The mitochondrial multi-omic response to exercise training across rat tissues.

Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.

Three Prospective Case Studies Examining Mifepristone's Efficacy in Patients with Treatment-Resistant PTSD.

Despite the availability of various treatment approaches for patients with posttraumatic stress disorder (PTSD), some patients do not respond to these therapies, and novel treatment approaches are needed. This study investigated the efficacy of mifepristone, a glucocorticoid receptor antagonist, in treatment-resistant PTSD patients. Three patients with PTSD who were resistant to standard psychological and pharmacological treatments were prescribed mifepristone (600-1,200 mg/day) for 1 week. A baseline-controlled single-case design was used, involving a 2-week baseline phase (no intervention), a 1-week intervention phase (mifepristone), and a 2-week postintervention phase. The primary outcome measure, self-reported PTSD symptom severity (PCL-5), was assessed daily, with participants providing their own control condition. Two of the three patients experienced a significant reduction in PTSD symptom severity after the intervention phase and no longer met the diagnostic criteria for PTSD. These positive results were maintained during long-term follow-up. These findings support the potential effectiveness of mifepristone in the treatment of patients with treatment-resistant PTSD. However, our findings must be interpreted with caution, and further studies with larger sample sizes and more rigorous designs are necessary to confirm the promising results.

Distal planar rotary scanner for endoscopic optical coherence tomography.

Optical coherence tomography (OCT) is becoming a more common endoscopic imaging modality for detecting and treating disease given its high resolution and image quality. To use OCT for 3-dimensional imaging of small lumen, embedding an optical scanner at the distal end of an endoscopic probe for circumferential scanning the probing light is a promising way to implement high-quality imaging unachievable with the conventional method of revolving an entire probe. To this end, the present work proposes a hollow and planar micro rotary actuator for its use as an endoscopic distal scanner. A miniaturized design of this ferrofluid-assisted electromagnetic actuator is prototyped to act as a full 360° optical scanner, which is integrated at the tip of a fiber-optic probe together with a gradient-index lens for use with OCT. The scanner is revealed to achieve a notably improved dynamic performance that shows a maximum speed of 6500 rpm, representing 325% of the same reported with the preceding design, while staying below the thermal limit for safe in-vivo use. The scanner is demonstrated to perform real-time OCT using human fingers as live tissue samples for the imaging tests. The acquired images display no shadows from the electrical wires to the scanner, given its hollow architecture that allows the probing light to pass through the actuator body, as well as the quality high enough to differentiate the dermis from the epidermis while resolving individual sweat glands, proving the effectiveness of the prototyped scanner design for endoscopic OCT application.

Evolution of therapeutic management of patients with ANCA associated vasculitis in France after licensing Rituximab use.

INTRODUCTION: In 2013, rituximab was approved in France for the treatment of ANCA-associated vasculitis (AAV). The aim of the study was to compare the treatment and health events of adult incident patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), included before rituximab approval (over 2010-2012, Group 1) and those included after rituximab approval (over 2014-2017, Group 2). METHOD: Data were extracted from the French National Health Insurance database (SNDS) including outpatient health care consumption and hospital discharge forms. Comparisons between inclusion periods were performed using Wilcoxon and χ² tests. Kaplan-Meier method was used to model the duration of treatment induction, maintenance, and off-drug periods. Fine and Gray tests were used to compare treatment phase durations. RESULTS: A total of 694 GPA and 283 MPA patients were included in Group 1, while 668 GPA and 463 MPA patients were included in Group 2. Between the two inclusion periods, the proportions of patients treated with rituximab increased in the induction and maintenance phases whereas treatment with azathioprine declined. These proportions remained stable in the case of methotrexate, cyclophosphamide, and glucocorticoid-treated patients. Frequency of first-time hospitalized infections, diabetes and renal failure during the first year after inclusion increased for both groups. LIMITATIONS OF THE STUDY: This is a retrospective study based on claims data including only 76% of people covered by health insurance in France. The period studied includes the learning phase of using rituximab. This study lacks biological data and precise quantitative analysis for the use of steroids, therefore the criteria for establishing diagnosis and therapeutic choice were unknown. CONCLUSIONS: Introduction of rituximab reduced the use of azathioprine without affecting the use of glucocorticoids or cyclophosphamide.

pyCOFBuilder: A Python Package for Automated Creation of Covalent Organic Framework Models Based on the Reticular Approach.

