasts from 91 Parkinson's disease patients and matched healthy controls, creating the largest publicly available Cell Painting image dataset to date at 48 terabytes. We use fixed weights from a convolutional deep neural network trained on ImageNet to generate deep embeddings from each image and train machine learning models to detect morphological disease phenotypes. Our platform's robustness and sensitivity allow the detection of individual-specific variation with high fidelity across batches and plate layouts. Lastly, our models confidently separate LRRK2 and sporadic Parkinson's disease lines from healthy controls (receiver operating characteristic area under curve 0.79 (0.08 standard deviation)), supporting the capacity of this platform for complex disease modeling and drug screening applications., (© 2022. The Author(s).)

β-Cells derived from stem cells hold great promise for cell replacement therapy for diabetes. Here we examine the ability of nuclear transfer embryonic stem cells (NT-ESs) derived from a patient with type 1 diabetes to differentiate into β-cells and provide a source of autologous islets for cell replacement. NT-ESs differentiate in vitro with an average efficiency of 55% into C-peptide-positive cells, expressing markers of mature β-cells, including MAFA and NKX6.1. Upon transplantation in immunodeficient mice, grafted cells form vascularized islet-like structures containing MAFA/C-peptide-positive cells. These β-cells adapt insulin secretion to ambient metabolite status and show normal insulin processing. Importantly, NT-ES-β-cells maintain normal blood glucose levels after ablation of the mouse endogenous β-cells. Cystic structures, but no teratomas, were observed in NT-ES-β-cell grafts. Isogenic induced pluripotent stem cell lines showed greater variability in β-cell differentiation. Even though different methods of somatic cell reprogramming result in stem cell lines that are molecularly indistinguishable, full differentiation competence is more common in ES cell lines than in induced pluripotent stem cell lines. These results demonstrate the suitability of NT-ES-β-cells for cell replacement for type 1 diabetes and provide proof of principle for therapeutic cloning combined with cell therapy., (© 2017 by the American Diabetes Association.)

The discovery of insulin more than 90 years ago introduced a life-saving treatment for patients with type 1 diabetes, and since then, significant progress has been made in clinical care for all forms of diabetes. However, no method of insulin delivery matches the ability of the human pancreas to reliably and automatically maintain glucose levels within a tight range. Transplantation of human islets or of an intact pancreas can in principle cure diabetes, but this approach is generally reserved for cases with simultaneous transplantation of a kidney, where immunosuppression is already a requirement. Recent advances in cell reprogramming and beta cell differentiation now allow the generation of personalized stem cells, providing an unlimited source of beta cells for research and for developing autologous cell therapies. In this review, we will discuss the utility of stem cell-derived beta cells to investigate the mechanisms of beta cell failure in diabetes, and the challenges to develop beta cell replacement therapies. These challenges include appropriate quality controls of the cells being used, the ability to generate beta cell grafts of stable cellular composition, and in the case of type 1 diabetes, protecting implanted cells from autoimmune destruction without compromising other aspects of the immune system or the functionality of the graft. Such novel treatments will need to match or exceed the relative safety and efficacy of available care for diabetes., (© 2015 The Authors.)

The recent finding that reprogrammed human pluripotent stem cells can be derived by nuclear transfer into human oocytes as well as by induced expression of defined factors has revitalized the debate on whether one approach might be advantageous over the other. Here we compare the genetic and epigenetic integrity of human nuclear-transfer embryonic stem cell (NT-ESC) lines and isogenic induced pluripotent stem cell (iPSC) lines, derived from the same somatic cell cultures of fetal, neonatal, and adult origin. The two cell types showed similar genome-wide gene expression and DNA methylation profiles. Importantly, NT-ESCs and iPSCs had comparable numbers of de novo coding mutations, but significantly more than parthenogenetic ESCs. As iPSCs, NT-ESCs displayed clone- and gene-specific aberrations in DNA methylation and allele-specific expression of imprinted genes. The occurrence of these genetic and epigenetic defects in both NT-ESCs and iPSCs suggests that they are inherent to reprogramming, regardless of derivation approach., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The recent precipitous rise in autoimmune diseases is placing an increasing clinical and economic burden on health systems worldwide. Current therapies are only moderately efficacious, often coupled with adverse side effects. Here, we show that recombinant human insulin-like growth factor-1 (rhIGF-1) stimulates proliferation of both human and mouse regulatory T (Treg) cells in vitro and when delivered systemically via continuous minipump, it halts autoimmune disease progression in mouse models of type 1 diabetes (STZ and NOD) and multiple sclerosis (EAE) in vivo. rhIGF-1 administration increased Treg cells in affected tissues, maintaining their suppressive properties. Genetically, ablation of the IGF-1 receptor specifically on Treg cell populations abrogated the beneficial effects of rhIGF-1 administration on the progression of multiple sclerotic symptoms in the EAE model, establishing a direct effect of IGF-1 on Treg cell proliferation. These results establish systemically delivered rhIGF-1 as a specific, effective stimulator of Treg cell action, underscoring the clinical feasibility of manipulating natural tolerance mechanisms to suppress autoimmune disease., (© 2014 The Authors. Published under the terms of the CC BY 4.0 license.)

