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The karyotype of Litoria (L.) paraewingi (Watson et al., 1971) (Big River State Forest, Victoria) is described here for the first time. It is prepared following tissue culture of toe clipping macerates, cryopreservation, reculture and conventional 4’,6-diamidino-2-phenylindole (DAPI) staining. The L. paraewingi karyotype is then compared to similarly processed IUCN (International Union for the Conservation of Nature) least concern members L. ewingii (Duméril et Bibron, 1841) (southern Victoria) and L. jervisiensis (Duméril et Bibron, 1841) (Myall Lakes National Park, New South Wales), all members of the same L. ewingii complex/group. The L. paraewingi diploid number is 2n = 26, the same as for the other two species. Litoria paraewingi chromosomes 1, 2, 6 and 7 are submetacentric, chromosomes 3 and 5 are subtelocentric and the remainder are metacentric. No secondary constriction or putative nucleolus organiser region (NOR) was readily identifiable following conventional DAPI staining in any scored L. paraewingi metaphase spread. Conversely, a putative NOR was readily identifiable on the long arm of chromosome 1 in all examined metaphase spreads for the other two species. The karyotypes of L. ewingii and L. jervisiensis here further differ from L. paraewingi with chromosome 1 being metacentric and chromosomes 8 and 10 being submetacentric for both former species. The L. jervisiensis karyotype differs from those of L. ewingii and L. paraewingi by DAPI staining with: (i) apparent relative length inversion of subtelocentric chromosome 3 and metacentric chromosome 4 and (ii) chromosome 6 being metacentric rather than submetacentric. All three species have a highly conserved chromosome morphology with respect to chromosomes 2, 5, 7, 9, 11, 12 and 13. The greatest gross morphological difference karyotypically is observed between L. paraewingi and L. jervisiensis. These karyotype data support the previous phylogenetic separation of these three species based upon genetic compatibility and behavioural, biochemical and molecular genetic analyses.

Abstract Three dimensional sensing is essential in order that machines may operate in and interact with complex dynamic environments. Solid-state beam scanning devices are seen as being key to achieving required system specifications in terms of sensing range, resolution, refresh rate and cost. Integrated optical phased arrays fabricated on silicon wafers are a potential solution, but demonstrated devices with system-level performance currently rely on expensive widely tunable source lasers. Here, we combine silicon nitride photonics and micro-electromechanical system technologies, demonstrating the integration of an active photonic beam-steering circuit into a piezoelectric actuated micro cantilever. An optical phased array, operating at a wavelength of 905 nm, provides output beam scanning over a range of 17° in one dimension, while the inclination of the entire circuit and consequently the angle of the output beam in a second dimension can be independently modified over a range of up to 40° using the piezoelectric actuator.

BackgroundBlack women are significantly more likely to experience severe maternal morbidity and are 3 times as likely to die from pregnancy-related causes compared to White women. Using a strengths-based wellness approach within an integrated supportive care program provided by a community doula could offer pragmatic solutions for Black maternal disparities. The Protective Assets Reinforced with Integrated Care and Technology (PARITY) program consists of a wellness technology platform, including informational links to wellness content and reinforcing motivational SMS text messages, as well as community-based doula support delivered both in person and through the technology platform to improve Black maternal wellness. ObjectiveThis pilot randomized controlled trial (RCT) and mixed methods evaluation aims to (1) determine the feasibility and acceptability of the PARITY intervention; (2) investigate the preliminary efficacy of the PARITY intervention on clinical outcomes (maternal blood pressure, gestational weight gain, and cesarean birth); and (3) investigate changes to wellness behavioral outcomes (nutrition, physical activity, sleep, and health care adherence) and empowered strengths (self-efficacy, social support, motivation, resilience, problem-solving, and self-regulation) in the intervention group compared to a control group. MethodsA 2-arm RCT and mixed methods evaluation will be conducted. Overall, 60 Black pregnant individuals will be randomized in a ratio of 1:1 to either the intervention or informational control group. Participants in the intervention group will receive access to the technology platform over a 12-week period that ends before birth. Intervention participants will be assigned a doula interventionist, who will meet with them 4 times during the intervention. All participants (intervention and control) will receive a referral for a birth doula at no cost, printed materials about having a healthy pregnancy, and community resources. Feasibility and acceptability will be assessed at the end of the program. Measures will be obtained at baseline (20-28 weeks), the 36th week of pregnancy, birth, and 6-12 weeks post partum. Summary statistics and distribution plots will be used to describe measured variables at each time point. A generalized linear mixed model with a shared random component will be used to analyze the effects of PARITY on clinical, wellness behavioral, and empowered strength outcomes, including baseline nutrition, physical activity, and sleep measures as covariates. For significant effects, post hoc contrasts will be adjusted using the Holm method to maintain comparison-wise error at or

Summary: Our understanding and management of reproductive health and related disorders such as infertility, menstrual irregularities, and pituitary disorders depend on understanding the intricate sex-specific mechanisms governing prolactin secretion. Using ex vivo experiments in acute slices, in parallel with in vivo calcium imaging (GRIN lens technology), we found that dopamine neurons inhibiting PRL secretion (TIDA), organize as functional networks both in and ex vivo. We defined an index of efficiency of networking (Ieff) using the duration of calcium events and the ability to form plastic economic networks. It determined TIDA neurons’ ability to inhibit PRL secretion in vivo. Ieff variations in both sexes demonstrated TIDA neurons’ adaptability to physiological changes. A variation in the number of active neurons contributing to the network explains the sexual dimorphism in basal [PRL]blood secretion patterns. These sex-specific differences in neuronal activity and network organization contribute to the understanding of hormone regulation.

The karyotype of the IUCN least concern red-backed toadlet Pseudophryne (P.) coriacea (Keferstein, 1868) from the New South Wales Central Coast is described following tissue culture of toe clipping macerates and conventional DAPI staining. The diploid number is 2n = 24. The karyotype is represented by six large and five small chromosomal pairs and one very small chromosomal pair. The very small chromosome 12 is 12% the size of chromosome 1. One of the large chromosomes is subtelocentric, two of the large chromosomes are submetacentric and the remaining chromosomes are metacentric. The putative nucleolus organiser region (NOR) is observed on chromosome 4. The diploid number and location of the putative NOR correlates to that of the previously published IUCN critically endangered P. corroboree (Moore 1953) and unpublished descriptions of the P. coriacea karyotype. This is the first described cell culture of a species from the genus Pseudophryne Fitzinger, 1843, first published analysis of the P. coriacea karyotype and the first published analysis of centromeric allocation of this genus. Globally there exists a large inventory of tissue samples in cryobanks that are not associated with known recovery mechanisms such as basic cell culture techniques. Detailed cytogenetic analyses of these cryobanked samples are therefore not possible. This work therefore enables: (i) a comparison of the P. coriacea karyotype with that of the critically endangered P. corroboree and (ii) a benchmark for repeat and future cytogenetic and genomic analyses of cryostored samples of this genus.

Many cognitive problems can be decomposed into series of subproblems that are solved sequentially by the brain. When subproblems are solved, relevant intermediate results need to be stored by neurons and propagated to the next subproblem, until the overarching goal has been completed. We will here consider visual tasks, which can be decomposed into sequences of elemental visual operations. Experimental evidence suggests that intermediate results of the elemental operations are stored in working memory as an enhancement of neural activity in the visual cortex. The focus of enhanced activity is then available for subsequent operations to act upon. The main question at stake is how the elemental operations and their sequencing can emerge in neural networks that are trained with only rewards, in a reinforcement learning setting. We here propose a new recurrent neural network architecture that can learn composite visual tasks that require the application of successive elemental operations. Specifically, we selected three tasks for which electrophysiological recordings of monkeys' visual cortex are available. To train the networks, we used RELEARNN, a biologically plausible four-factor Hebbian learning rule, which is local both in time and space. We report that networks learn elemental operations, such as contour grouping and visual search, and execute sequences of operations, solely based on the characteristics of the visual stimuli and the reward structure of a task. After training was completed, the activity of the units of the neural network elicited by behaviorally relevant image items was stronger than that elicited by irrelevant ones, just as has been observed in the visual cortex of monkeys solving the same tasks. Relevant information that needed to be exchanged between subroutines was maintained as a focus of enhanced activity and passed on to the subsequent subroutines. Our results demonstrate how a biologically plausible learning rule can train a recurrent neural network on multistep visual tasks.

