Notes

Supplementing of an β-mannanase compound minimizes post-weaning looseness of the bowels and also antibiotic use in piglets on an substitute diet with a lot more soybean dinner.
Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation2,3, may be feasible in rare instances.Accumulating evidence indicates that gut microorganisms have a pathogenic role in autoimmune diseases, including in multiple sclerosis1. Studies of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis)2,3, as well as human studies4-6, have implicated gut microorganisms in the development or severity of multiple sclerosis. However, it remains unclear how gut microorganisms act on the inflammation of extra-intestinal tissues such as the spinal cord. Here we show that two distinct signals from gut microorganisms coordinately activate autoreactive T cells in the small intestine that respond specifically to myelin oligodendrocyte glycoprotein (MOG). After induction of experimental autoimmune encephalomyelitis in mice, MOG-specific CD4+ T cells are observed in the small intestine. Experiments using germ-free mice that were monocolonized with microorganisms from the small intestine demonstrated that a newly isolated strain in the family Erysipelotrichaceae acts similarly to an adjuvant to enhance the responses of T helper 17 cells. Shotgun sequencing of the contents of the small intestine revealed a strain of Lactobacillus reuteri that possesses peptides that potentially mimic MOG. Mice that were co-colonized with these two strains showed experimental autoimmune encephalomyelitis symptoms that were more severe than those of germ-free or monocolonized mice. These data suggest that the synergistic effects that result from the presence of these microorganisms should be considered in the pathogenicity of multiple sclerosis, and that further study of these microorganisms may lead to preventive strategies for this disease.Temperature controls plant growth and development, and climate change has already altered the phenology of wild plants and crops1. However, the mechanisms by which plants sense temperature are not well understood. The evening complex is a major signalling hub and a core component of the plant circadian clock2,3. The evening complex acts as a temperature-responsive transcriptional repressor, providing rhythmicity and temperature responsiveness to growth through unknown mechanisms2,4-6. The evening complex consists of EARLY FLOWERING 3 (ELF3)4,7, a large scaffold protein and key component of temperature sensing; ELF4, a small α-helical protein; and LUX ARRYTHMO (LUX), a DNA-binding protein required to recruit the evening complex to transcriptional targets. ELF3 contains a polyglutamine (polyQ) repeat8-10, embedded within a predicted prion domain (PrD). Here we find that the length of the polyQ repeat correlates with thermal responsiveness. We show that ELF3 proteins in plants from hotter climates, with no detectable PrD, are active at high temperatures, and lack thermal responsiveness. The temperature sensitivity of ELF3 is also modulated by the levels of ELF4, indicating that ELF4 can stabilize the function of ELF3. In both Arabidopsis and a heterologous system, ELF3 fused with green fluorescent protein forms speckles within minutes in response to higher temperatures, in a PrD-dependent manner. A purified fragment encompassing the ELF3 PrD reversibly forms liquid droplets in response to increasing temperatures in vitro, indicating that these properties reflect a direct biophysical response conferred by the PrD. The ability of temperature to rapidly shift ELF3 between active and inactive states via phase transition represents a previously unknown thermosensory mechanism.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Despite the widespread implementation of public health measures, coronavirus disease 2019 (COVID-19) continues to spread in the United States. To facilitate an agile response to the pandemic, we developed How We Feel, a web and mobile application that collects longitudinal self-reported survey responses on health, behaviour and demographics. Here, we report results from over 500,000 users in the United States from 2 April 2020 to 12 May 2020. We show that self-reported surveys can be used to build predictive models to identify likely COVID-19-positive individuals. We find evidence among our users for asymptomatic or presymptomatic presentation; show a variety of exposure, occupational and demographic risk factors for COVID-19 beyond symptoms; reveal factors for which users have been SARS-CoV-2 PCR tested; and highlight the temporal dynamics of symptoms and self-isolation behaviour. These results highlight the utility of collecting a diverse set of symptomatic, demographic, exposure and behavioural self-reported data to fight the COVID-19 pandemic.Inflammatory bowel disease (IBD) is a complex disorder that imposes a growing health burden. Multiple genetic associations have been identified in IBD, but the mechanisms underlying many of these associations are poorly understood. Animal models are needed to bridge this gap, but conventional laboratory mouse strains lack the genetic diversity of human populations. To more accurately model human genetic diversity, we utilized a panel of chromosome (Chr) substitution strains, carrying chromosomes from the wild-derived and genetically divergent PWD/PhJ (PWD) strain on the commonly used C57BL/6J (B6) background, as well as their parental B6 and PWD strains. Two models of IBD were used, TNBS- and DSS-induced colitis. Compared with B6 mice, PWD mice were highly susceptible to TNBS-induced colitis, but resistant to DSS-induced colitis. Using consomic mice, we identified several PWD-derived loci that exhibited profound effects on IBD susceptibility. The most pronounced of these were loci on Chr1 and Chr2, which yielded high susceptibility in both IBD models, each acting at distinct phases of the disease. Leveraging transcriptomic data from B6 and PWD immune cells, together with a machine learning approach incorporating human IBD genetic associations, we identified lead candidate genes, including Itga4, Pip4k2a, Lcn10, Lgmn, and Gpr65.Technologies that rely on quantum bits (qubits) require long coherence times and high-fidelity operations1. Superconducting qubits are one