Allergic contact dermatitis (ACD) is triggered by an aberrant hyperinflammatory immune response to innocuous chemical compounds and ranks as the world's most prevalent occupational skin condition. Although a variety of immune effector cells are activated during ACD, regulatory T (Treg) cells are crucial in controlling the resulting inflammation. Insulin-like growth factor-1 (IGF-1) regulates cell proliferation and differentiation and accelerates wound healing and regeneration in several organs including the skin. Recently IGF-1 has also been implicated in protection from autoimmune inflammation by expansion of Treg cells. Here, we demonstrate that ectopic expression of IGF-1 in mouse skin suppresses ACD in a Treg cell-specific manner, increasing the number of Foxp3+ Treg cells in the affected area and stimulating lymphocyte production of the anti-inflammatory cytokine interleukin 10. Similar therapeutic effects can be achieved with systemic or topical delivery of IGF-1, implicating this growth factor as a promising new therapeutic option for the treatment of ACD., (© 2014. Published by The Company of Biologists Ltd.)

The transfer of somatic cell nuclei into oocytes can give rise to pluripotent stem cells that are consistently equivalent to embryonic stem cells, holding promise for autologous cell replacement therapy. Although methods to induce pluripotent stem cells from somatic cells by transcription factors are widely used in basic research, numerous differences between induced pluripotent stem cells and embryonic stem cells have been reported, potentially affecting their clinical use. Because of the therapeutic potential of diploid embryonic stem-cell lines derived from adult cells of diseased human subjects, we have systematically investigated the parameters affecting efficiency of blastocyst development and stem-cell derivation. Here we show that improvements to the oocyte activation protocol, including the use of both kinase and translation inhibitors, and cell culture in the presence of histone deacetylase inhibitors, promote development to the blastocyst stage. Developmental efficiency varied between oocyte donors, and was inversely related to the number of days of hormonal stimulation required for oocyte maturation, whereas the daily dose of gonadotropin or the total number of metaphase II oocytes retrieved did not affect developmental outcome. Because the use of concentrated Sendai virus for cell fusion induced an increase in intracellular calcium concentration, causing premature oocyte activation, we used diluted Sendai virus in calcium-free medium. Using this modified nuclear transfer protocol, we derived diploid pluripotent stem-cell lines from somatic cells of a newborn and, for the first time, an adult, a female with type 1 diabetes.

Ca(2+)-activated Cl(-) channels (CaCCs) contribute to airway Cl(-) and fluid secretion, and were implicated in the modulation of disease severity and as a therapeutic target in cystic fibrosis (CF). Previous in vitro studies suggested that members of the CLCA gene family, including the murine mCLCA3, contribute to CaCCs. However, the role of mCLCA3 in ion transport in native airway epithelia has not been studied, to the best of our knowledge. In this study, we used mCLCA3-deficient mice and determined bioelectric properties in freshly excised tracheal tissue, airway morphology, and gene expression studies, to determine the role of mCLCA3 in airway ion transport and airway structure. Bioelectric measurements did not detect any differences in basal short-circuit current, amiloride-sensitive Na(+) absorption, cyclic adenosine monophosphate-dependent Cl(-) secretion, and activation of Ca(2+)-activated (uridine-5'-triphosphate-mediated) Cl(-) secretion in mCLCA3-deficient mice compared with wild-type mice. Moreover, no histological changes were observed in the respiratory tract or any other tissues of mCLCA3-deficient mice when compared with wild-type control mice. The intratracheal instillation of IL-13 produced an approximately 30-fold up-regulation of mCLCA3 transcripts without inducing CaCC activity in wild-type airways, and induced goblet-cell hyperplasia and mucin gene expression to similar levels in both genotypes. Further, multiple specific reverse-transcriptase quantitative PCR assays for other CaCC candidates, including mCLCA1, mCLCA2, mCLCA4, mCLCA5, mCLCA6, mCLCA7, mBEST1, mBEST2, mCLC4, mTTYH3, and mTMEM16A, failed to identify the differential expression of genes in the respiratory tract that may compensate for a lack of mCLCA3 function. Together, these findings argue against a role of mCLCA3 in CaCC-mediated Cl(-) secretion in murine respiratory epithelia.