Abstract Background A significant proportion of Canadian adults is impacted by chronic noncommunicable diseases. These conditions may be improved by peer-led health promotion interventions that target modifiable risk factors; however, to date, there is mixed evidence on the effectiveness of these interventions. Unlike other health promotion programs, Hans Kai is grounded in a holistic model of health that simultaneously addresses multiple determinants of health at different levels of human ecology. In Hans Kai, a set of informational sessions that are delivered in a group setting by healthcare professionals are followed by regular peer-led group meetings in a self-governed support group setting that is designed to promote implementation of newly learned health competences. The Hans Kai trial described here aims to evaluate the efficacy of the Hans Kai program in promoting the health and wellbeing of its participants and investigate the experiences of the Hans Kai participants and facilitators. Methods This research will involve a mixed methods trial combining an experimental component with a qualitative component. The experimental component will involve a 6-month 2-group parallel superiority randomized controlled trial (RCT) in which 105 participants will be randomly assigned to two conditions, an intervention group (n = 70) that will participate in the Hans Kai program and a control group (n = 35) that will have access to standard care using a computer-generated random sequence; blinding will not occur. The RCT will test the impact of the program on several health outcomes and will be followed by a 12–18-month observational follow-up study that will provide data on the long-term durability of the 6-month RCT health outcomes. The qualitative component will investigate the experiences of program participants (n = 30) and facilitators (n = 15) to identify the main strengths and limitations of Hans Kai, uncover potential implementation issues, and elucidate the mechanisms through which the program works. The population of interest will include adults aged 18 + with or without chronic health conditions who self-report an interest in taking control of their own health and improving their lifestyle. In the RCT, all outcomes of interest will be measured using a multi-method approach, involving self-report questionnaires and objective indicators, and within-subject mean changes in outcomes over time between the two groups will be compared to address the RCT aims. Similarly, in the qualitative component, a multi-method approach, involving in-depth individual interviews, photovoice, and online surveys, will be used to reach a deeper and more nuanced understanding of the program strengths, how the program works, and for which people it is more effective. Adaptable components of the program will also be investigated and modified according to the feedback provided by the RCT participants. In the mixed methods integration of evidence, the qualitative findings will be used to explain the quantitative RCT results. Discussion The RCT findings will help support the further development and use of Hans Kai as well as other peer-led health promotion interventions. Trial registration United Stated Clinical Trial Registry ClinicalTrials.gov (registration# NCT03949725; Protocol version 2, June 22nd, 2022).

Abstract Background Potassium regulation in the body is primarily done in the kidney. In addition to this, hyperkalemia, occurs in approximately 10% of individuals with chronic kidney disease (CKD) and is associated with elevated all-cause mortality. Individuals with CKD are often told to restrict dietary potassium (K), however, this recommendation is based on low quality evidence. Reduced quality of life, limited dietary choices and nutritional deficiencies are all potential negative outcomes that may occur when restricting dietary K in CKD patients. There is a need for randomized controlled trials investigating the impact of dietary K modification on serum K concentrations in people with CKD. Methods A randomized 2-period crossover design comparing a liberalized K fruit and vegetable diet where participants will be required to consume ~ 3500 mg of dietary K daily, to a standard K restricted diet where participants will be required to consume

Abstract Background Monepantel is an anti‐helminthic drug that also has anti‐cancer properties. Despite several studies over the years, the molecular target of monepantel in mammalian cells is still unknown, and its mechanism‐of‐action is not fully understood, though effects on cell cycle, mTOR signalling and autophagy have been implicated. Methods Viability assays were performed on >20 solid cancer cell cells, and apoptosis assays were performed on a subset of these, including 3D cultures. Genetic deletion of BAX/BAK and ATG were used to establish roles of apoptosis and autophagy in killing activity. RNA‐sequencing was performed on four cell lines after monepantel treatment, and differentially regulated genes were confirmed by Western blotting. Results We showed that monepantel has anti‐proliferative activity on a broad range of cancer cell lines. In some, this was associated with induction of apoptosis which was confirmed using a BAX/BAK‐deficient cell line. However, proliferation is still inhibited in these cells following monepantel treatment, indicating cell‐cycle disruption as the major anti‐cancer effect. Previous studies have also indicated autophagic cell death occurs following monepantel treatment. We showed autophagy induction in multiple cell lines; however, deletion of a key autophagy regulator ATG7 had minimal impact on monepantel’s anti‐proliferative activity, suggesting autophagy is associated with, but not required for its anti‐tumour effects. Transcriptomic analysis of four cell lines treated with monepantel revealed downregulation of many genes involved in the cell cycle, and upregulation of genes linked to ATF4‐mediated ER stress responses, especially those involved in amino‐acid metabolism and protein synthesis. Conclusions As these outcomes are all associated with mTOR signalling, cell cycle and autophagy, we now provide a likely triggering mechanism for the anti‐cancer activity of monepantel.

Abstract Background Hypertensive disorders of pregnancy are a leading cause of maternal and fetal morbidity and mortality and a significant risk factor for future cardiovascular disease development in women. This study aimed to explore lifestyle wellness-related variables and how they impact the risk of hypertension in pregnancy. Methods This is a secondary analysis of data from the prospective cohort study Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be (nuMoM2b). Data was collected through questionnaires, clinical evaluations, and medical records review at 8 academic medical centers in the United States. Four study visits were scheduled throughout the participant’s pregnancy (visits one–four): 60–136, 160–216, and 220–296 weeks gestation and birth. A series of statistical modeling and logistical regression were performed using 15 lifestyle variables related to sleep, nutrition, resilience, illness avoidance, and physical activity were selected as predictor variables with an outcome variable of hypertension. Results Of 9289 nulliparous participants considered for inclusion in our analyses, 1464 had any HDP during study participation, and 554 participants had complete data available for the study and were included in our final sample. Results were statistically significant at a level of p

Gonadotropes in the pituitary secrete follicle-stimulating hormone and luteinizing hormone to control gonadal function and fertility, but whether they exert actions on extra-gonadal organs is not fully understood. Here the authors report that gonadotropes regulate liver steatosis independent of the ovaries in mice.

Background: Individuals with chronic kidney disease (CKD) can develop metabolic acidosis which, in turn, is associated with faster progression of CKD and an increased need for dialysis. Oral sodium bicarbonate (the current standard of care therapy for metabolic acidosis) is poorly tolerated leading to low adherence. Base-producing or alkalizing Fruit and vegetables have potential as an alternative treatment for metabolic acidosis as they have been shown to reduce acid load arising from the diet. Objective: This trial will evaluate the feasibility of providing base-producing fruit and vegetables as a dietary treatment for metabolic acidosis, compared with oral sodium bicarbonate. Design: A 2-arm, open-label, dual-center, randomized controlled feasibility trial. Setting: Two Canadian sites: a nephrology clinic in Winnipeg, Manitoba, and a nephrology clinic in Halifax, Nova Scotia. Participants: Adult participants with G3-G5 CKD and metabolic acidosis. Measurements: Participants will undergo baseline measurements and attend 5 study visits over 12 months at which they will have a measurement of feasibility criteria as well as blood pressure, blood and urine biochemistry, 5-repetition chair stand test (STS5), and questionnaires to assess quality of life and symptoms. Furthermore, participants fill out Automated Self-Administered 24-hour recalls (ASA-24) in the beginning, middle, and end of trial. Methods: A total of 40 eligible participants will be randomized 1:1 to either base-producing fruit and vegetables (experimental) group or sodium bicarbonate (control) group, beginning from a daily dose of 1500 mg. Limitations: Using self-administered dietary assessments, lack of supervision over the consumption of study treatments and the possible disappointment of the control group for not receiving fruit and vegetables would be considered as limitations for this study. However, we are planning to undertake proper practices to overcome the possible limitations. These practices are discussed throughout the article in detail. Conclusions: This study will generate data on base-producing fruit and vegetables consumption as a dietary treatment for metabolic acidosis in CKD. The data will be used to design a future multi-center trial looking at slowing CKD progression in people with metabolic acidosis. Trial Registration: This study is registered on clinicaltrials.gov with the identifier NCT05113641.