of the leading platforms for achieving these objectives2,3. However, the coherence of superconducting qubits is affected by the breaking of Cooper pairs of electrons4-6. The experimentally observed density of the broken Cooper pairs, referred to as quasiparticles, is orders of magnitude higher than the value predicted at equilibrium by the Bardeen-Cooper-Schrieffer theory of superconductivity7-9. Previous work10-12 has shown that infrared photons considerably increase the quasiparticle density, yet even in the best-isolated systems, it remains much higher10 than expected, suggesting that another generation mechanism exists13. Here we provide evidence that ionizing radiation from environmental radioactive materials and cosmic rays contributes to this observed difference. The effect of ionizing radiation leads to an elevated quasiparticle density, which we predict would ultimately limit the coherence times of superconducting qubits of the type measured here to milliseconds. We further demonstrate that radiation shielding reduces the flux of ionizing radiation and thereby increases the energy-relaxation time. Albeit a small effect for today's qubits, reducing or mitigating the impact of ionizing radiation will be critical for realizing fault-tolerant superconducting quantum computers.The Last Glacial Maximum (LGM), one of the best studied palaeoclimatic intervals, offers an excellent opportunity to investigate how the climate system responds to changes in greenhouse gases and the cryosphere. Previous work has sought to constrain the magnitude and pattern of glacial cooling from palaeothermometers1,2, but the uneven distribution of the proxies, as well as their uncertainties, has challenged the construction of a full-field view of the LGM climate state. Here we combine a large collection of geochemical proxies for sea surface temperature with an isotope-enabled climate model ensemble to produce a field reconstruction of LGM temperatures using data assimilation. The reconstruction is validated with withheld proxies as well as independent ice core and speleothem δ18O measurements. Our assimilated product provides a constraint on global mean LGM cooling of -6.1 degrees Celsius (95 per cent confidence interval -6.5 to -5.7 degrees Celsius). Given assumptions concerning the radiative forcing of greenhouse gases, ice sheets and mineral dust aerosols, this cooling translates to an equilibrium climate sensitivity of 3.4 degrees Celsius (2.4-4.5 degrees Celsius), a value that is higher than previous LGM-based estimates but consistent with the traditional consensus range of 2-4.5 degrees Celsius3,4.Fifty years of Moore's law scaling in microelectronics have brought remarkable opportunities for the rapidly evolving field of microscopic robotics1-5. Electronic, magnetic and optical systems now offer an unprecedented combination of complexity, small size and low cost6,7, and could be readily appropriated for robots that are smaller than the resolution limit of human vision (less than a hundred micrometres)8-11. However, a major roadblock exists there is no micrometre-scale actuator system that seamlessly integrates with semiconductor processing and responds to standard electronic control signals. Here we overcome this barrier by developing a new class of voltage-controllable electrochemical actuators that operate at low voltages (200 microvolts), low power (10 nanowatts) and are completely compatible with silicon processing. To demonstrate their potential, we develop lithographic fabrication-and-release protocols to prototype sub-hundred-micrometre walking robots. Every step in this process is performed in parallel, allowing us to produce over one million robots per four-inch wafer. These results are an important advance towards mass-manufactured, silicon-based, functional robots that are too small to be resolved by the naked eye.Atmospheric warming threatens to accelerate the retreat of the Antarctic Ice Sheet by increasing surface melting and facilitating 'hydrofracturing'1-7, where meltwater flows into and enlarges fractures, potentially triggering ice-shelf collapse3-5,8-10. The collapse of ice shelves that buttress11-13 the ice sheet accelerates ice flow and sea-level rise14-16. However, we do not know if and how much of the buttressing regions of Antarctica's ice shelves are vulnerable to hydrofracture if inundated with water. Here we provide two lines of evidence suggesting that many buttressing regions are vulnerable. First, we trained a deep convolutional neural network (DCNN) to map the surface expressions of fractures in satellite imagery across all Antarctic ice shelves. Second, we developed a stability diagram of fractures based on linear elastic fracture mechanics to predict where basal and dry surface fractures form under current stress conditions. We find close agreement between the theoretical prediction and the DCNN-mapped fractures, despite limitations associated with detecting fractures in satellite imagery. Finally, we used linear elastic fracture mechanics theory to predict where surface fractures would become unstable if filled with water. Many regions regularly inundated with meltwater today are resilient to hydrofracture-stresses are low enough that all water-filled fractures are stable. Conversely, 60 ± 10 per cent of ice shelves (by area) both buttress upstream ice and are vulnerable to hydrofracture if inundated with water. The DCNN map confirms the presence of fractures in these buttressing regions. Increased surface melting17 could trigger hydrofracturing if it leads to water inundating the widespread vulnerable regions we identify. These regions are where atmospheric warming may have the largest impact on ice-sheet mass balance.Stars form by accreting material from their surrounding disks. There is a consensus that matter flowing through the disk is channelled onto the stellar surface by the stellar magnetic field. This is thought to be strong enough to truncate the disk close to the corotation radius, at which the disk rotates at the same rate as the star. Spectro-interferometric studies in young stellar objects show that hydrogen emission (a well known tracer of accretion activity) mostly comes from a region a few milliarcseconds across, usually located within the dust sublimation radius1-3. The