Background: Factors determining the onset and severity of chronic obstructive pulmonary disease remain poorly understood. Previous studies demonstrated that airway surface dehydration in βENaC-overexpressing (βENaC-Tg) mice on a mixed genetic background caused either neonatal mortality or chronic obstructive lung disease suggesting that the onset of lung disease was modulated by the genetic background., Methods: To test this hypothesis, we backcrossed βENaC-Tg mice onto two inbred strains (C57BL/6 and BALB/c) and studied effects of the genetic background on neonatal mortality, airway ion transport and airway morphology. Further, we crossed βENaC-Tg mice with CFTR-deficient mice to validate the role of CFTR in early lung disease., Results: We demonstrate that the C57BL/6 background conferred increased CFTR-mediated Cl(-) secretion, which was associated with decreased mucus plugging and mortality in neonatal βENaC-Tg C57BL/6 compared to βENaC-Tg BALB/c mice. Conversely, genetic deletion of CFTR increased early mucus obstruction and mortality in βENaC-Tg mice., Conclusions: We conclude that a decrease or absence of CFTR function in airway epithelia aggravates the severity of early airway mucus obstruction and related mortality in βENaC-Tg mice. These results suggest that genetic or environmental factors that reduce CFTR activity may contribute to the onset and severity of chronic obstructive pulmonary disease and that CFTR may serve as a novel therapeutic target.

Chronic lung disease remains the major cause of morbidity and mortality of cystic fibrosis (CF) patients. Cftr mutant mice developed severe intestinal obstruction, but did not exhibit the characteristic CF ion transport defects (i.e. deficient cAMP-dependent Cl(-) secretion and increased Na(+) absorption) in the lower airways, and failed to develop CF-like lung disease. These observations led to the generation of transgenic mice with airway-specific overexpression of the epithelial Na(+) channel (ENaC) as an alternative approach to mimic CF ion transport pathophysiology in the lung. Studies of the phenotype of βENaC-transgenic mice demonstrated that increased airway Na(+) absorption causes airway surface liquid (ASL) depletion, reduced mucus transport and a spontaneous CF-like lung disease with airway mucus obstruction and chronic airway inflammation. Here, we summarize approaches that can be applied for studies of the complex in vivo pathogenesis and preclinical evaluation of novel therapeutic strategies in this model of CF lung disease., (Copyright © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Studies in cystic fibrosis patients and mice overexpressing the epithelial Na(+) channel beta-subunit (betaENaC-Tg) suggest that raised airway Na(+) transport and airway surface liquid (ASL) depletion are central to the pathogenesis of cystic fibrosis lung disease. However, patients or mice with Liddle gain-of-function betaENaC mutations exhibit hypertension but no lung disease. To investigate this apparent paradox, we compared the airway phenotype (nasal versus tracheal) of Liddle with CFTR-null, betaENaC-Tg, and double mutant mice. In mouse nasal epithelium, the region that functionally mimics human airways, high levels of CFTR expression inhibited Liddle epithelial Nat channel (ENaC) hyperfunction. Conversely, in mouse trachea, low levels of CFTR failed to suppress Liddle ENaC hyperfunction. Indeed, Na(+) transport measured in Ussing chambers ("flooded" conditions) was raised in both Liddle and betaENaC-Tg mice. Because enhanced Na(+) transport did not correlate with lung disease in these mutant mice, measurements in tracheal cultures under physiologic "thin film" conditions and in vivo were performed. Regulation of ASL volume and ENaC-mediated Na(+) absorption were intact in Liddle but defective in betaENaC-Tg mice. We conclude that the capacity to regulate Na(+) transport and ASL volume, not absolute Na(+) transport rates in Ussing chambers, is the key physiologic function protecting airways from dehydration-induced lung disease.

Studies to date suggest that PC is a genetically very heterogeneous disease. High-risk families, in which multiple men are affected likely, reflect the contributions of a number of genes, some that are rare and highly penetrant, while others are more common and weakly penetrant. In this review, we have discussed only the first type of loci, and found that the identification of such genomic regions is a formidable problem. Replication between seemingly similar data sets is weak, likely reflecting the older age of onset associated with the disease, the inability to collect affected individuals from more than two generations in a family, and the variation seen in disease presentation, in addition to the underlying locus heterogeneity. Indeed, the definition of PC is ever changing, as diagnostic criteria and tools for pinpointing early lesions improve. Are we making progress? Clearly the answer is yes. The ability to divide large data sets into homogenous subset of families likely to share common genetic under-pinnings has improved power to identify loci and reproducibility between loci is now more common. Indeed, several groups report linkage to loci on chromosomes 1, 17, 19, and 22. Key to our continued success is our ever increasing ability to understand the disease. Identifying the subset of men who are likely to get clinically significant disease is the goal of genetic studies like these, and identifying the underlying loci is the key for developing diagnostics. The willingness of the community to work together has been an important factor in the successes the community has enjoyed to date, and will likely be as important as we move forward to untangle the genetics of this complex and common disorder.