Abstract Background Neurons are highly specialized cells with a complex morphology generated by various membrane trafficking steps. They contain Golgi outposts in dendrites, which are formed from somatic Golgi tubules. In trafficking membrane fusion is mediated by a specific combination of SNARE proteins. A functional SNARE complex contains four different helices, one from each SNARE subfamily (R-, Qa, Qb and Qc). Loss of the two Qb SNAREs vti1a and vti1b from the Golgi apparatus and endosomes leads to death at birth in mice with massive neurodegeneration in peripheral ganglia and defective axon tracts. Methods Hippocampal and cortical neurons were isolated from Vti1a −/− Vti1b −/− double deficient, Vti1a −/− Vti1b +/− , Vti1a +/− Vti1b −/− and Vti1a +/− Vti1b +/− double heterozygous embryos. Neurite outgrowth was determined in cortical neurons and after stimulation with several neurotrophic factors or the Rho-associated protein kinase ROCK inhibitor Y27632, which induces exocytosis of enlargeosomes, in hippocampal neurons. Moreover, postsynaptic densities were isolated from embryonic Vti1a −/− Vti1b −/− and Vti1a +/− Vti1b +/− control forebrains and analyzed by western blotting. Results Golgi outposts were present in Vti1a −/− Vti1b +/− and Vti1a +/− Vti1b −/− dendrites of hippocampal neurons but not detected in the absence of vti1a and vti1b. The length of neurites was significantly shorter in double deficient cortical neurons. These defects were not observed in Vti1a −/− Vti1b +/− and Vti1a +/− Vti1b −/− neurons. NGF, BDNF, NT-3, GDNF or Y27632 as stimulator of enlargeosome secretion did not increase the neurite length in double deficient hippocampal neurons. Vti1a −/− Vti1b −/− postsynaptic densities contained similar amounts of scaffold proteins, AMPA receptors and NMDA receptors compared to Vti1a +/− Vti1b +/− , but much more TrkB, which is the receptor for BDNF. Conclusion The absence of Golgi outposts did not affect the amount of AMPA and NMDA receptors in postsynaptic densities. Even though TrkB was enriched, BDNF was not able to stimulate neurite elongation in Vti1a −/− Vti1b −/− neurons. Vti1a or vti1b function as the missing Qb-SNARE together with VAMP-4 (R-SNARE), syntaxin 16 (Qa-SNARE) and syntaxin 6 (Qc-SNARE) in induced neurite outgrowth. Our data show the importance of vti1a or vti1b for two pathways of neurite elongation.

IntroductionWith the prevalence of obesity increasing, many weight-loss programs were created to aid in combating the trend. The Weight Loss Clinic (WLC) was created to provide personalized support for lifestyle changes using a multidisciplinary team with medical oversight. This study evaluated the clinically-managed weight loss program at the Wellness Institute.MethodsThis was a prospective evaluation of a newly established program between January 2019–August 2020. Participants who entered the weight loss program were approached to learn about the evaluation. A total of 41 participants were included. The primary outcomes included changes in body weight and achievement of more than 5% initial body weight loss. Outcome measures were collected pre-and post-program and the data was analyzed through paired t-tests on R studio.ResultsGreater body weight-loss was seen in completers pre-COVID-19 compared to those who completed during the pandemic (Mean, ±SD; 7.51 ± 6.24 kg n = 13 p

Summary: Gonadotropes in the anterior pituitary gland are essential for fertility and provide a functional link between the brain and the gonads. To trigger ovulation, gonadotrope cells release massive amounts of luteinizing hormone (LH). The mechanism underlying this remains unclear. Here, we utilize a mouse model expressing a genetically encoded Ca2+ indicator exclusively in gonadotropes to dissect this mechanism in intact pituitaries. We demonstrate that female gonadotropes exclusively exhibit a state of hyperexcitability during the LH surge, resulting in spontaneous [Ca2+]i transients in these cells, which persist in the absence of any in vivo hormonal signals. L-type Ca2+ channels and transient receptor potential channel A1 (TRPA1) together with intracellular reactive oxygen species (ROS) levels ensure this state of hyperexcitability. Consistent with this, virus-assisted triple knockout of Trpa1 and L-type Ca2+ subunits in gonadotropes leads to vaginal closure in cycling females. Our data provide insight into molecular mechanisms required for ovulation and reproductive success in mammals.

The mission of WEST (tungsten-W Environment in Steady-state Tokamak) is to explore long pulse operation in a full tungsten (W) environment for preparing next-step fusion devices (ITER and DEMO) with a focus on testing the ITER actively cooled W divertor in tokamak conditions. Following the successful completion of phase 1 (2016-2021), phase 2 started in December 2022 with the lower divertor made entirely of actively cooled ITER-grade tungsten mono-blocks. A boronization prior the first plasma attempt allowed for a smooth startup with the new divertor. Despite the reduced operating window due to tungsten, rapid progress has been made in long pulse operation, resulting in discharges with a pulse length of 100 s and an injected energy of around 300 MJ per discharge. Plasma startup studies were carried out with equatorial boron nitride limiters to compare them with tungsten limiters, while Ion Cyclotron Resonance Heating assisted startup was attempted. High fluence operation in attached regime, which was the main thrust of the first campaigns, already showed the progressive build up of deposits and appearance of dust, impacting the plasma operation as the plasma fluence increased. In total, the cumulated injected energy during the first campaigns reached 43 GJ and the cumulated plasma time exceeded 5 h. Demonstration of controlled X-Point Radiator regime is also reported, opening a promising route for investigating plasma exhaust and plasma-wall interaction issues in more detached regime. This paper summarises the lessons learned from the manufacturing and the first operation of the ITER-grade divertor, describing the progress achieved in optimising operation in a full W environment with a focus on long pulse operation and plasma wall interaction.

This paper presents the thermal behavior of non-resonant (quasi-static) piezoelectric biaxial MEMS scanners with Bragg reflectors. These scanners were developed for LIDAR (LIght Detection And Ranging) applications using a pulsed 1550 nm laser with an average power of 2 W. At this power, a standard metal (gold) reflector can overheat and be damaged. The Bragg reflector developed here has up to 24 times lower absorption than gold, which limits heating of the mirror. However, the use of such a reflector involves a technological process completely different from that used for gold and induces, for example, different final stresses on the mirror. In view of the high requirements for optical power, the behavior of this reflector in the event of an increase in temperature needs to be studied and compared with the results of previous studies using gold reflectors. This paper shows that the Bragg reflector remains functional as the temperature rises and undergoes no detrimental deformation even when heated to 200 °C. In addition, the 2D-projection model revealed a 5% variation in optical angle at temperatures up to 150 °C and stability of 2D scanning during one hour of continuous use at 150 °C. The results of this study demonstrate that a biaxial piezoelectric MEMS scanner equipped with Bragg reflector technology can reach a maximum temperature of 150 °C, which is of the same order of magnitude as can be reached by scanners with gold reflectors.

