A maternal brain hormone that builds bone.

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

Increasing acceptance of AI-generated digital twins through clinical trial applications.

Today's approach to medicine requires extensive trial and error to determine the proper treatment path for each patient. While many fields have benefited from technological breakthroughs in computer science, such as artificial intelligence (AI), the task of developing effective treatments is actually getting slower and more costly. With the increased availability of rich historical datasets from previous clinical trials and real-world data sources, one can leverage AI models to create holistic forecasts of future health outcomes for an individual patient in the form of an AI-generated digital twin. This could support the rapid evaluation of intervention strategies in silico and could eventually be implemented in clinical practice to make personalized medicine a reality. In this work, we focus on uses for AI-generated digital twins of clinical trial participants and contend that the regulatory outlook for this technology within drug development makes it an ideal setting for the safe application of AI-generated digital twins in healthcare. With continued research and growing regulatory acceptance, this path will serve to increase trust in this technology and provide momentum for the widespread adoption of AI-generated digital twins in clinical practice.

Investigating the lignocellulolytic gut microbiome of huhu grubs (Prionoplus reticularis) using defined diets and dietary switch.

The huhu beetle (Prionoplus reticularis) is the largest endemic beetle found throughout Aotearoa New Zealand, and is characterised by feeding on wood during its larval stage. It has been hypothesised that its gut microbiome plays a fundamental role in the degradation of wood. To explore this idea we examined the fungal and bacterial community composition of huhu grubs' frass, using amplicon sequencing. Grubs were reared on an exclusive diet of either a predominantly cellulose source (cotton) or lignocellulose source (pine) for 4 months; subsequently a diet switch was performed and the grubs were grown for another 4 months. The fungal community of cellulose-reared huhu grubs was abundant in potential cellulose degraders, contrasting with the community of lignocellulose-reared grubs, which showed abundant potential soft rot fungi, yeasts, and hemicellulose and cellulose degraders. Cellulose-reared grubs showed a less diverse fungal community, however, diet switch from cellulose to lignocellulose resulted in a change in community composition that showed grubs were still capable of utilising this substrate. Conversely, diet seemed to have a limited influence on huhu grub gut bacterial communities.

Soils of two Antarctic Dry Valleys exhibit unique microbial community structures in response to similar environmental disturbances.

BACKGROUND: Isolating the effects of deterministic variables (e.g., physicochemical conditions) on soil microbial communities from those of neutral processes (e.g., dispersal) remains a major challenge in microbial ecology. In this study, we disturbed soil microbial communities of two McMurdo Dry Valleys of Antarctica exhibiting distinct microbial biogeographic patterns, both devoid of aboveground biota and different in macro- and micro-physicochemical conditions. We modified the availability of water, nitrogen, carbon, copper ions, and sodium chloride salts in a laboratory-based experiment and monitored the microbial communities for up to two months. Our aim was to mimic a likely scenario in the near future, in which similar selective pressures will be applied to both valleys. We hypothesized that, given their unique microbial communities, the two valleys would select for different microbial populations when subjected to the same disturbances. RESULTS: The two soil microbial communities, subjected to the same disturbances, did not respond similarly as reflected in both 16S rRNA genes and transcripts. Turnover of the two microbial communities showed a contrasting response to the same environmental disturbances and revealed different potentials for adaptation to change. These results suggest that the heterogeneity between these microbial communities, reflected in their strong biogeographic patterns, was maintained even when subjected to the same selective pressure and that the 'rare biosphere', at least in these samples, were deeply divergent and did not act as a reservoir for microbiota that enabled convergent responses to change in environmental conditions. CONCLUSIONS: Our findings strongly support the occurrence of endemic microbial communities that show a structural resilience to environmental disturbances, spanning a wide range of physicochemical conditions. In the highly arid and nutrient-limited environment of the Dry Valleys, these results provide direct evidence of microbial biogeographic patterns that can shape the communities' response in the face of future environmental changes.

Endohelminth diversity in the invasive Clarias gariepinus (Burchell, 1822) from two freshwater lakes: Naivasha and Ol'Bolossat, Kenya.