origin of the hydrogen emission could be the stellar magnetosphere, a rotating wind or a disk. In the case of intermediate-mass Herbig AeBe stars, the fact that Brackett γ (Brγ) emission is spatially resolved rules out the possibility that most of the emission comes from the magnetosphere4-6 because the weak magnetic fields (some tenths of a gauss) detected in these sources7,8 result in very compact magnetospheres. In the case of T Tauri sources, their larger magnetospheres should make them easier to resolve. The small angular size of the magnetosphere (a few tenths of a milliarcsecond), however, along with the presence of winds9,10 make the interpretation of the observations challenging. Here we report optical long-baseline interferometric observations that spatially resolve the inner disk of the T Tauri star TW Hydrae. We find that the near-infrared hydrogen emission comes from a region approximately 3.5 stellar radii across. This region is within the continuum dusty disk emitting region (7 stellar radii across) and also within the corotation radius, which is twice as big. This indicates that the hydrogen emission originates in the accretion columns (funnel flows of matter accreting onto the star), as expected in magnetospheric accretion models, rather than in a wind emitted at much larger distance (more than one astronomical unit).The properties of knots are exploited in a range of applications, from shoelaces to the knots used for climbing, fishing and sailing1. Although knots are found in DNA and proteins2, and form randomly in other long polymer chains3,4, methods for tying5 different sorts of knots in a synthetic nanoscale strand are lacking. Molecular knots of high symmetry have previously been synthesized by using non-covalent interactions to assemble and entangle molecular chains6-15, but in such instances the template and/or strand structure intrinsically determines topology, which means that only one type of knot is usually possible. Here we show that interspersing coordination sites for different metal ions within an artificial molecular strand enables it to be tied into multiple knots. Three topoisomers-an unknot (01) macrocycle, a trefoil (31) knot6-15, and a three-twist (52) knot-were each selectively prepared from the same molecular strand by using transition-metal and lanthanide ions to guide chain folding in a manner reminiscent of the action of protein chaperones16. We find that the metal-ion-induced folding can proceed with stereoinduction in the case of one knot, a lanthanide(III)-coordinated crossing pattern formed only with a copper(I)-coordinated crossing of particular handedness. In an unanticipated finding, metal-ion coordination was also found to translocate an entanglement from one region of a knotted molecular structure to another, resulting in an increase in writhe (topological strain) in the new knotted conformation. The knot topology affects the chemical properties of the strand whereas the tighter 52 knot can bind two different metal ions simultaneously, the looser 31 isomer can bind only either one copper(I) ion or one lutetium(III) ion. The ability to tie nanoscale chains into different knots offers opportunities to explore the modification of the structure and properties of synthetic oligomers, polymers and supramolecules.Substantial research over the past two decades has established that extracellular matrix (ECM) elasticity, or stiffness, affects fundamental cellular processes, including spreading, growth, proliferation, migration, differentiation and organoid formation. Linearly elastic polyacrylamide hydrogels and polydimethylsiloxane (PDMS) elastomers coated with ECM proteins are widely used to assess the role of stiffness, and results from such experiments are often assumed to reproduce the effect of the mechanical environment experienced by cells in vivo. However, tissues and ECMs are not linearly elastic materials-they exhibit far more complex mechanical behaviours, including viscoelasticity (a time-dependent response to loading or deformation), as well as mechanical plasticity and nonlinear elasticity. Here we review the complex mechanical behaviours of tissues and ECMs, discuss the effect of ECM viscoelasticity on cells, and describe the potential use of viscoelastic biomaterials in regenerative medicine. Recent work has revealed that matrix viscoelasticity regulates these same fundamental cell processes, and can promote behaviours that are not observed with elastic hydrogels in both two- and three-dimensional culture microenvironments. These findings have provided insights into cell-matrix interactions and how these interactions differentially modulate mechano-sensitive molecular pathways in cells. Moreover, these results suggest design guidelines for the next generation of biomaterials, with the goal of matching tissue and ECM mechanics for in vitro tissue models and applications in regenerative medicine.Glandular epithelia, including the mammary and prostate glands, are composed of basal cells (BCs) and luminal cells (LCs)1,2. Many glandular epithelia develop from multipotent basal stem cells (BSCs) that are replaced in adult life by distinct pools of unipotent stem cells1,3-8. However, adult unipotent BSCs can reactivate multipotency under regenerative conditions and upon oncogene expression3,9-13. This suggests that an active mechanism restricts BSC multipotency under normal physiological conditions, although the nature of this mechanism is unknown. Here we show that the ablation of LCs reactivates the multipotency of BSCs from multiple epithelia both in vivo in mice and in vitro in organoids. Bulk and single-cell RNA sequencing revealed that, after LC ablation, BSCs activate a hybrid basal and luminal cell differentiation program before giving rise to LCs-reminiscent of the genetic program that regulates multipotency during embryonic development7. By predicting ligand-receptor pairs from single-cell data14, we find that TNF-which is secreted by LCs-restricts BC multipotency under normal physiological conditions. By contrast, the Notch, Wnt and EGFR pathways were activated in BSCs and their progeny after LC ablation; blocking these pathways, or stimulating the TNF pathway, inhibited regeneration-induced BC multipotency. Our study demonstrates that