Covalent organic frameworks (COFs) have gained significant popularity in recent years due to their unique ability to provide a high surface area and customizable pore geometry and chemistry, making them an ideal choice for a wide range of applications. However, exploring COFs experimentally can be arduous and time-consuming due to their immense number of potential structures. As a result, computational high-throughput studies have become an attractive option. Nevertheless, generating COF structures can also be a challenging and time-consuming task. To address this challenge, here, we introduce the pyCOFBuilder, an open-source Python package designed to facilitate the generation of COF structures for computational studies. The pyCOFBuilder software provides an easy-to-use set of functionalities to generate COF structures following the reticular approach. In this paper, we describe the implementation, main features, and capabilities of the pyCOFBuilder, demonstrating its utility for generating COF structures with varying topologies and chemical properties. pyCOFBuilder is freely available on GitHub at https://github.com/lipelopesoliveira/pyCOFBuilder.

Staged breast reconstruction utilizing primary nipple repositioning surgery prior to nipple-sparing mastectomy.

Staged nipple-sparing mastectomy (NSM) following mastopexy or breast reduction has become increasingly utilized in patients with large or ptotic breasts. The safety and efficacy of this approach has been demonstrated in recent years. However, the optimal timing between stages has not been established. The authors provide their experience with this staged approach with emphasis on timing between stages. An institutional review board approved this retrospective study. Data of all patients at a single institution who underwent staged NSM following mastopexy or reduction mammaplasty for therapeutic or prophylactic oncologic surgical management from 2016 to 2020 were reviewed. Timing between stages as well as surgical, oncologic, aesthetic, and patient-reported outcomes were evaluated. Nineteen patients (38 breasts) underwent staged NSM following planned mastopexy/breast reduction. The mean time interval between stages was 25 weeks. No patients developed nipple areolar complex necrosis. Infection and hematoma were seen in one breast (2.6%) and seroma in two (5.3%) after NSM. Delayed wound healing was seen in eight breasts (21.1%) after first stage mastopexy/reduction and in 12 breasts (31.6%) after NSM. Skin flap necrosis was noted in two breasts (5.3%) after NSM. No patients developed oncological recurrence. Mean patient-reported post-operative satisfaction and well-being scores were 63 and 67 out of 100, respectively. The authors describe their experience with staged NSM following nipple repositioning procedures. Their results suggest that this procedure can be performed safely with cosmetically favorable results if surgeons wait an average of 25 weeks between first and second stage procedures.

Support for dermatological research in Sub-Saharan Africa: insights from African hair and skin research programs.

BACKGROUND: The structure and physiology of skin and hair in people of African ancestry are different from other ethnic categories and studies from other continents cannot necessarily be extrapolated to Sub-Saharan Africa (SSA) due to the differences in genetics, lifestyle, climate, cultures, and hair and skin care practices. The aim of this report is to highlight the recent advances in local skin and hair research in SSA from a grant program. METHODS: African Hair and Skin Research Grants from an industrial sponsor were awarded between 2013 and 2022 on five main topics: acne, hair and scalp, keloid scars, atopic dermatitis, and air pollution. A literature search in Scopus identified publications on these topics in African or black skin in SSA and worldwide to provide insight into the impact of the program. RESULTS: The number of publications from around the world on the skin and hair of people of African ancestry has increased significantly over the past 30 years on all five topics, especially as a result studies conducted in the United States. Fewer studies have been conducted in SSA but there has been an increasing number of publications over the past 10 years, especially from South Africa. CONCLUSIONS: Scientific and clinical partnerships between the industry, academia, and public healthcare sectors have contributed to a steady increase in hair and skin publications from SSA, which may be useful for the development of tailored products and public educational campaigns to raise awareness of the risks of using inappropriate products.