The concept of self-management in healthcare includes disease prevention, self-diagnosis, self-treatment and appropriate consultation with health care practitioners. Within the context of childrens' ailments the decision-maker will usually be a carer. The aim of this study was to examine carers' management of minor childhood ailments within urban and rural settings. The subjects were primary schoolchildren (4-12 years of age) and the respondents were their parents or carers. Data were gathered using a pre-piloted structured questionnaire. The questionnaires were distributed through and collected by the head teachers of the 13 participating schools. Of the 491 questionnaires distributed, 306 (62%) were returned and suitable for analysis. In total, 96 (31%) children had experienced a minor ailment in the preceding 2 weeks; the most commonly reported were cold, headache and gastrointestinal disturbance. Ninety-five respondents indicated how they managed this episode; the most common response was to treat the child with a medicine which they already had in the house (41%). A further 24 obtained a medicine specifically to manage the episode; 12 on prescription and 12 purchased an over-the-counter (OTC) medicine. The majority of respondents (86%) felt that they based their management decision on their own experience, only 10 felt their action was influenced by the advice of a pharmacist or doctor. Fifty children (16%) were reported to have a chronic illness. Several respondents volunteered comments suggesting that they would be cautious in their use of OTC medicines. This study indicates that in the majority of cases, carers manage children's minor ailments without recourse to professional advice.

Natural selection is one of the most fundamental processes in biology. However, there is still a controversy over the importance of selection in microevolution of molecular traits. Despite the general lack of data most authors hold the view that selection on molecular characters may be important, but at lower rates than selection on most phenotypic traits. Here we present evidence that natural selection may contribute substantially to molecular variation on a scale of meters only. In populations of the marine snail Littorina saxatilis living on exposed rocky shores, steep microclines in allele frequencies between splash and surf zone groups are present in the enzyme aspartate aminotransferase (allozyme locus Aat; EC. 2.6.1.1). We followed one population over 7 years, including a period of strong natural perturbation. The surf zone part of the population dominated by the allele Aat100 was suddenly eliminated by a bloom of a toxin-producing microflagellate. Downshore migration of splash zone snails with predominantly Aat120 alleles resulted in a drastic increase in surf zone frequency of Aat120, from 0.4 to 0.8 over 2 years. Over the next four to six generations, however, the frequency of Aat120 returned to the original value. We estimated the coefficient of selection of Aat120 in the surf zone to be about 0.4. Earlier studies show similar or even sharper Aat clines in other countries. Thus, we conclude that microclinal selection is an important evolutionary force in this system.

The marine gastropod Littorina saxatilis has different ecotypes in shores only a few meters apart. This has both taxonomic and evolutionary implications. Here we report on an extreme type of within-shore dimorphism in shell characters. In the wave-exposed rocky shores in northwestern Spain, we found one form of L. saxatilis in the upper-level barnacle zone. It had a white, ridged shell, with black bands in the grooves. Another form confined to the lower-shore mussel belt had a smooth shell that was either white and tessellated or darkly colored. These two forms cooccured in a narrow midshore zone together with individuals that had combined characters, but were present in low frequencies (11%-29%). We used principal-component analysis of metric shell characters to study variation in shell size and shape. We found that the upper-shore form was larger than the lower-shore form. We also found small but significant differences in shell shape. Experiments in a common laboratory environment suggested the differences in shell ornamentation and color are inherited, but the individuals did not develop the morph-specific characters until a shell height of about 3 mm. The occurrence of mainly two distinct forms may suggest the presence of two species that hybridize. An analysis of five polymorphic enzyme loci in populations of snails from three geographically separated sites indicated, however, that there was no positive correlation between morphological distances and genetic distances among populations on a geographic scale (tens of kilometers). Thus, we rejected the hypothesis of two species. However, on a microgeographic scale (meters), genetic differentiation between groups with the same form was less than differentiation between forms. This indicated a partial barrier to gene flow between the two forms, and preliminary mate choice data suggested this was caused by nonrandom mating in the midshore zone of overlap., (© 1993 The Society for the Study of Evolution.)