heterotypic communication between LCs and BCs is essential to maintain lineage fidelity in glandular epithelial stem cells.For many tumor types chemotherapy still represents the therapy of choice and many standard treatments are based on the use of platinum (PT) drugs. However, de novo or acquired resistance to platinum is frequent and leads to disease progression. In Epithelial Ovarian Cancer (EOC) patients, PT-resistant recurrences are very common and improving the response to treatment still represents an unmet clinical need. To identify new modulators of PT-sensitivity, we performed a loss-of-function screening targeting 680 genes potentially involved in the response of EOC cells to platinum. We found that SGK2 (Serum-and Glucocorticoid-inducible kinase 2) plays a key role in PT-response. We show here that EOC cells relay on the induction of autophagy to escape PT-induced death and that SGK2 inhibition increases PT sensitivity inducing a block in the autophagy cascade due to the impairment of lysosomal acidification. Mechanistically we demonstrate that SGK2 controls autophagy in a kinase-dependent manner by binding and inhibiting the V-ATPase proton pump. Accordingly, SGK2 phosphorylates the subunit V1H (ATP6V1H) of V-ATPase and silencing or chemical inhibition of SGK2, affects the normal autophagic flux and sensitizes EOC cells to platinum. Hence, we identified a new pathway that links autophagy to the survival of cancer cells under platinum treatment in which the druggable kinase SGK2 plays a central role. Our data suggest that blocking autophagy via SGK2 inhibition could represent a novel therapeutic strategy to improve patients' response to platinum.Cancer can metastasize from early lesions without detectable tumors. Despite extensive studies on metastasis in cancer cells from patients with detectable primary tumors, mechanisms for early metastatic dissemination are poorly understood. Her2 promotes breast cancer early dissemination by inhibiting p38, but the downstream pathway in this process was unknown. Using early lesion breast cancer models, we demonstrate that the effect of p38 suppression by Her2 on early dissemination is mediated by MK2 and heat shock protein 27 (Hsp27). The early disseminating cells in the MMTV-Her2 breast cancer model are Her2highp-p38lowp-MK2lowp-Hsp27low, which also exist in human breast carcinoma tissues. Suppression of p38 and MK2 by Her2 reduces MK2-mediated Hsp27 phosphorylation, and unphosphorylated Hsp27 binds to β-catenin and enhances its phosphorylation by Src, leading to β-catenin activation and disseminating phenotypes in early lesion breast cancer cells. Pharmacological inhibition of MK2 promotes, while inhibition of a p38 phosphatase Wip1 suppresses, early dissemination in vivo. These findings identify Her2-mediated suppression of the p38-MK2-Hsp27 pathway as a novel mechanism for cancer early dissemination, and provide a basis for new therapies targeting early metastatic dissemination in Her2+ breast cancer.The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.Nucleic acid detection by isothermal amplification and the collateral cleavage of reporter molecules by CRISPR-associated enzymes is a promising alternative to quantitative PCR. Here, we report the clinical validation of the specific high-sensitivity enzymatic reporter unlocking (SHERLOCK) assay using the enzyme Cas13a from Leptotrichia wadei for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-the virus that causes coronavirus disease 2019 (COVID-19)-in 154 nasopharyngeal and throat swab samples collected at Siriraj Hospital, Thailand. Within a detection limit of 42 RNA copies per reaction, SHERLOCK was 100% specific and 100% sensitive with a fluorescence readout, and 100% specific and 97% sensitive with a lateral-flow readout. For the full range of viral load in the clinical samples, the fluorescence readout was 100% specific and 96% sensitive. For 380 SARS-CoV-2-negative pre-operative samples from patients undergoing surgery, SHERLOCK was in 100% agreement with quantitative PCR with reverse transcription. The assay, which we show is amenable to multiplexed detection in a single lateral-flow strip incorporating an internal control for ribonuclease contamination, should facilitate SARS-CoV-2 detection in settings with limited resources.In a special miniseries highlighting the different surgical techniques to the inflatable penile prosthesis (IPP), Wilson's Workshop seeks to bring forth skill considerations for the modern implanter. Each work is authored by a highly regarded surgeon who has truly honed the art of their respective approach. Today, most implanters are comfortable with either the penoscrotal or suprapubic incision. The following work directs the spotlight onto a much newer and less known technique, IPP implant via the subcoronal incision. SHP leads the Urology Center of Excellence in Seoul, South Korea, and has implanted more than 700 IPPs using the subcoronal approach since 2015. Here, he will share the clinical pearls of this novel incision gathered through trial and error over many repetitions. We are hopeful that this work will peak the interest of inquisitive minds and help disseminate improved implant techniques.In a pilot study, we wanted to influence the food selection of employees in a pediatric clinic bistro aiming to increase the sale of "healthy" grain buns (number and proportion of all sold buns). During basic assessment, the mean weekly sale of grain buns was 98 (52.3%) and in the second week of highlighting them on a green napkin under a transparent hood (intervention 1) reached 124 (54.6%). However, just when starting intervention 2 (position in front of the display), the bistro was closed due to the Coronavirus pandemic. Thus, necessary public health measures stopped our interventional public health experiment.The emergence of digital pathology - an image-based environment for the acquisition, management and interpretation of pathology information supported by computational techniques for data extraction and analysis - is changing the pathology ecosystem. In particular, by virtue of our new-found ability to generate and curate digital libraries, the field of machine vision can now be effectively applied to histopathological subject matter by individuals who do