Using artificial odors to optimize attractiveness of host decoy traps to malaria vectors.

Malaria vector surveillance tools often incorporate features of hosts that are attractive to blood-seeking females. The recently developed host decoy trap (HDT) combines visual, thermal, and olfactory stimuli associated with human hosts and has shown great efficacy in terms of collecting malaria vectors. Synthetic odors and yeast-produced carbon dioxide (CO2) could prove useful by mimicking the human odors currently used in HDTs and provide standardized and easy-to-use olfactory attractants. The objective of this study was to test the attractiveness of various olfactory attractant cues in HDTs to capture malaria vectors. We compared 4 different odor treatments in outdoor field settings in southern Benin and western Burkina Faso: the standard HDT using a human, HDT with yeast-produced CO2, HDT with an artificial odor blend, and HDT with yeast-produced CO2 plus artificial odor blend. In both experimental sites, the standard HDT that incorporated a real human produced the greatest catch of Anopheles gambiae s.l (Diptera: Culicidae). The alternatives tested were still effective at collecting target vector species, although the most effective included CO2, either alone (Benin) or in combination with synthetic odor (Burkina Faso). The trap using synthetic human odor alone caught the fewest An. gambiae s.l. compared to the other baited traps. Both Anopheles coluzzii and Anopheles gambiae were caught by each trap, with a predominance of An. coluzzii. Synthetic baits could, therefore, represent a more standardized and easier-to-deploy approach than using real human odor baits for a robust vector monitoring strategy.

History of the hip joint pectineofoveal fold.

Although Josias Weitbrecht described the retinacula of the hip joint in his 1742 Syndesmologia, the anatomist Cesare Amantini of Perugia specifically studied the medial retinacula he referred to as the pectineofoveal fold in a late 19th-century monograph. This particular synovial fold stretches from the lesser trochanter to the osteocartilaginous junction of the femoral head along a virtual line connecting the lesser trochanter and the fovea for the ligament of the head. Although mentioned by some anatomists and radiologists, and despite its possible involvement in specific hip joint pathologies (fractures, impingements), it is surprising that Amantini's pectineofoveal fold remains ignored by most anatomy and clinical anatomy books. This study aims to verify if Cesare Amantini effectively drew attention to this synovial fold for the first time and coined the term "pectineofoveal fold," as well as determine whether most classical textbooks (i.e., published from 1890 to 2017) acknowledge the discovery and include it in the description of the hip joint. A possible evolutionary link between this synovial fold and the ambiens and pectineus muscles exists and should be discussed.

Distinct genomic contexts predict gene presence-absence variation in different pathotypes of Magnaporthe oryzae.

Fungi use the accessory gene content of their pangenomes to adapt to their environments. While gene presence-absence variation contributes to shaping accessory gene reservoirs, the genomic contexts that shape these events remain unclear. Since pangenome studies are typically species-wide and do not analyze different populations separately, it is yet to be uncovered whether presence-absence variation patterns and mechanisms are consistent across populations. Fungal plant pathogens are useful models for studying presence-absence variation because they rely on it to adapt to their hosts, and members of a species often infect distinct hosts. We analyzed gene presence-absence variation in the blast fungus, Magnaporthe oryzae (syn. Pyricularia oryzae), and found that presence-absence variation genes involved in host-pathogen and microbe-microbe interactions may drive the adaptation of the fungus to its environment. We then analyzed genomic and epigenomic features of presence-absence variation and observed that proximity to transposable elements, gene GC content, gene length, expression level in the host, and histone H3K27me3 marks were different between presence-absence variation genes and conserved genes. We used these features to construct a model that was able to predict whether a gene is likely to experience presence-absence variation with high precision (86.06%) and recall (92.88%) in M. oryzae. Finally, we found that presence-absence variation genes in the rice and wheat pathotypes of M. oryzae differed in their number and their genomic context. Our results suggest that genomic and epigenomic features of gene presence-absence variation can be used to better understand and predict fungal pangenome evolution. We also show that substantial intra-species variation can exist in these features.