Fish parasitology contributes to our understanding of the potential risks posed by diverse groups of parasitic organisms on fish stocks in either wild and culture systems. This study was conducted in May 2023 and aimed at assessing the diversity of endohelminths in the invasive North African catfish Clarias gariepinus (Burchell, 1822) obtained from two freshwater lakes, Naivasha and Ol'Bolossat, in Kenya. Parasitological examination of 66 and 35 fish samples collected from the two lakes respectively was achieved using light and scanning electron microscopy methods. Results revealed endohelminth diversity broadly classified as four digeneans, two nematodes, and one cestode. Seven taxa of endohelminths were found in C. gariepinus samples, but only four of these taxa could be identified up to the species level. Six of the taxa (Diplostomum sp., Tylodelphys mashonense, Plagiorchioidea sp., Paracamallanus cyathopharynx, Contracaecum sp., and Tetracampos ciliotheca) were common in samples from the two lakes. Glossidium pedatum only occurred in samples from Lake Ol'Bolossat. Parasite prevalence ranged from 8.6 (T. mashonense) to 100% (Diplostomum sp., T. ciliotheca, and Contracaecum sp.) and mean intensity from 1.4 (T. mashonense) to 16.9 (Diplostomum sp.). The diversity and richness indices were comparatively higher in fish samples from Lake Ol'Bolossat and attributed to the occurrence of G. pedatum in the Ol'Bolossat. However, parasitic infestation of fish samples from the two lakes depicted close similarity, both in diversity and prevalence. These findings form an important baseline data for further follow-up studies, and they suggest the need for further molecular analyses to fully describe three of the taxa only identified up to the genus level.

Asymmetric allostery in estrogen receptor-α homodimers drives responses to the ensemble of estrogens in the hormonal milieu.

The estrogen receptor-α (ER) is thought to function only as a homodimer but responds to a variety of environmental, metazoan, and therapeutic estrogens at subsaturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations-receptor conformational heterodimers-mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining the binding of the same ligand in crystal structures of ER in the agonist vs. antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist vs. antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from the ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric vs. dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing different modes for ligand-dependent regulation of ER activity.

Knowledge, attitudes and practices of fresh Nile perch value chain handlers towards food safety requirements in Uganda.

In the continuum from 'farm to fork', the proficiency of food handlers in terms of knowledge, attitudes, and practices (KAP) is essential for ensuring improved food safety outcomes. This study evaluated the KAP of fresh Nile perch fish handlers regarding food safety requirements within Uganda. A cross-sectional survey involving fish handlers (n = 466) engaged in handling fresh Nile perch and fisheries products in both local and export market chains. The study was conducted at 30 gazetted fish landing sites on Lake Victoria, 15 licensed fish export factories, and 9 local markets authorized to sell fisheries products. Data on demographic, knowledge, attitude, and practices was collected using structured questionnaire. Demographic data was analysed using frequencies and percentages. Ordinary least squares bivariate and multivariate regression analyses were performed to determine factors associated with knowledge, attitudes, and practices regarding food safety requirements. Fish handlers (49.8 %) demonstrated good knowledge with the majority (74.6 %) from the export market chain. Majority (81.3 %) of market stall handlers had poor knowledge of food safety requirements. Most (68.2 %) fresh Nile perch fish handlers had limited awareness of food-borne pathogens. Only 31.8 % had knowledge about E. coli, Salmonella spp, and Staphylococcus spp. Furthermore, over 63 % believed that consuming contaminated fish could transmit HIV, Covid-19, and Ebola. Male gender, higher income, and advanced education were positively correlated with fish handlers' knowledge of food safety requirements. Fish handlers (57 %) in the local market chain exhibited poor attitudes. Being a male fish handler was significantly (ß = 3.43, 95 % CI: 1.65-5.21, P = 0.001) associated with positive attitudes compared to being female. Education at different levels was significantly (Primary (ß = 3.19, 95 % CI: 1.05-5.33, P = 0.004); Secondary level (ß = 5.883, 95 % CI: 3.52-8.23, P = 0.001); Tertiary (ß = 6.09, 95 % CI: 3.03-9.15, P = 0.001)) associated with positive attitudes compared to no education. Practices ensuring food safety were common in the factories and the export market. The study suggests the need for interventions that promote knowledge transfer and food safety culture, particularly in the local market chain.