not have deep expertise in machine vision techniques. Although these novel approaches have already advanced the detection, classification, and prognostication of diseases in the fields of radiology and oncology, renal pathology is just entering the digital era, with the establishment of consortia and digital pathology repositories for the collection, analysis and integration of pathology data with other domains. The development of machine-learning approaches for the extraction of information from image data, allows for tissue interrogation in a way that was not previously possible. The application of these novel tools are placing pathology centre stage in the process of defining new, integrated, biologically and clinically homogeneous disease categories, to identify patients at risk of progression, and shifting current paradigms for the treatment and prevention of kidney diseases.Impairments in social interaction and communication, in combination with restricted, repetitive behaviors and interests, define the neurodevelopmental diagnosis of autism spectrum disorder (ASD). The biological underpinnings of ASD are not well known, but the hypothesis of serotonin (5-HT) involvement in the neurodevelopment of ASD is one of the longest standing. Reuptake through the 5-HT transporter (5-HTT) is the main pathway decreasing extracellular 5-HT in the brain and a marker for the 5-HT system, but in vivo investigations of the 5-HTT and the 5-HT system in ASD are scarce and so far inconclusive. To quantify possible alterations in the 5-HT system in ASD, we used positron emission tomography and the radioligand [11C]MADAM to measure 5-HTT availability in the brain of 15 adults with ASD and 15 controls. Moreover, we examined correlations between regional 5-HTT availability and behavioral phenotype assessments regarding ASD core symptoms. In the ASD group, we found significantly lower 5-HTT availability in total gray matter, brainstem, and 9 of 18 examined subregions of gray matter. In addition, several correlations between regional 5-HTT availability and social cognitive test performance were found. The results confirm the hypothesis that 5-HTT availability is lower in the brain of adult individuals with ASD, and are consistent with the theory of 5-HT involvement in ASD neurodevelopment. The findings endorse the central role of 5-HT in the physiology of ASD, and confirm the need for a continued investigation of the 5-HT system in order to disentangle the biology of ASD.
Little is known about the long-term skeletal impact of bariatric procedures, particularly the increasingly commonly performed gastric sleeve surgery (GS). We examined bone density (BMD) change following three types of bariatric surgery Roux-en-Y gastric bypass (RYGB), GS and laparoscopic adjustable gastric banding (LAGB), compared with diet, over 36 months.

Non-randomized, prospective study of participants with severe obesity (n = 52), undergoing weight-loss interventions RYGB (n = 7), GS (n = 21), LAGB (n = 11) and diet (n = 13). Measurements of calciotropic indices, gut hormones (fasting and post prandial) peptide YY (PYY), glucagon-like peptide 1 (GLP1) and adiponectin together with dual-X-ray absorptiometry and quantitative computed tomography scans were performed thorough the study.

All groups lost weight during the first 12 months. Despite weight stability from 12 to 36 months and supplementation of calcium and vitamin D, there was progressive bone loss at the total hip (TH) over 36 months in RYGBwas also observed at LS and non-weight-bearing forearms. These BMD changes were independent of weight and age differences. We, therefore, recommend close monitoring of bone health following RYGB and GS surgeries.Accurate assessment of childhood adiposity is important both for individuals and populations. We compared fat mass (FM) predictions from a novel prediction model based on height, weight and demographic factors (height-weight equation) with FM from bioelectrical impedance (BIA) and dual-energy X-ray absorptiometry (DXA), using the deuterium dilution method as a reference standard. FM data from all four methods were available for 174 ALSPAC Study participants, seen 2002-2003, aged 11-12-years. FM predictions from the three approaches were compared to the reference standard using; R2, calibration (slope and intercept) and root mean square error (RMSE). R2 values were high from 'height-weight equation' (90%) but lower than from DXA (95%) and BIA (91%). Whilst calibration intercepts from all three approaches were close to the ideal of 0, the calibration slope from the 'height-weight equation' (slope = 1.02) was closer to the ideal of 1 than DXA (slope = 0.88) and BIA (slope = 0.87) assessments. The 'height-weight equation' provided more accurate individual predictions with a smaller RMSE value (2.6 kg) than BIA (3.1 kg) or DXA (3.4 kg). Predictions from the 'height-weight equation' were at least as accurate as DXA and BIA and were based on simpler measurements and open-source equation, emphasising its potential for both individual and population-level FM assessments.
Tumour hypoxia is associated with metastatic disease, and while there have been many mechanisms proposed for why tumour hypoxia is associated with metastatic disease, it remains unclear whether one precise mechanism is the key reason or several in concert. Somatic evolution drives cancer progression and treatment resistance, fuelled not only by genetic and epigenetic mutation but also by selection from interactions between tumour cells, normal cells and physical micro-environment. Ecological habitats influence evolutionary dynamics, but the impact on tempo of evolution is less clear.

We explored this complex dialogue with a combined clinical-theoretical approach by simulating a proliferative hierarchy under heterogeneous oxygen availability with an agent-based model. Predictions were compared against histology samples taken from glioblastoma patients, stained to elucidate areas of necrosis and TP53 expression heterogeneity.

Results indicate that cell division in hypoxic environments is effectively upregulated, with low-oxygen niches providing avenues for tumour cells to spread. Analysis of human data indicates that cell division is not decreased under hypoxia, consistent with our results.