Pharmacotherapy to Improve Cognitive Functioning After Acquired Brain Injury: A Meta-Analysis and Meta-Regression.

Cognitive impairments, common sequelae of acquired brain injury (ABI), significantly affect rehabilitation and quality of life. Currently, there is no solid evidence-base for pharmacotherapy to improve cognitive functioning after ABI, nevertheless off-label use is widely applied in clinical practice. This meta-analysis and meta-regression aims to quantitatively aggregate the available evidence for the effects of pharmacological agents used in the treatment of cognitive impairments following ABI. We conducted a comprehensive search of Embase, Medline Ovid, and Cochrane Controlled Trials Register databases for randomized controlled and crossover trials. Meta-analytic effects were calculated for each pharmaceutical agent and targeted neuromodulator system. Cognitive outcome measures were aggregated across cognitive domains. Of 8,216 articles, 41 studies (4,434 patients) were included. The noradrenergic agent methylphenidate showed a small, significant positive effect on cognitive functioning in patients with traumatic brain injury (TBI; k = 14, d = 0.34, 95% confidence interval: 0.12-0.56, P = 0.003). Specifically, methylphenidate was found to improve cognitive functions related to executive memory, baseline speed, inhibitory control, and variability in responding. The cholinergic drug donepezil demonstrated a large effect size, albeit based on a limited number of studies (k = 3, d = 1.68, P = 0.03). No significant effects were observed for other agents. Additionally, meta-regression analysis did not identify significant sources of heterogeneity in treatment response. Our meta-analysis supports the use of methylphenidate for enhancing cognitive functioning in patients with TBI. Although donepezil shows potential, it warrants further research. These results could guide clinical decision making, inform practice guidelines, and direct future pharmacotherapeutic research in ABI.

Simulated Guidance in Interpreting Nano-Patterned Co70Fe30 Film Imaging with Differential Phase Contrast.

Our paper introduces a simulation-based framework designed to interpret differential phase contrast (DPC) magnetic imaging within the transmission electron microscope (TEM). We investigate patterned magnetic membranes, particularly focusing on nano-patterned Co70Fe30 thin-film membranes fabricated via focused ion beam (FIB) milling. Our direct magnetic imaging reveals regular magnetic domain patterns in these carefully prepared systems. Notably, the observed magnetic structure aligns precisely with micromagnetic simulations based on the dimensions of the underlying nanostructures. This agreement emphasizes the usefulness of micromagnetic simulations, not only for the interpretation of DPC data, but also for the prediction of possible microstructures in magnetic sensor systems with nano-patterns.

Assessing perceptual chromatic equiluminance using a reflexive pupillary response.

Equiluminant stimuli help assess the integrity of colour perception and the relationship of colour to other visual features. As a result of individual variation, it is necessary to calibrate experimental visual stimuli to suit each individual's unique equiluminant ratio. Most traditional methods rely on training observers to report their subjective equiluminance point. Such paradigms cannot easily be implemented on pre-verbal or non-verbal observers. Here, we present a novel Pupil Frequency-Tagging Method (PFTM) for detecting a participant's unique equiluminance point without verbal instruction and with minimal training. PFTM analyses reflexive pupil oscillations induced by slow (< 2 Hz) temporal alternations between coloured stimuli. Two equiluminant stimuli will induce a similar pupil dilation response regardless of colour; therefore, an observer's equiluminant point can be identified as the luminance ratio between two colours for which the oscillatory amplitude of the pupil at the tagged frequency is minimal. We compared pupillometry-based equiluminance ratios to those obtained with two established techniques in humans: minimum flicker and minimum motion. In addition, we estimated the equiluminance point in non-human primates, demonstrating that this new technique can be successfully employed in non-verbal subjects.