Abstract Duchenne muscular dystrophy is a severe neuromuscular disease causing a progressive muscle wasting due to mutations in the DMD gene that lead to the absence of dystrophin protein. Adeno-associated virus (AAV)-based therapies aiming to restore dystrophin in muscles, by either exon skipping or microdystrophin expression, are very promising. However, the absence of dystrophin induces cellular perturbations that hinder AAV therapy efficiency. We focused here on the impact of the necrosis-regeneration process leading to nuclear centralization in myofiber, a common feature of human myopathies, on AAV transduction efficiency. We generated centronucleated myofibers by cardiotoxin injection in wild-type muscles prior to AAV injection. Intramuscular injections of AAV1 vectors show that transgene expression was drastically reduced in regenerated muscles, even when the AAV injection occurred 10 months post-regeneration. We show also that AAV genomes were not lost from cardiotoxin regenerated muscle and were properly localised in the myofiber nuclei but were less transcribed leading to muscle transduction defect. A similar defect was observed in muscles of the DMD mouse model mdx. Therefore, the regeneration process per se could participate to the AAV-mediated transduction defect observed in dystrophic muscles which may limit AAV-based therapies.

Abstract Background Rheumatic and musculoskeletal diseases (RMD) are associated with depression, fatigue, and disturbed sleep – symptoms that often impact behavior and activity. Patient reported outcomes (PROs) are a way of collecting information on the patient symptom experience directly from the individual. The purpose of this study was to measure and compare user smartphone sensor and activity data in adults with RMDs and assess associations with PROs. Methods We invited adults with RMDs enrolled in the FORWARD Databank to participate by installing a custom app on their smartphone and answering PROs (pain, global, HAQ-II) questions daily and weekly over 3 years. Passive data collected included mobility distance, unique calls and text messages, call durations, and number of missed calls. Confounders included sociodemographic, clinical, passive phone behavior, and seasonal factors. Kappa statistics between PRO and flares were computed to measure agreement. The agreement between daily and weekly VAS pain was estimated using the intraclass (ICC) correlation of a two-way random effect model. The relationship between the weekly PRO outcomes and the passive phone data was analyzed with a linear mixed-effect model (LMM), including a random intercept for participant and slope for time in the study with an unstructured covariate structure. Results Of the 446 participants, the mean (SD) age was 54 (12) years, most (65.5%) had rheumatoid arthritis (RA), the vast majority (91%) were female, and the US Northeast has the least representation (12%). Longer reaction times, interaction diversity, and higher mobility were associated with worse PROs while longer text messages were associated with better PROs. Participants in this study showed good levels of adherence which holds promise for future interventions using passive behavior measures in self-management and clinical follow-up. Conclusion This is the first study to examine passive smartphone behavior with PROs in RMDs and we found significant associations between these behaviors and important health outcomes of pain and function. As smartphone usage continues to change, future studies should validate and expand on our findings with a goal of finding changes in patient symptoms passively through mobile device monitoring.

With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and performed whole genome sequencing of 3 MMV020291-resistant populations. This revealed 3 nonsynonymous single nucleotide polymorphisms in 2 genes; 2 in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wild-type parasites, which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade RBCs. Additionally, the series inhibits the actin-1-dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro cosedimentation experiments using recombinant P. falciparum proteins indicate that potent MMV020291 analogues disrupt the formation of filamentous actin in the presence of profilin. Altogether, this study identifies the first compound series interfering with the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.

Central integration of peripheral appetite-regulating signals ensures maintenance of energy homeostasis. Thus, plasticity of circulating molecule access to neuronal circuits involved in feeding behavior plays a key role in the adaptive response to metabolic changes. However, the mechanisms involved remain poorly understood despite their relevance for therapeutic development. Here, we investigated the role of median eminence mural cells, including smooth muscle cells and pericytes, in modulating gut hormone effects on orexigenic/anorexigenic circuits. We found that conditional activation of median eminence vascular cells impinged on local blood flow velocity and altered ghrelin-stimulated food intake by delaying ghrelin access to target neurons. Thus, activation of median eminence vascular cells modulates food intake in response to peripheral ghrelin by reducing local blood flow velocity and access to the metabolic brain.

Abstract Background Chronic kidney disease (CKD) is associated with a reduced quality of life and an increased risk of kidney failure, cardiovascular events, and all-cause mortality. Accumulation of nitrogen-based uremic toxins leads to worsening of symptoms in individuals with CKD. Many uremic toxins, such as indoxyl and p-cresol sulphate, are produced exclusively by the gut microbiome through the proteolytic digestion of aromatic amino acids. Strategies to reduce the production of these toxins by the gut microbiome in individuals with CKD may lessen symptom burden and delay the onset of dialysis. One such strategy is to change the overall metabolism of the gut microbiome so that less uremic toxins are produced. This can be accomplished by manipulating the energy source available to the microbiome. Fermentable carbohydrates which reach the gut microbiome, like resistant starch (RS), have been shown to inhibit or reduce bacterial amino acid metabolism. This study aims to investigate the effects of resistant potato starch (RPS) as a prebiotic in individuals with CKD before the onset of dialysis. Methods This is a double-blind, randomized two-period crossover trial. Thirty-six eligible participants will consent to follow a 26-week study regimen. Participants will receive 2 sachets per day containing either 15 g of RPS (MSPrebiotic, resistant potato starch treatment) or 15 g cornstarch (Amioca TF, digestible starch control). Changes in blood uremic toxins will be investigated as the primary outcome. Secondary outcomes include the effect of RPS consumption on symptoms, quality of life and abundance, and diversity and functionality of the gut microbiome. Discussion This randomized trial will provide further insight into whether the consumption of RPS as a prebiotic will reduce uremic toxins and symptoms in individuals who have CKD. Trial registration ClinicalTrials.gov NCT04961164 . Registered on 14 July 2021

Background: People living with chronic kidney disease (CKD) have identified diet as an important aspect of their life and care. Understanding current consumption patterns in this population, and how they relate to patient perspectives of dietary recommendations, may help identify and design potential dietary intervention strategies in CKD. Objective: To investigate the dietary intake patterns of people with advanced-stage CKD, as well as subjective perspectives regarding dietary recommendations from participants and their caregivers. Design: Mixed-methods study with a sequential explanatory design. Setting: Manitoba, Canada. Participants: Individuals with late-stage CKD (CKD stages G4-G5, including dialysis) participating in the Canadian Frailty Observation and Interventions Trial (CanFIT). Methods: First, quantitative data were collected via a cross-sectional dietary assessment, using three 24-hour dietary recalls, a 36-question short diet questionnaire (SDQ), and a Nutrition Quality of Life (NQoL) tool (n = 59). Second, qualitative data were collected during 2 focus groups ( n 1 = 12 and n 2 = 7) held with a subsample of individuals who had completed the dietary surveys, along with their caregivers. Focus groups explored topics related to diet and CKD; transcribed data were analyzed thematically. In the interpretation stage, the qualitative findings were combined with the quantitative results to help explain the latter and reach a deeper understanding of the subjective experiences of adults with CKD. Results: Quantitatively, nearly all (48/51; 94%) participants (mean age 70.8 ± 10.8 years) reported energy intakes below recommendations and most (86%) did not achieve recommended fiber intake. In addition, 15/21 (71%) of patients on dialysis had low protein intake. Qualitatively, 2 themes were identified: (1) Lacking/Needing dietary guidance—incomplete “information overload,” and (2) Experiencing difficulty in adapting to restrictions. Within the former theme, participants spoke of getting too much information at once, often at the wrong time. Within the latter theme, participants spoke of a loss of appetite, and cheating on their dietary recommendations. Limitations: Potential recall bias recalling dietary patterns, small sample size limiting generalizability, self-selection bias. Conclusion: Despite the reported lifestyle changes made by individuals with CKD, which negatively impacted their lives, many had suboptimal nutrition, especially in terms of energy and fiber. In addition, those on dialysis were not eating enough protein, which could be due to changing dietary recommendations as CKD progresses. Qualitative findings provided additional insight into how requisite CKD-dietary changes were perceived and how participants coped with these changes. The timing and delivery of the dietary education within CKD care in Manitoba may not be working for people with CKD as they progress through the disease.