Our results suggest that hypoxia could be a crucible that effectively warps evolutionary velocity, making key mutations more likely. Thus, key tumour ecological niches such as hypoxic regions may alter the evolutionary tempo, driving mutations fuelling tumour heterogeneity.
Our results suggest that hypoxia could be a crucible that effectively warps evolutionary velocity, making key mutations more likely. Thus, key tumour ecological niches such as hypoxic regions may alter the evolutionary tempo, driving mutations fuelling tumour heterogeneity.Calcium-dependent proteolytic calpains are implicated in a variety of physiological processes, as well as pathologies associated with calcium overload. However, the mechanism by which calpain is activated remains elusive since intracellular calcium levels under physiological conditions do not reach the high concentration range required to trigger calpain activation. From a candidate screening using the abundance of the calpain target glutamate receptor GluRIIA at the Drosophila neuromuscular junction as a readout, we uncovered that calpain activity was inhibited upon knockdown of Ttm50, a subunit of the Tim23 complex known to be involved in the import of proteins across the mitochondrial inner membrane. Unexpectedly, Ttm50 and calpain are co-localized at calcium stores Golgi and endoplasmic reticulum (ER), and Ttm50 interacts with calpain via its C-terminal domain. This interaction is required for calpain localization at Golgi/ER, and increases calcium sensitivity of calpain by roughly an order of magnitude. Our findings reveal the regulation of calpain activation by Ttm50, and shed new light on calpain-associated pathologies.The endothelin system has an important role in bone modelling during orthodontic tooth movement (OTM); however, little is known about the involvement of endothelin B receptors (ETB) in this process. The aim of this study was to evaluate the role of ETB in bone modelling during OTM using ETB knockout rats (ETB-KO). Thirty-two male rats were divided into 4 groups (n = 8 per group) the ETB-KO appliance group, ETB-KO control group, wild type (ETB-WT) appliance group, and ETB-WT control group. The appliance consisted of a super-elastic closed-coil spring placed between the first and second left maxillary molar and the incisors. Tooth movement was measured on days 0 and 35, and maxillary alveolar bone volume, osteoblast, and osteoclast volume were determined histomorphometrically on day 35 of OTM. Next, we determined the serum endothelin 1 (ET-1) level and gene expression levels of the osteoclast activity marker cathepsin K and osteoblast activity markers osteocalcin and dentin matrix acidic phosphoprotein 1 (DMP1) on day 35. The ETB-KO appliance group showed significantly lower osteoblast activity, diminished alveolar bone volume and less OTM than the ETB-WT appliance group. Our results showed that ETB is involved in bone modelling in the late stage of OTM.This work explores what Fast Field-Cycling Nuclear Magnetic Resonance (FFC-NMR) relaxometry brings for the study of sarcoma to guide future in vivo analyses of patients. We present the results of an ex vivo pilot study involving 10 cases of biopsy-proven sarcoma and we propose a quantitative method to analyse 1H NMR relaxation dispersion profiles based on a model-free approach describing the main dynamical processes in the tissues and assessing the amplitude of the Quadrupole Relaxation Enhancement effects due to 14N. This approach showed five distinct groups of dispersion profiles indicating five discrete categories of sarcoma, with differences attributable to microstructure and rigidity. Data from tissues surrounding sarcomas indicated very significant variations with the proximity to tumour, which may be attributed to varying water content but also to tissue remodelling processes due to the sarcoma. This pilot study illustrates the potential of FFC relaxometry for the detection and characterisation of sarcoma.Over the past decade, pharmacogenetics (PGx) became an essential tool for personalized medicine although its clinical implementation is still limited. We aimed to assess the current level of knowledge, applications, and expectations of Flemish pharmacists and physicians towards PGx and determine the factors that influence healthcare professionals' knowledge of PGx, aiming to guide future implementation initiatives. A web-based cross-sectional survey was conducted from 8 March 2019 to 8 April 2019, targeting pharmacists, physicians, and trainees of both professions. Ten questions were used to assess the participants' knowledge about PGx. Multivariable linear regression was used to assess the association of profession, experience, practice setting, and prior education with the level of PGx knowledge. In total, 201 Flemish healthcare providers participated, including 100 pharmacists, 73 physicians, and 28 trainees. The majority (78%) of participants were unfamiliar with the basic principles of PGx and its application in clinical practice. The mean percentage of correct answers achieved for the knowledge assessment questions was 34%. Only 9% had counseled patients, while 8% assisted other healthcare professionals on PGx tests the past year. Participants' PGx knowledge was significantly affected by their profession, practice setting, and level of prior education independent of years of experience. These findings provide insight into factors affecting the knowledge of PGx and the current level of PGx implementation in Flemish clinical practice. This may form a basis for developing educational initiatives to enhance the clinical application of PGx in Flanders.The aim of this study was to investigate the size of the change and asymmetry in fatigability of gluteus maximus muscles during endurance training in short-track. The research has taken into account the position of athletes during skating and the problem of fatigue and pain in these muscles. The research covered involved eight female athletes of the Polish National Team in short track, which had been prepared to the Olympic Games in PyeongChang. The surface electromyography (sEMG) system was used to measure fatigue of right and left gluteus maximus muscles, in the modified Biering-Sorensen test. The test was