Ultrasensitive and multiplexed tracking of single cells using whole-body PET/CT.

In vivo molecular imaging tools are crucially important for elucidating how cells move through complex biological systems; however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upward of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a statistical tracking algorithm (PEPT-EM) to achieve a sensitivity of 4 becquerel per cell and a streamlined workflow to reliably label single cells with over 50 becquerel per cell of 18F-fluorodeoxyglucose (FDG). To demonstrate the potential of the method, we tracked the fate of more than 70 melanoma cells after intracardiac injection and found they primarily arrested in the small capillaries of the pulmonary, musculoskeletal, and digestive organ systems. This study bolsters the evolving potential of PET in offering unmatched insights into the earliest phases of cell trafficking in physiological and pathological processes and in cell-based therapies.

Circadian-Dependent Intermittent Fasting Influences Ischemic Tolerance and Dendritic Spine Remodeling.

BACKGROUND: Preconditioning by intermittent fasting is linked to improved cognition and motor function, and enhanced recovery after stroke. Although the duration of fasting was shown to elicit different levels of neuroprotection after ischemic stroke, the impact of time of fasting with respect to the circadian cycles remains unexplored. METHODS: Cohorts of mice were subjected to a daily 16-hour fast, either during the dark phase (active-phase intermittent fasting) or the light phase (inactive-phase intermittent fasting) or were fed ad libitum. Following a 6-week dietary regimen, mice were subjected to transient focal cerebral ischemia and underwent behavioral functional assessment. Brain samples were collected for RNA sequencing and histopathologic analyses. RESULTS: Active-phase intermittent fasting cohort exhibited better poststroke motor and cognitive recovery as well as reduced infarction, in contrast to inactive-phase intermittent fasting cohort, when compared with ad libitum cohort. In addition, protection of dendritic spine density/morphology and increased expression of postsynaptic density protein-95 were observed in the active-phase intermittent fasting. CONCLUSIONS: These findings indicate that the time of daily fasting is an important factor in inducing ischemic tolerance by intermittent fasting.

Wild herbivores and cattle have differing effects on postfire herbaceous vegetation recovery in an African savanna.

Fire and herbivory have profound effects on vegetation in savanna ecosystems, but little is known about how different herbivore groups influence vegetation dynamics after fire. We assessed the separate and combined effects of herbivory by cattle and wild meso- and megaherbivores on postfire herbaceous vegetation cover, species richness, and species turnover in a savanna ecosystem in central Kenya. We measured these vegetation attributes for five sampling periods (from 2013 to 2017) in prescribed burns and unburned areas located within a series of replicated long-term herbivore exclosures that allow six different combinations of cattle and wild meso- and megaherbivores (elephants and giraffes). Vegetation cover (grasses, mainly) and species richness were initially reduced by burning but recovered by 15-27 months after fire, suggesting strong resilience to infrequent fire. However, the rates of recovery differed in plots accessible by different wild and domestic herbivore guilds. Wildlife (but not cattle) delayed postfire recovery of grasses, and the absence of wildlife (with or without cattle) delayed recovery of forbs. Herbivory by only cattle increased grass species richness in burned relative to unburned areas. Herbivory by cattle (with or without wildlife), however, reduced forb species richness in burned relative to unburned areas. Herbivory by wild ungulates (but not cattle) increased herbaceous species turnover in burned relative to unburned areas. Megaherbivores had negligible modifying effects on these results. This study demonstrates that savanna ecosystems are remarkably resilient to infrequent fires, but postfire grazing by cattle and wild mesoherbivores exerts different effects on recovery trajectories of herbaceous vegetation.

An antioxidant and anti-ER stress combination therapy elevates phosphorylation of α-Syn at serine 129 and alleviates post-TBI PD-like pathology in a sex-specific manner in mice.