La fístula colecistocolónica (FCC) es la segunda fístula colecistoentérica más común, asociada en la mayoría de los casos a enfermedad litiásica. Los síntomas suelen ser mínimos o inespecíficos, siendo infrecuente su diagnóstico preoperatorio. Si bien la incidencia de FCC causada por cáncer de vesícula biliar comprende el 1,7 % de los casos, es necesario sospecharla para adoptar la mejor estrategia terapéutica.

Purpose: A descriptive qualitative study was conducted to explore perceptions and experiences related to pelvic health in the postpartum period among a cohort of women residing in communities with less than 50,000 residents. Methods: A semi-structured interview approach guided by the Theory of Planned Behavior was used. Postpartum individuals (

In order to fulfil the special requirements of antigen-specific activation and communication with other immune cells, B lymphocytes require finely regulated endosomal vesicle trafficking. How the endosomal machinery is regulated in B cells remains largely unexplored. In our previous proximity proteomic screen, we identified the SNARE protein Vti1b as one of the strongest candidates getting accumulated to the sites of early BCR activation. In this report, we follow up on this finding and investigate the localisation and function of Vti1b in B cells. We found that GFP-fused Vti1b was concentrated at the Golgi complex, around the MTOC, as well as in the Rab7+ lysosomal vesicles in the cell periphery. Upon BCR activation with soluble antigen, Vti1b showed partial localization to the internalized antigen vesicles, especially in the periphery of the cell. Moreover, upon BCR activation using surface-bound antigen, Vti1b polarised to the immunological synapse, colocalising with the Golgi complex, and with lysosomes at actin foci. To test for a functional role of Vti1b in early B cell activation, we used primary B cells isolated from Vit1b-deficient mouse. However, we found no functional defects in BCR signalling, immunological synapse formation, or processing and presentation of the internalized antigen, suggesting that the loss of Vti1b in B cells could be compensated by its close homologue Vti1a or other SNAREs.

This paper presents the fabrication and characterization of a biaxial MEMS (MicroElectroMechanical System) scanner based on PZT (Lead Zirconate Titanate) which incorporates a low-absorption dielectric multilayer coating, i.e., a Bragg reflector. These 2 mm square MEMS mirrors, developed on 8-inch silicon wafers using VLSI (Very Large Scale Integration) technology are intended for long-range (>100 m) LIDAR (LIght Detection And Ranging) applications using a 2 W (average power) pulsed laser at 1550 nm. For this laser power, the use of a standard metal reflector leads to damaging overheating. To solve this problem, we have developed and optimised a physical sputtering (PVD) Bragg reflector deposition process compatible with our sol-gel piezoelectric motor. Experimental absorption measurements, performed at 1550 nm and show up to 24 times lower incident power absorption than the best metallic reflective coating (Au). Furthermore, we validated that the characteristics of the PZT, as well as the performance of the Bragg mirrors in terms of optical scanning angles, were identical to those of the Au reflector. These results open up the possibility of increasing the laser power beyond 2W for LIDAR applications or other applications requiring high optical power. Finally, a packaged 2D scanner was integrated into a LIDAR system and three-dimensional point cloud images were obtained, demonstrating the scanning stability and operability of these 2D MEMS mirrors.

Building blocks with amine functionality are crucial in the chemical industry. Biocatalytic syntheses and chemicals derived from renewable resources are increasingly desired to achieve sustainable production of these amines. As a result, renewable materials such as furfurals, especially furfurylamines like 5-(hydroxymethyl)furfurylamine (HMFA) and 2,5-di(aminomethyl)furan (DAF), are gaining increasing attention. In this study, we identified four different amine transaminases (ATAs) that catalyze the reductive amination of 5-(hydroxymethyl)furfural (HMF) and 2,5-diformylfuran (DFF). We successfully immobilized these ATAs on glutaraldehyde-functionalized amine beads using multiple binding and on amine beads by site-selective binding of the unique Cα-formylglycine within an aldehyde tag. All immobilized ATAs were efficiently reused in five repetitive cycles of reductive amination of HMF with alanine as co-substrate, while the ATA from Silicibacter pomeroyi (ATA-Spo) also exhibited high stability for reuse when isopropylamine was used as an amine donor. Additionally, immobilized ATA-Spo yielded high conversion in the batch syntheses of HMFA and DAF using alanine (87% and 87%, respectively) or isopropylamine (99% and 98%, respectively) as amine donors. We further demonstrated that ATA-Spo was effective for the reductive amination of HMF with alanine or isopropylamine in continuous-flow catalysis with high conversion up to 12 days (48% and 41%, respectively).

Abstract Background Obesity has become a major driver in the burden of chronic diseases. The Canadian Clinical Practice Guidelines recommend a lifestyle intervention for the management and prevention of obesity. This includes behavior modification, dietary counseling, and physical activity. With the market overwhelmed with weight loss programs, the majority are focused on low-calorie diets and general recommendations for exercise. Most are not personalized and are not administered by healthcare professionals. An interdisciplinary team of highly trained healthcare professionals has the ability to provide medically sound and safe advice in all aspects of an individuals’ life, such as lifestyle, sleep, mental health, and behaviors. A clinically managed weight loss program is defined as a team including a dietitian, exercise professional, psychologist, and/or physician or nurse practitioner oversight. With limiting results in the literature regarding clinically managed weight loss programs, it is difficult to conclude whether it may be effective. Therefore, the objective of this systematic review is to assess clinically managed weight loss programs, with a physician or nurse practitioner oversight in comparison with non-clinically managed weight loss programs with no physician oversight or nurse practitioner oversight in adults who are living with overweight or obesity. Methods A literature search will be executed by a knowledge synthesis librarian on MEDLINE, Cochrane Central, Embase, PsycINFO, and CINAHL. The data collected will be extracted, stored, and managed in MS Excel 2016. The extraction of the data will include study details, study population details, health team details, intervention details, and outcome details. Discussion The prevalence of obesity has been increasing throughout the decades. The results from this systematic review may aid in recommending a more clinically safe weight loss program for those who struggle with overweight or obesity. Systematic review registration PROSPERO CRD42020170014

Background: Resistant starches (RSs) are not digested by human digestive enzymes and pass through the upper digestive tract to become substrates for colonic bacteria. Resistant starch supplementation has shown promising results in altering the microbiota of animal models of chronic kidney disease (CKD). Resistant starch consumption may influence the production of uremic toxins in CKD. Objective: To conduct a systematic review to determine whether the consumption of RS reduces the progression of kidney disease in adult patients with CKD. Design: We included randomized controlled trials comparing RS supplementation to placebo, no treatment, or standard care. Cochrane Central, Embase, MEDLINE, Web of Science, and CINAHL databases were searched. There was no limitation on publication date, but only English manuscripts were included. The search was conducted in July 2020. Patients: Adult outpatient populations with CKD, using any recognized diagnostic criteria. Measurements: The primary outcome was change in glomerular filtration rate (GFR) from baseline through the end of the trial in patients not on dialysis; secondary outcomes included change in uremic toxin concentrations (p-cresol/p-cresyl sulfate [p-CS], indoxyl sulfate [IS]) and inflammatory markers (tumor necrosis factor alpha [TNF-α], C-reactive protein [CRP], interleukin 6 [IL-6]) from baseline through the end of the trial, and changes in self-reported symptom scores. Methods: The Cochrane Collaboration Risk of Bias tool was used to assess risk of bias in included studies. The systematic review results are reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Results: We identified 4 unique studies, reported in 9 publications that met our inclusion criteria, including a total of 215 enrolled participants. Results were calculated using data from the longest reported follow-up time. The primary outcome of changes in kidney function markers was only studied in 1 trial; this trial reported an increase in creatinine and a decrease in blood urea nitrogen; no changes in GFR were reported. A review of the secondary outcomes showed an overall decline in IS, TNF-α, and IL-6, in RS groups, but with mixed results in p-CS and CRP/high-sensitivity CRP. Safety data showed that RS was well tolerated with no reports of excessive side effects. Limitations: We determined a meta-analysis was not feasible due to clinical heterogeneity between study populations and differences in reported outcomes in the included studies. Conclusion: There is limited and inconsistent evidence on the impact of RS in adult patients with CKD. Further research is needed to determine the safety and efficacy of RS supplementation in this population.