conducted five times during the training before training, after warmup, and after each of 3 series of the endurance training. Comparing the mean frequency of the surface electromyography power spectrum of the test, statistically significant reduction of the average frequency value of the right muscle from 55.61 ± 7.08 to 48.64 ± 4.48 Hz and left muscle from 58.78 ± 4.98 to 53.18 ± 4.62 Hz was reported, which prove the muscle fatigue. In subsequent series tests, the sEMG signal frequency of begin decrease more than the end of the each measurement, which determines the fatigue threshold. The size of the d Cohen effect in fatigue drops along with subsequent five tests during the training. Skaters has higher frequency reduction of the right lower limb, which indicates its greater fatigue during skateing. The fatigue and asymmetry in muscle observed in short-track has implications for training and performance.The giant magnetocaloric effect was quantified in CoMn1-xFexGe (x = 0.085-0.12) nom. at. % polycrystals across the high temperature hexagonal (P63/mmc) to low temperature orthorhombic (Pnma) phase transition via differential scanning calorimetry (DSC) and multiple (thermo) magnetization measurements. It was found that increasing Fe content led to the decrease of both the martensitic transformation temperature and entropy change ([Formula see text]) at the point of the phase transition. Moreover, first-time magnetocaloric measurements resulted in irreproducible entropy change versus temperature diagrams, which was attributed to the release of internal pressure in bulk samples that disintegrated into powder upon transformation. CoMn1-xFexGe demonstrated larger magnetic field-induced entropy changes and giant magnetocaloric effect (MCE) compared to other CoMnGe alloys doped with Si, Sn, Ti, and Ga. However, the observed brittleness and apparent change in volume at the magnetic transition was posited to influence the material's potential for regenerative applications.The transcription factor BMAL1/ARNTL is a non-redundant component of the clock pathway that regulates circadian oscillations of gene expression. Loss of BMAL1 perturbs organismal homeostasis and usually exacerbates pathological responses to many types of insults by enhancing oxidative stress and inflammation. Surprisingly, we observed improved locomotor recovery and spinal cord white matter sparing in Bmal1-/- mice after T9 contusive spinal cord injury (SCI). While acute loss of neurons and oligodendrocytes was unaffected, Bmal1 deficiency reduced the chronic loss of oligodendrocytes at the injury epicenter 6 weeks post SCI. At 3 days post-injury (dpi), decreased expression of genes associated with cell proliferation, neuroinflammation and disruption of the blood spinal cord barrier (BSCB) was also observed. Moreover, intraspinal extravasation of fibrinogen and immunoglobulins was decreased acutely at dpi 1 and subacutely at dpi 7. Subacute decrease of hemoglobin deposition was also observed. Finally, subacutely reduced levels of the leukocyte marker CD45 and even greater reduction of the pro-inflammatory macrophage receptor CD36 suggest not only lower numbers of those cells but also their reduced inflammatory potential. These data indicate that Bmal1 deficiency improves SCI outcome, in part by reducing BSCB disruption and hemorrhage decreasing cytotoxic neuroinflammation and attenuating the chronic loss of oligodendrocytes.The feasibility and safety of microwave ablation in elderly hepatocellular carcinoma (HCC) patients remains unknown. The aim of this study was to evaluate the feasibility and safety of surgical microwave ablation for HCC in patients older than 80 years of age. This retrospective study enrolled consecutive 114 patients older than 80 years of age who underwent surgical microwave ablation for HCC between July 1994 and December 2017. We analyzed perioperative outcomes and long-term outcomes to clarify the prognostic factors. The 1-, 3-, 5-year overall survival and recurrence-free survival rates were 97.3%, 76.0%, 49.2% and 84.2%, 44.7%, and 32.5%, respectively. The overall major morbidity rates (Clavien-Dindo grade IIIA or above) were 2.6%. There were no cases of mortality. Multivariate analysis showed that hepatitis C virus antibody (HCV-Ab) positivity and the presence of multiple tumors were independent prognostic factors for long-term outcomes. The overall survival rate of patients with HCV-Ab negative and single tumor was better than that of other patients (p = 0.026). Surgical microwave ablation was feasible and safe for elderly patients with HCC. Elderly patients with HCV-Ab negative and single tumor would be expected to have better long-term outcomes after surgical microwave ablation.An amendment to this paper has been published and can be accessed via a link at the top of the paper.This paper presents the results of the experiments which were performed using the optical biopsy system specially developed for in vivo tissue classification during the percutaneous needle biopsy (PNB) of the liver. The proposed system includes an optical probe of small diameter acceptable for use in the PNB of the liver. The results of the feasibility studies and actual tests on laboratory mice with inoculated hepatocellular carcinoma and in clinical conditions on patients with liver tumors are presented and discussed. Monte Carlo simulations were carried out to assess the diagnostic volume and to trace the sensing depth. Fluorescence and diffuse reflectance spectroscopy measurements were used to monitor metabolic and morphological changes in tissues. The tissue oxygen saturation was evaluated using a recently developed approach to neural network fitting of diffuse reflectance spectra. The Support Vector Machine Classification was applied to identify intact liver and tumor tissues. Analysis of the obtained results shows the high sensitivity and specificity of the proposed multimodal method. This approach allows to obtain information before the tissue sample is taken, which makes it possible to significantly reduce the number of false-negative biopsies.Mutations in CHMP2B, encoding a protein in the endosomal sorting complexes required for transport (ESCRT) machinery, causes frontotemporal dementia linked to chromosome 