Clinical studies have shown that traumatic brain injury (TBI) increases the onset of Parkinson's disease (PD) in later life by >50%. Oxidative stress, endoplasmic reticulum (ER) stress, and inflammation are the major drivers of both TBI and PD pathologies. We presently evaluated if curtailing oxidative stress and ER stress concomitantly using a combination of apocynin and tert-butylhydroquinone and salubrinal during the acute stage after TBI in mice reduces the severity of late-onset PD-like pathology. The effect of multiple low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on post-TBI neurodegeneration was also evaluated. The combo therapy elevated the level of phosphorylation at serine 129 (pS129) of α-Syn in the pericontusional cortex of male mice at 72 h post-TBI. Motor and cognitive deficits induced by TBI lasted at least 3 months and the combo therapy curtailed these deficits in both sexes. At 3 months post-TBI, male mice given combo therapy exhibited significantly lesser α-Syn aggregates in the SN and higher TH+ cells in the SNpc, compared to vehicle control. However, the aggregate number was not significantly different between groups of female mice. Moreover, TBI-induced loss of TH+ cells was negligible in female mice irrespective of treatment. The MPTP treatment aggravated PD-like pathology in male mice but had a negligible effect on the loss of TH+ cells in female mice. Thus, the present study indicates that mitigation of TBI-induced oxidative stress and ER stress at the acute stage could potentially reduce the risk of post-TBI PD-like pathology at least in male mice, plausibly by elevating pS129-α-Syn level.

Asymmetric Allostery in Estrogen Receptor-α Homodimers Drives Responses to the Ensemble of Estrogens in the Hormonal Milieu.

The estrogen receptor-α (ER) is thought to function only as a homodimer, but responds to a variety of environmental, metazoan, and therapeutic estrogens at sub-saturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations -receptor conformational heterodimers-mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining binding of the same ligand in crystal structures of ER in the agonist versus antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist versus antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric versus dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing new modes for ligand-dependent regulation of ER activity. Significance: The estrogen receptor-α (ER) regulates transcription in response to a hormonal milieu that includes low levels of estradiol, a variety of environmental estrogens, as well as ER antagonists such as breast cancer anti-hormonal therapies. While ER has been studied as a homodimer, the variety of ligand and receptor concentrations in different tissues means that the receptor can be occupied with two different ligands, with only one ligand in the dimer, or as a monomer. Here, we use X-ray crystallography and molecular dynamics simulations to reveal a new mode for ligand regulation of ER activity whereby sequence-identical homodimers can act as functional or conformational heterodimers having unique signaling characteristics, with ligand-selective allostery operating across the dimer interface integrating two different signaling outcomes.

Multiscale Finite Element Modeling of Left Ventricular Growth in Simulations of Valve Disease.

Multiscale models of the cardiovascular system are emerging as effective tools for investigating the mechanisms that drive ventricular growth and remodeling. These models can predict how molecular-level mechanisms impact organ-level structure and function and could provide new insights that help improve patient care. MyoFE is a multiscale computer framework that bridges molecular and organ-level mechanisms in a finite element model of the left ventricle that is coupled with the systemic circulation. In this study, we extend MyoFE to include a growth algorithm, based on volumetric growth theory, to simulate concentric growth (wall thickening/thinning) and eccentric growth (chamber dilation/constriction) in response to valvular diseases. Specifically in our model, concentric growth is controlled by time-averaged total stress along the fiber direction over a cardiac cycle while eccentric growth responds to time-averaged intracellular myofiber passive stress over a cardiac cycle. The new framework correctly predicted different forms of growth in response to two types of valvular diseases, namely aortic stenosis and mitral regurgitation. Furthermore, the model predicted that LV size and function are nearly restored (reversal of growth) when the disease-mimicking perturbation was removed in the simulations for each valvular disorder. In conclusion, the simulations suggest that time-averaged total stress along the fiber direction and time-averaged intracellular myofiber passive stress can be used to drive concentric and eccentric growth in simulations of valve disease.

Key to the North American tribes and genera of herb, rose, bramble, and inquiline gall wasps (Hymenoptera, Cynipoidea, Cynipidaesensu lato).

Robust keys exist for the family-level groups of Cynipoidea. However, for most regions of the world, keys to genera are not available. To address this gap as it applies to North America, a fully illustrated key is provided to facilitate identification of the tribes and genera of rose gall, herb gall, and inquiline gall wasps known from the region. For each taxon covered, a preliminary diagnosis and an updated overview of taxonomy, biology, distribution, and natural history are provided.