Pancreatic islets are highly vascularized micro-organs ensuring whole body glucose homeostasis. Islet vascular cells play an integral part in sustaining adequate insulin release by beta cells. In particular, recent studies have demonstrated that islet pericytes regulate local blood flow velocity and are required for maintenance of beta cell maturity and function. In addition, increased metabolic demand accompanying obesity alters islet pericyte morphology. Here, we sought to explore the effects of metabolic stress on islet pericyte functional response to stimulation in a mouse model of type 2 diabetes, directly in the pancreas in vivo . We found that high fat diet induced islet pericyte hypertrophy without alterations in basal local blood flow. However, optogenetic stimulation of pericyte activity revealed impaired islet vascular responses, despite increased expression of genes encoding proteins directly or indirectly involved in cell contraction. These findings suggest that metabolic stress impinges upon islet pericyte function, which may contribute to beta cell failure during T2D.

Antibodies plays critical roles in the adaptive immune response to infectious agents including malaria. Here the authors defined antibody interactions with -Fcγ-receptors expressed on immune cells with sporozoites of Plasmodium falciparum, and identified specific target epitopes of antibodies.

Thorough understanding of the role of CD4 T cells in immunity can be greatly assisted by the study of responses to defined specificities. This requires knowledge of Plasmodium-derived immunogenic epitopes, of which only a few have been identified, especially for the mouse C57BL/6 background. We recently developed a TCR transgenic mouse line, termed PbT-II, that produces CD4+ T cells specific for an MHC class II (I-Ab)-restricted Plasmodium epitope and is responsive to both sporozoites and blood-stage P. berghei. Here, we identify a peptide within the P. berghei heat shock protein 90 as the cognate epitope recognised by PbT-II cells. We show that C57BL/6 mice infected with P. berghei blood-stage induce an endogenous CD4 T cell response specific for this epitope, indicating cells of similar specificity to PbT-II cells are present in the naïve repertoire. Adoptive transfer of in vitro activated TH1-, or particularly TH2-polarised PbT-II cells improved control of P. berghei parasitemia in C57BL/6 mice and drastically reduced the onset of experimental cerebral malaria. Our results identify a versatile, potentially protective MHC-II restricted epitope useful for exploration of CD4 T cell-mediated immunity and vaccination strategies against malaria.

We document and evaluate the aerosol schemes as implemented in the physical and Earth system models, the Global Coupled 3.1 configuration of the Hadley Centre Global Environment Model version 3 (HadGEM3-GC3.1) and the United Kingdom Earth System Model (UKESM1), which are contributing to the sixth Coupled Model Intercomparison Project (CMIP6). The simulation of aerosols in the present-day period of the historical ensemble of these models is evaluated against a range of observations. Updates to the aerosol microphysics scheme are documented as well as differences in the aerosol representation between the physical and Earth system configurations. The additional Earth system interactions included in UKESM1 lead to differences in the emissions of natural aerosol sources such as dimethyl sulfide, mineral dust and organic aerosol and subsequent evolution of these species in the model. UKESM1 also includes a stratospheric–tropospheric chemistry scheme which is fully coupled to the aerosol scheme, while GC3.1 employs a simplified aerosol chemistry mechanism driven by prescribed monthly climatologies of the relevant oxidants. Overall, the simulated speciated aerosol mass concentrations compare reasonably well with observations. Both models capture the negative trend in sulfate aerosol concentrations over Europe and the eastern United States of America (US) although the models tend to underestimate sulfate concentrations in both regions. Interactive emissions of biogenic volatile organic compounds in UKESM1 lead to an improved agreement of organic aerosol over the US. Simulated dust burdens are similar in both models despite a 2-fold difference in dust emissions. Aerosol optical depth is biased low in dust source and outflow regions but performs well in other regions compared to a number of satellite and ground-based retrievals of aerosol optical depth. Simulated aerosol number concentrations are generally within a factor of 2 of the observations, with both models tending to overestimate number concentrations over remote ocean regions, apart from at high latitudes, and underestimate over Northern Hemisphere continents. Finally, a new primary marine organic aerosol source is implemented in UKESM1 for the first time. The impact of this new aerosol source is evaluated. Over the pristine Southern Ocean, it is found to improve the seasonal cycle of organic aerosol mass and cloud droplet number concentrations relative to GC3.1 although underestimations in cloud droplet number concentrations remain. This paper provides a useful characterisation of the aerosol climatology in both models and will facilitate understanding in the numerous aerosol–climate interaction studies that will be conducted as part of CMIP6 and beyond.

Abstract Background Primary hypertension accounts for almost 95% of all cases of high blood pressure and is a major modifiable risk factor for cardiovascular diseases. Lifestyle interventions have been shown to prevent hypertension. One of the prominent potential therapeutic lifestyle strategies to prevent or manage hypertension is increasing dietary protein as a macronutrient or as bioactive peptides. An emerging plant-based protein source that may have anti-hypertensive properties is hemp seed. Methods/design A randomized, double-blind, crossover clinical trial will be conducted on 35 hypertensive participants aged 18–75 years, with a BMI between 18.5 and 40 kg/m2, systolic blood pressure (SBP) between 130 and 160 mmHg and diastolic blood pressure (DBP) ≤ 110 mmHg. The trial will be conducted for a period of 22 weeks and will consist of three treatment periods of 6 weeks, separated by 2-week washout periods. The treatments will be consumed twice a day and consist of 25 g casein, hemp seed protein (HSP), or HSP plus HSP hydrolysate (HSP+). The primary outcome of this trial is 24-h SBP, measured on the first day of first phase and the last day of each phase. Office-measured blood pressure, pulse-wave velocity and augmentation index and anthropometrics will be determined at the first and last days of each period. Also, body composition will be assessed by dual x-ray absorptiometry (DXA) scan on the first day of the first phase and within the last 2 days of each treatment period. Blood samples will be collected on the first and last 2 days of each treatment phase whereas urine samples will be collected on the first day of the first phase plus the last day of each phase to be analyzed for specific biomarkers. Discussion This trial protocol is designed to evaluate the hypotensive potential of consuming whole HSP, and HSP+, in comparison to casein protein. This study will be the first trial investigating the potential anti-hypertensive benefit of dietary hemp protein plus bioactive peptide consumption in humans. Trial registration National Clinical Trial (NCT), ID: NCT03508895 . Registered on 28 June 2018. Retrospectively registered on the publicly accessible Registry Databank at ClinicalTrials.gov ( http://ClinicalTrials.gov ).

The ECRH system formerly used in Tore Supra is being upgraded to start on WEST in 2023, at a power level of 1MW and frequency of 105 GHz. Its ultimate 3MW/1000s capability is expected to enlarge the WEST operational domain by increasing margins with respect to H-mode access, and by providing additional flexibility in terms of achievable scenarios using impurity and/or MHD control. This flexibility is made possible using an antenna based on three steerable mirrors for controlled power injection. In order to determine an appropriate range of EC wave injection angles for WEST scenarios, the fast and reliable ray-tracing code REMA has been interfaced with the WEST IMAS database. This allows the EC power damping rate to be quickly assessed, as well as deposition profiles to be predicted in realistic plasma conditions. Based on a typical WEST discharge at central magnetic field B0~3.6 T, central line-averaged electron density nl~4 × 1019 m−3 and central electron temperature Te0~3keV, ray-tracing calculations have been performed. Comprehensive poloidal and toroidal angle scans, as well as variations of Bt, nl and Te0 with respect to the reference parameters have allowed an adequate range of injection angles to be determined for efficient use of ECRH and/or ECCD in typical WEST scenarios, and compared with the mechanical limits set by the antenna mechanical characteristics. In order to further characterize the effect of this new power source in WEST scenarios, EC wave deposition and current profiles from ray-tracing calculations have been included in integrated simulation codes. It has been shown that this additional power source could allow central electron heating to be achieved, potentially alleviating the issue of radiative collapse caused by impurities observed in some situations.