3 (FTD3). FTD, the second most common form of pre-senile dementia, can also be caused by genetic mutations in other genes, including TANK-binding kinase 1 (TBK1). How FTD-causing disease genes interact is largely unknown. We found that partial loss function of Ik2, the fly homologue of TBK1 also known as I-kappaB kinase ε (IKKε), enhanced the toxicity of mutant CHMP2B in the fly eye and that Ik2 overexpression suppressed the effect of mutant CHMP2B in neurons. Partial loss of function of Spn-F, a downstream phosphorylation target of Ik2, greatly enhanced the mutant CHMP2B phenotype. An interactome analysis to understand cellular processes regulated by Spn-F identified a network of interacting proteins including Spn-F, Ik2, dynein light chain, and Hook, an adaptor protein in early endosome transport. Partial loss of function of dynein light chain or Hook also enhanced mutant CHMP2B toxicity. These findings identify several evolutionarily conserved genes, including ik2/TBK1, cut up (encoding dynein light chain) and hook, as genetic modifiers of FTD3-associated mutant CHMP2B toxicity and implicate early endosome transport as a potential contributing pathway in FTD.The development of intraventricular haemorrhages (IVH) in preterm newborns is triggered by a disruption of the vessels responsible for cerebral microcirculation. Analysis of the stresses exerted on vessel walls enables the identification of the critical values of cerebral blood flow (CBF) associated with the development of IVH in preterm infants. The purpose of the present study is the estimation of these critical CBF values using the biomechanical stresses obtained by the finite element modelling of immature brain capillaries. The properties of the endothelial cells and basement membranes employed were selected on the basis of published nanoindentation measurements using atomic force microscopes. The forces acting on individual capillaries were derived with a mathematical model that accounts for the peculiarities of microvascularity in the immature brain. Calculations were based on clinical measurements obtained from 254 preterm infants with the gestational age ranging from 23 to 30 weeks, with and without diagnosis of IVH. No distinction between the affected and control groups with the gestational age of 23 to 26 weeks was possible. For infants with the gestational age of 27 to 30 weeks, the CBF value of 17.03 ml/100 g/min was determined as the critical upper value, above which the likelihood of IVH increases.Porous silica anti-reflection (AR) films are of importance in solar cells' photon harvest. However, the usual utilized method to fabricate AR films is the two-step method since the formation of porous silica NPs (first step) and silica coating sol (second step) always require chemical systems at distinct pH values. To reduce the complexity of the process, we choose cationic emulsion as an approach to produce the porosity and propose a convenient one-step route to get high-performance antireflective films. A single layer SiO2 anti-reflective (AR) film with high optical transmittance up to 97.5% at 740 nm was fabricated from composite sol that was made from cationic emulsion nanolatex and tetraethylorthosilicate under acid catalysis condition. After calcination, the transmittance of AR coated glasses still held the transmittance of 96% at 550 nm. Composited with SiO2, Al2O3, or TiO2 sol binders, the transmittance of AR coated glasses could be recovered as high as 97.9% at 650 nm and the pencil hardness was further strengthened up to 6H. The composite sol can keep stable at least one month at ambient temperature without any visible precipitation. Therefore, the proposed method is promising for developing high-performance AR films effectively and economically.We investigated whether intravenous iron supplementation improves fatigue and general health in non-anemic repeat adult blood donors with iron deficiency (ferritin ≤ 50 µg/L). Of 1,487 potentially eligible participants, 203 were randomly assigned to a single intravenous dose of 800 mg iron-carboxymaltose and 202 to placebo; 393 participants completed the trial. At 6 to 8 weeks after intervention, self-rated mean fatigue scores (numeric rating scale from 1-10, primary outcome) were 3.9 ± 1.8 in the iron supplementation group and 4.0 ± 2.2 in the placebo group, showing no group difference (p = 0.819). Pre-specified subgroup analyses of gender, ferritin  less then  25 µg/L and fatigue ≥ 4 points, as well as exploratory analyses of lower ferritin cut-offs did not reveal any between-group differences. In terms of secondary outcomes, the mean differences were 114.2 µg/L for ferritin (95% CI 103.1-125.3) and 5.7 g/L for hemoglobin (95% CI 4.3-7.2) with significantly higher values in the iron supplementation group. No group differences were observed for different measures of general well-being and other clinical and safety outcomes. Intravenous iron supplementation compared with placebo resulted in increase of ferritin and hemoglobin levels in repeat blood donors with low iron stores, yet had no effect on fatigue and general well-being.The methods for isolating rare cells such as circulating tumor cells (CTCs) can be generally classified into two categories those based on physical properties (e.g., size) and methods based on biological properties (e.g., immunoaffinity). CellSearch, the only FDA-approved method for the CTC-based cancer prognosis, relies on immunoaffinity interactions between CTCs and antibodies immobilized on magnetic particles. Immunoaffinity-based CTC isolation has also been employed in microfluidic devices, which show higher capture efficiency than CellSearch. We report here our investigation of combining size-based microfiltration into a microfluidic device with immunoaffinity for enhanced capture efficiency of CTCs. The device consists of four serpentine main channels, and each channel contains an array of lateral filters that create a two-dimensional flow. The main flow is through the serpentine channel, allowing the majority of the sample to pass by while the secondary flow goes through the lateral filters. The device design is optimized to make all fluid particles interact with filters.
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