Considerations on implementation of the newest treatment for symptomatic uterine fibroids: Oral GnRH antagonists.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women's quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

Intraspecific Variation of Transposable Elements Reveals Differences in the Evolutionary History of Fungal Phytopathogen Pathotypes.

Transposable elements (TEs) contribute to intraspecific variation and play important roles in the evolution of fungal genomes. However, our understanding of the processes that shape TE landscapes is limited, as is our understanding of the relationship between TE content, population structure, and evolutionary history of fungal species. Fungal plant pathogens, which often have host-specific populations, are useful systems in which to study intraspecific TE content diversity. Here, we describe TE dynamics in five lineages of Magnaporthe oryzae, the fungus that causes blast disease of rice, wheat, and many other grasses. We identified differences in TE content across these lineages and showed that recent lineage-specific expansions of certain TEs have contributed to overall greater TE content in rice-infecting and Setaria-infecting lineages. We reconstructed the evolutionary histories of long terminal repeat-retrotransposon expansions and found that in some cases they were caused by complex proliferation dynamics of one element and in others by multiple elements from an older population of TEs multiplying in parallel. Additionally, we found evidence suggesting the recent transfer of a DNA transposon between rice- and wheat-infecting M. oryzae lineages and a region showing evidence of homologous recombination between those lineages, which could have facilitated such a transfer. By investigating intraspecific TE content variation, we uncovered key differences in the proliferation dynamics of TEs in various pathotypes of a fungal plant pathogen, giving us a better understanding of the evolutionary history of the pathogen itself.

Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity.

Urocortin 2 (UCN2) acts as a ligand for the G protein-coupled receptor corticotropin-releasing hormone receptor 2 (CRHR2). UCN2 has been reported to improve or worsen insulin sensitivity and glucose tolerance in vivo. Here we show that acute dosing of UCN2 induces systemic insulin resistance in male mice and skeletal muscle. Inversely, chronic elevation of UCN2 by injection with adenovirus encoding UCN2 resolves metabolic complications, improving glucose tolerance. CRHR2 recruits Gs in response to low concentrations of UCN2, as well as Gi and ß-Arrestin at high concentrations of UCN2. Pre-treating cells and skeletal muscle ex vivo with UCN2 leads to internalization of CRHR2, dampened ligand-dependent increases in cAMP, and blunted reductions in insulin signaling. These results provide mechanistic insights into how UCN2 regulates insulin sensitivity and glucose metabolism in skeletal muscle and in vivo. Importantly, a working model was derived from these results that unifies the contradictory metabolic effects of UCN2.

Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset.

Ubiquitin-proteasome system (UPS) dysfunction is associated with the pathology of a wide range of human diseases, including myopathies and muscular atrophy. However, the mechanistic understanding of specific components of the regulation of protein turnover during development and disease progression in skeletal muscle is unclear. Mutations in KLHL40, an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein, result in severe congenital nemaline myopathy, but the events that initiate the pathology and the mechanism through which it becomes pervasive remain poorly understood. To characterize the KLHL40-regulated ubiquitin-modified proteome during skeletal muscle development and disease onset, we used global, quantitative mass spectrometry-based ubiquitylome and global proteome analyses of klhl40a mutant zebrafish during disease progression. Global proteomics during skeletal muscle development revealed extensive remodeling of functional modules linked with sarcomere formation, energy, biosynthetic metabolic processes, and vesicle trafficking. Combined analysis of klh40 mutant muscle proteome and ubiquitylome identified thin filament proteins, metabolic enzymes, and ER-Golgi vesicle trafficking pathway proteins regulated by ubiquitylation during muscle development. Our studies identified a role for KLHL40 as a regulator of ER-Golgi anterograde trafficking through ubiquitin-mediated protein degradation of secretion-associated Ras-related GTPase1a (Sar1a). In KLHL40-deficient muscle, defects in ER exit site vesicle formation and downstream transport of extracellular cargo proteins result in structural and functional abnormalities. Our work reveals that the muscle proteome is dynamically fine-tuned by ubiquitylation to regulate skeletal muscle development and uncovers new disease mechanisms for therapeutic development in patients.