Biocatalytic syntheses often require unfavorable conditions, which can adversely affect enzyme stability. Consequently, improving the stability of biocatalysts is needed, and this is often achieved by immobilization. In this study, we aimed to compare the stability of soluble and immobilized transaminases from different species. A cysteine in a consensus sequence was converted to a single aldehyde by the formylglycine-generating enzyme for directed single-point attachment to amine beads. This immobilization was compared to cross-linked enzyme aggregates (CLEAs) and multipoint attachments to glutaraldehyde-functionalized amine- and epoxy-beads. Subsequently, the reactivity and stability (i.e., thermal, storage, and solvent stability) of all soluble and immobilized transaminases were analyzed and compared under different conditions. The effect of immobilization was highly dependent on the type of enzyme, the immobilization strategy, and the application itself, with no superior immobilization technique identified. Immobilization of HAGA-beads often resulted in the highest activities of up to 62 U/g beads, and amine beads were best for the hexameric transaminase from Luminiphilus syltensis. Furthermore, the immobilization of transaminases enabled its reusability for at least 10 cycles, while maintaining full or high activity. Upscaled kinetic resolutions (partially performed in a SpinChemTM reactor) resulted in a high conversion, maintained enantioselectivity, and high product yields, demonstrating their applicability.

Abstract Tropospheric aerosol radiative forcing has persisted for many years as one of the major causes of uncertainty in global climate model simulations. To sample the range of plausible aerosol and atmospheric states and perform robust statistical analyses of the radiative forcing, it is important to account for the combined effects of many sources of model uncertainty, which is rarely done due to the high computational cost. This paper describes the designs of two ensembles of the Met Office Hadley Centre Global Environment Model‐U.K. Chemistry and Aerosol global climate model and provides the first analyses of the uncertainties in aerosol radiative forcing and their causes. The first ensemble was designed to comprehensively sample uncertainty in the aerosol state, while the other samples additional uncertainties in the physical model related to clouds, humidity, and radiation, thereby allowing an analysis of uncertainty in the aerosol effective radiative forcing. Each ensemble consists of around 200 simulations of the preindustrial and present‐day atmospheres. The uncertainty in aerosol radiative forcing in our ensembles is comparable to the range of estimates from multimodel intercomparison projects. The mean aerosol effective radiative forcing is −1.45 W/m2 (credible interval of −2.07 to −0.81 W/m2), which encompasses but is more negative than the −1.17 W/m2 in the 2013 Atmospheric Chemistry and Climate Model Intercomparison Project and −0.90 W/m2 in the Intergovernmental Panel on Climate Change Fifth Assessment Report. The ensembles can be used to reduce aerosol radiative forcing uncertainty by challenging them with multiple measurements as well as to isolate potential causes of multimodel differences.

BackgroundInterventions that focus on the self-management of heart failure are vital to promoting health in patients with heart failure. Mobile health (mHealth) apps are becoming more integrated into practice to promote self-management strategies for chronic diseases, optimize care delivery, and reduce health disparities. ObjectiveThe purpose of this study was to explore the experience of using a self-management mHealth intervention in individuals with heart failure to inform a future mHealth intervention study. MethodsThis study used a qualitative descriptive design. Participants were enrolled in the intervention groups of a larger parent study using a mobile app related to self-management of heart failure. The purposive, convenient, criterion-based sample for this qualitative analysis comprised 10 patients who responded to phone calls and were willing to be interviewed. Inclusion criteria for the parent study were adults who were hospitalized at Nebraska Medical Center with a primary diagnosis and an episode of acute decompensated heart failure; discharged to home without services such as home health care; had access to a mobile phone; and were able to speak, hear, and understand English. ResultsStudy participants were middle-aged (mean age 55.8, SD 12 years; range 36-73 years). They had completed a mean of 13.5 (SD 2.2) years (range 11-17 years) of education. Of the 10 participants, 6 (60%) were male. Half of them (5/10, 50%) were New York Heart Association Classification Class III patients and the other half were Class IV patients. The intervention revealed four self-management themes, including (1) I didn’t realize, and now I know; (2) It feels good to focus on my health; (3) I am the leader of my health care team; and (4) My health is improving. ConclusionsParticipants who used a self-management mHealth app intervention for heart failure reported an overall positive experience. Their statements were organized into four major themes. The education provided during the study increased self-awareness and promoted self-management of their heart failure. The mHealth app supported patient empowerment, resulting in better heart failure management and improved quality of life. Participants advocated for themselves by becoming the leader of their health, especially when communicating with their health care team. Finally, the mHealth app was used by the participants as a self-management tool to assist in symptom management and improve their overall health. Future research should study symptom evaluation, medication tracking, and possibly serve as a health provider communication platform to empower individuals to be leaders in their chronic disease management.

Abstract l‐amino acid oxidases (LAAOs) catalyze the oxidative deamination of l‐amino acids to corresponding α‐keto acids. Here, we describe the heterologous expression of four fungal LAAOs in Pichia pastoris. cgLAAO1 from Colletotrichum gloeosporioides and ncLAAO1 from Neurospora crassa were able to convert substrates not recognized by recombinant 9His‐hcLAAO4 from the fungus Hebeloma cylindrosporum described earlier thereby broadening the substrate spectrum for potential applications. 9His‐frLAAO1 from Fibroporia radiculosa and 9His‐laLAAO2 from Laccaria amethystine were obtained only in low amounts. All four enzymes were N‐glycosylated. We generated mutants of 9His‐hcLAAO4 lacking N‐glycosylation sites to further understand the effects of N‐glycosylation. All four predicted N‐glycosylation sites were glycosylated in 9His‐hcLAAO4 expressed in P. pastoris. Enzymatic activity was similar for fully glycosylated 9His‐hcLAAO4 and variants without one or all N‐glycosylation sites after acid activation of all samples. However, activity without acid treatment was low in a variant without N‐glycans. This was caused by the absence of a hypermannosylated N‐glycan on asparagine residue N54. The lack of one or all of the other N‐glycans was without effect. Our results demonstrate that adoption of a more active conformation requires a specific N‐glycosylation during biosynthesis.

Objectives: The COVID-19 pandemic has caused considerable stress throughout the world. Little is known about how postpartum women who gave birth during the early months of the pandemic were impacted. The purpose of this study was to explore and describe the associations between potential risk, protective factors, and psychological distress among postpartum women who gave birth during the early months of the COVID-19 pandemic. Methods: Postpartum women over the age of 18 years who gave birth in the US hospitals between March and July of 2020 and spoke English completed a survey about their experiences. Demographic and health variables were measured via self-report. Stress was measured using the Perceived Stress Scale-10. Mastery was measured with the Pearlin Mastery Scale. Resilience was measured with the Connor–Davidson Resilience Scale-2. Results: This study included 885 women. Participants had higher stress and lower resilience relative to pre-pandemic norms. Participants had high levels of depression, anxiety, and stress. Women who had an infant admitted to the neonatal intensive care unit had more stress. Income, full-time employment, and partnered relationships were associated with lower stress. Resilience and mastery were related to lower stress, depression, and anxiety. Black, Indigenous, or People of Color women showed higher stress and lower resiliency. Single women were likely to report lower levels of mastery than partnered women. Conclusion: Stress, depression, and anxiety were high in postpartum women in this study. Income, partnered relationships, and employment security, along with protective traits such as mastery and resilience, may reduce the impact of stress on postpartum women in a pandemic. Care models should be modified to support women during a pandemic. Health disparities exist in postpartum stress. Future interventions should focus on building resiliency and mastery and ensuring appropriate resources are available to postpartum women in a pandemic.