A survey of severe asthma in Canada: results from the CASCADE practice reflective program.

BACKGROUND: Since the last guidance was published by the Canadian Thoracic Society, there have been several advances in the clinical management of severe asthma. To gain a better understanding of the current standards of care and treatment patterns of patients, the CASCADE practice reflective program was established to conduct a real-world analysis of severe asthma management among specialists in Canada with a goal of identifying areas of opportunity to enhance patient management and outcomes. METHODS: The CASCADE program was a two-part practice reflective and assessment program delivered through an on-line portal for selected specialists (Respirologists and Allergists) in Canada. The program consisted of a one-time overview survey of physician practice to establish overall practice parameters, followed by a review of at least 5 severe asthma patients to establish the current landscape of severe asthma management. RESULTS: The program collected practice overview surveys from 78 specialists (52 Respirologists, 24 Allergists, and 2 General practice physicians with an interest in respiratory disease) in 8 provinces. Practices included a variety of types in both large metropolitan centres and smaller regional settings. There were 503 patients reviewed and included in the program. Most (65%) patients were currently using a biologic treatment, 30% were biologic naive, and 5% had used a biologic treatment in the past. Most patients (53%) were reported to have mixed allergic and eosinophilic phenotypes, despite a perception that allergic, eosinophilic and mixed phenotypes were evenly balanced in the physician practice. Overall, patients currently treated with biologic agents had parameters suggesting higher control and were more satisfied with treatment. However, there was less than optimal treatment satisfaction for more than half of all patients, particularly for those patients not treated with a biologic agent. CONCLUSIONS: Phenotyping is hampered by poor availability for several assessments, and the full range of treatments are not currently fully utilized, partly due to physician familiarity with the agents and partly due to prescribing restrictions. Even when treated with biologic agents, patient satisfaction can still be improved.

Brushing aside doubts: an evaluation of the beat-sheet brushing technique for detecting the Nearctic tree trunk sheetweaver (Araneae: Linyphiidae).

It is important to have reliable information on the presence/absence, population structure, and density of animals across their natural range. Detecting small organisms, however, such as the Nearctic tree trunk sheetweaver spider Drapetisca alteranda Chamberlin 1909 (Araneae: Linyphiidae), presents challenges due to its diminutive size and cryptic nature. We used a capture/recapture study to determine the detection and recapture probabilities of this spider using a standard beat sheet technique adopted for surveying tree trunks. Spiders were released on 3 different tree species that provided a range of microhabitats, including variable bark surface area and furrow depth/width. Microhabitat features played a small role in the timing of spider recapture (i.e., slower rate of recapture as furrowing increased). However, our results demonstrated 100% detection across replicate experiments and individual recapture probabilities exceeding 90% in most situations, with no significant differences in recapture observed among tree species and with respect to tree circumference. Furthermore, we show that most spiders could be recaptured within 2 sampling revolutions around the tree trunk, and there was no difference in the probability of collecting male and female spiders (although they differ markedly in size). Finally, we found no difference among brushers, supporting the idea that this method is replicable across collectors and studies. Collectively, we establish confidence in the ecological knowledge obtained with this technique and encourage its application with similar species and systems.

Non-pharmacological interventions for traumatic brain injury.

Heterogeneity and variability of symptoms due to the type, site, age, sex, and severity of injury make each case of traumatic brain injury (TBI) unique. Considering this, a universal treatment strategy may not be fruitful in managing outcomes after TBI. Most of the pharmacological therapies for TBI aim at modifying a particular pathway or molecular process in the sequelae of secondary injury rather than a holistic approach. On the other hand, non-pharmacological interventions such as hypothermia, hyperbaric oxygen, preconditioning with dietary adaptations, exercise, environmental enrichment, deep brain stimulation, decompressive craniectomy, probiotic use, gene therapy, music therapy, and stem cell therapy can promote healing by modulating multiple neuroprotective mechanisms. In this review, we discussed the major non-pharmacological interventions that are being tested in animal models of TBI as well as in clinical trials. We evaluated the functional outcomes of various interventions with an emphasis on the links between molecular mechanisms and outcomes after TBI.