Efficacy and safety of intravenous imatinib in COVID-19 ARDS: a randomized, double-blind, placebo-controlled clinical trial.

PURPOSE: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. RESULTS: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). CONCLUSIONS: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

The concepts and origins of cell mortality.

Organismal death is foundational to the evolution of life, and many biological concepts such as natural selection and life history strategy are so fashioned only because individuals are mortal. Organisms, irrespective of their organization, are composed of basic functional units-cells-and it is our understanding of cell death that lies at the heart of most general explanatory frameworks for organismal mortality. Cell death can be exogenous, arising from transmissible diseases, predation, or other misfortunes, but there are also endogenous forms of death that are sometimes the result of adaptive evolution. These endogenous forms of death-often labeled programmed cell death, PCD-originated in the earliest cells and are maintained across the tree of life. Here, we consider two problematic issues related to PCD (and cell mortality generally). First, we trace the original discoveries of cell death from the nineteenth century and place current conceptions of PCD in their historical context. Revisions of our understanding of PCD demand a reassessment of its origin. Our second aim is thus to structure the proposed origin explanations of PCD into coherent arguments. In our analysis we argue for the evolutionary concept of PCD and the viral defense-immunity hypothesis for the origin of PCD. We suggest that this framework offers a plausible account of PCD early in the history of life, and also provides an epistemic basis for the future development of a general evolutionary account of mortality.

A one health framework to advance food safety and security: An on-farm case study in the Rwandan dairy sector.

In Rwanda, cattle and milk hold a cultural and historical significance, providing an opportunity for pro-dairy governmental policies aimed to alleviate food insecurity, malnutrition, and improve livelihoods. The government of Rwanda has identified strategies to grow the dairy sector through strategic investment to achieve these goals. It is estimated two-thirds of lactating cows in Rwanda have clinical or subclinical mastitis, which reduces milk production and increases the risk of milk as a source for zoonotic disease if the milk is consumed undercooked or unpasteurized. This case study outlines the implementation of a One Health framework that integrates education, research, and outreach in Rwanda to improve food safety and food security, for the social, economic, and health benefit of Rwandans and their livestock. Twenty-five Rwandan Extension Specialists participated in the Dairy Dynamic Management education, research, and outreach program. Once trained, the extension specialists supported 30 small holder dairy farmers in performing proper husbandry and animal health practices for mastitis control and reduction of bacterial counts in the udder. Over the 16-week program, 30 small holder dairy farmers and 100 dairy cows were surveyed weekly for animal husbandry, animal health, and mastitis indicators. Outcomes were evaluated by monitoring animal health, foodborne pathogens in milk, and compliance to animal husbandry protocols. Quarter milk samples were collected weekly and evaluated for the presence of bacteria that are common causes of mastitis. We found a statistically significant reduction of mean total bacterial counts and prevalence of bacterial species in quarters over the 16-week training (P ≤ .01). Smallholders were monitored through observing farmers performing hygienic milking protocols. Farmers conducted the protocol correctly greater than 90% of the time by the end of the 16-week program for 5 of 7 steps for proper hygienic milking procedures, indicating farmers were eager to learn and adopt the procedures. However, follow-up and retraining with Extension Specialists is vital to continued success. We demonstrate that an integrative One Health education, research, and outreach program can be successful in improving animal health, food safety, and food security and this framework can be applied to other agricultural sectors and geographic regions.