Climate models predict that plants will face extreme fluctuations in water availability in future global change scenarios. Then, forage production will be more frequently subjected to the destabilizing pressure of sequentially occurring waterlogging and drought events. While the isolated effects of drought (D) and waterlogging (WL) are well characterized, little is known about the consequences when both stresses occur sequentially. We hypothesized that plants sequentially subjected to opposite water scenarios (D followed by WL or vice versa) are less stress tolerant than plants experiencing repetitions of the same type of water stress (i.e., D + D or WL + WL) due to contrasting acclimation and allocation to either shoots (WL) or roots (D). Chloris gayana (a tropical forage grass capable of tolerating either D and WL) plants were randomly assigned to nine treatments (a sequence of two stress rounds—WL or D—each followed by a recovery phase at field capacity). Relative growth rates and allometric responses were measured after each stress round and recovery period. In the first round of stress, both WL and D reduced plant RGR similarly, despite their allocation being opposite—prioritizing shoots or roots under WL and D, respectively. The high recovery displayed after either WL or D overrode any possible acclimation of the plants facing a second round of water stress. We conclude that the tolerance of C. gayana to sequential water stress (either for WL or D) is likely to depend more heavily on its recovery ability than on its previous adjustment to any stress scenario that may evoke memory responses. Knowledge like this could help improve forage grass breeding and the selection of cultivars for poorly drained soils subject to sequential stress events.

Abstract Background In multicellular organisms, alternative splicing is central to tissue differentiation and identity. Unicellular protists lack multicellular tissue but differentiate into variable cell types during their life cycles. The role of alternative splicing in transitions between cell types and establishing cellular identity is currently unknown in any unicellular organism. Results To test whether alternative splicing in unicellular protists plays a role in cellular differentiation, we conduct RNA-seq to compare splicing in female and male sexual stages to asexual intraerythrocytic stages in the rodent malaria parasite Plasmodium berghei. We find extensive changes in alternative splicing between stages and a role for alternative splicing in sexual differentiation. Previously, general gametocyte differentiation was shown to be modulated by specific transcription factors. Here, we show that alternative splicing establishes a subsequent layer of regulation, controlling genes relating to consequent sex-specific differentiation of gametocytes. Conclusions We demonstrate that alternative splicing is reprogrammed during cellular differentiation of a unicellular protist. Disruption of an alternative splicing factor, PbSR-MG, perturbs sex-specific alternative splicing and decreases the ability of the parasites to differentiate into male gametes and oocysts, thereby reducing transmission between vertebrate and insect hosts. Our results reveal alternative splicing as an integral, stage-specific phenomenon in these protists and as a regulator of cellular differentiation that arose early in eukaryotic evolution.

Summary: GABAergic interneurons migrate long distances through stereotyped migration programs toward specific laminar positions. During their migration, GABAergic interneurons are morphologically alike but then differentiate into a rich array of interneuron subtypes critical for brain function. How interneuron subtypes acquire their final phenotypic traits remains largely unknown. Here, we show that cerebellar molecular layer GABAergic interneurons, derived from the same progenitor pool, use separate migration paths to reach their laminar position and differentiate into distinct basket cell (BC) and stellate cell (SC) GABAergic interneuron subtypes. Using two-photon live imaging, we find that SC final laminar position requires an extra step of tangential migration supported by a subpopulation of glutamatergic granule cells (GCs). Conditional depletion of GCs affects SC differentiation but does not affect BCs. Our results reveal how timely feedforward control of inhibitory interneuron migration path regulates their terminal differentiation and, thus, establishment of the local inhibitory circuit assembly.

The purpose of this study was to describe the experiences of women who gave birth in a US hospital during the COVID-19 pandemic. Women who gave birth between March and July 2020 completed a survey on the experience of giving birth during a pandemic. Of this, 885 women were consented and participated in the study; 22.5% of women reported hypertension, 33.8% reported anxiety, 18.6% reported depression, and 1.13% reported testing positive for COVID-19. Of this, 61% of women reported inadequate support for childbirth, and 20.5% reported that they did not feel safe giving birth in the hospital. Women who tested positive for COVID-19 were more likely to be of Asian race, have a cesarean delivery, not have a birth partner present, and discontinue breastfeeding before 6 weeks. Pandemic-related changes to maternity care practices may have impacted birthing women’s perceptions of safety and support in the hospital environment and affected symptoms of stress. Health care policy and maternity care practices should promote feelings of safety and control and overall experience for women giving birth in the hospital during a pandemic.

In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2+ stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2+ PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2+ PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.

Translating satellite imagery into maps requires intensive effort and time, especially leading to inaccurate maps of the affected regions during disaster and conflict. The combination of availability of recent datasets and advances in computer vision made through deep learning paved the way toward automated satellite image translation. To facilitate research in this direction, we introduce the Satellite Imagery Competition using a modified SpaceNet dataset. Participants had to come up with different segmentation models to detect positions of buildings on satellite images. In this work, we present five approaches based on improvements of U-Net and Mask R-Convolutional Neuronal Networks models, coupled with unique training adaptations using boosting algorithms, morphological filter, Conditional Random Fields and custom losses. The good results—as high as AP=0.937 and AR=0.959—from these models demonstrate the feasibility of Deep Learning in automated satellite image annotation.

Abstract l‐amino acid oxidases (LAAOs) are flavoenzymes that catalyze the oxidative deamination of l‐amino acids to the corresponding α‐keto acids, ammonia, and hydrogen peroxide. Here, we show the overexpression, purification, and the characterization of LAAO4 from the fungus Hebeloma cylindrosporum in the yeast Pichia pastoris with a 9His‐tag and compare this with the recently characterized 6His‐hcLAAO4 expressed in E. coli. The expression of the enzyme with an ER‐signal sequence in P. pastoris resulted in a glycosylated, secreted protein. The enzymatic activity without activation was higher after expression in P. pastoris compared to E. coli. Due to treatment with acidic pH, a striking increase of activity could be detected for both expression systems resulting in similar specific activities after acid activation. Regarding the substrate spectrum, temperature stability, Km, and vmax values, hcLAAO4 showed very few differences when produced in these two expression systems. A higher yield of hcLAAO4 could be obtained by fermentation.

Magma ascending from the storage region toward the surface may crystallize small and rapidly-grown crystals, designated as microlites. Upon decompression, the rapid changes of the microlite textures, such as number density and crystal size, directly impact the rheology of the magma in the volcanic conduit, and eventually control the effusive vs. explosive style of the subaerial eruption. This is of prime importance for volcanic risk assessment involving highly viscous silica-rich magmas that are prone to fragmentation. To this aim, we present a theoretical modeling of plagioclase nucleation and growth in rhyolitic-like melts, based on previous decompression experiments. Thus, the modeling is valid for plagioclase crystallization in rhyolitic melts decompressed at 875°C from 200 MPa to final pressures of 50, 75, or 100 MPa, which represents effective undercooling (ΔTeff) of 110, 80 and 55°C, respectively. Our results of nucleation-rate calculation using the Classical Nucleation Theory (CNT; case of homogeneous nucleation) and values of crystal-melt interfacial energy (σ) either from literature or empirically calculated, strongly disagree with previously-determined experimental nucleation rates. By inverting the CNT calculation using the experimentally-determined nucleation rates, we propose plagioclase-liquid interfacial energies from 0.041 to 0.059 J.m−2 with ΔTeff increasing from 55 to 110°C, which is about 2–3 times lower than σ determined empirically and macroscopically. We modeled plagioclase growth rates by atom diffusion in melt (following Fick's second law adapted to multicomponent systems), considering a crystal-melt interface advancing over time (as crystal grows) and a chemically-closed finite reservoir (no component supply). The component limiting plagioclase growth has been determined to be CaO, for which we calculated diffusion coefficients from 10−14 to 10−15 m2/s (conditions of a silicic melt, 875°C, and H2O saturation pressures from 50 to 100 MPa). The overall good agreement between the model and the experimental growth laws validates diffusion as the main process controlling isothermal decompression-induced plagioclase growth under moderate ΔTeff < 110°C. Combining both calculations, crystal number density and size, may be relevant to predict plagioclase microlite textures in ascending rhyolitic magmas, which may now be incorporated in conduit flow models to assess the magma rheological behavior that controls eruption dynamics.