Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial ...nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18-24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-Wolbachia curative therapy times to between one and two weeks.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A growing sector of humanitarian surgical nongovernmental organizations (NGOs) is providing care in low- and middle-income countries. Minimal data exists regarding this extremely heterogeneous ...community. This study aims to describe the demographics and clinical practices of surgical NGOs. We hypothesize there are identifiable attributes of such organizations which correlate with success.
A survey was sent to 83 US-based surgical NGOs directly providing general or subspecialty surgical care in low- and middle-income countries. Further information was obtained from organizations’ websites. Descriptive statistics were performed to analyze organizational attributes and define protocol-driven practices.
Thirty NGOs (36%) responded, averaging 20 ± 11 y of operation. Annually, US humanitarian surgical organizations performed a wide range of operations (10-15,000) with 52% performing fewer than 200 operations per year. Sixty-seven percent of responders were classified as strongly protocol-driven. Only twenty percent reported deviation from standard US practice occurs often or very often, most commonly in pain management (18%), preoperative workup (16%), and operative technique (16%).
To our knowledge, this is the first effort to describe the characteristics and clinical practices of the humanitarian surgical sector. There exists a wide scope of clinical practice among responding surgical NGOs, however mostly consistent with US standards, with a prevalance of protocol-driven clinical approach. Developing consensus-based protocols may help standardize and improve quality of care for surgical NGOs.
•Survey of practices/characteristics of US-based humanitarian surgical organizations.•Diverse scope and breadth of practice between organizations within the humanitarian surgical sector.•Organizations report infrequent or inconsequential variation from US standard practices.•Most organizations abide by protocol-driven practices, which correlate with their longevity and impact.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The development of highly stable and efficient wide-bandgap (WBG) perovskite solar cells (PSCs) based on bromine-iodine (Br-I) mixed-halide perovskite (with Br greater than 20%) is critical to create ...tandem solar cells. However, issues with Br-I phase segregation under solar cell operational conditions (such as light and heat) limit the device voltage and operational stability. This challenge is often exacerbated by the ready defect formation associated with the rapid crystallization of Br-rich perovskite chemistry with antisolvent processes. We combined the rapid Br crystallization with a gentle gas-quench method to prepare highly textured columnar 1.75-electron volt Br-I mixed WBG perovskite films with reduced defect density. With this approach, we obtained 1.75-electron volt WBG PSCs with greater than 20% power conversion efficiency, approximately 1.33-volt open-circuit voltage (
), and excellent operational stability (less than 5% degradation over 1100 hours of operation under 1.2 sun at 65°C). When further integrated with 1.25-electron volt narrow-bandgap PSC, we obtained a 27.1% efficient, all-perovskite, two-terminal tandem device with a high
of 2.2 volts.
Mixed-halide perovskites offer bandgap tunability essential for multijunction solar cells; however, a detrimental halide segregation under light is often observed. Here we combine simultaneous in ...situ photoluminescence and X-ray diffraction measurements to demonstrate clear differences in compositional and optoelectronic changes associated with halide segregation in MAPb(Br0.5I0.5)3 and FA0.83Cs0.17Pb(Br0.4I0.6)3 films. We report evidence for low-barrier ionic pathways in MAPb(Br0.5I0.5)3, which allow for the rearrangement of halide ions in localized volumes of perovskite without significant compositional changes to the bulk material. In contrast, FA0.83Cs0.17Pb(Br0.4I0.6)3 lacks such low-barrier ionic pathways and is, consequently, more stable against halide segregation. However, under prolonged illumination, it exhibits a considerable ionic rearrangement throughout the bulk material, which may be triggered by an initial demixing of A-site cations, altering the composition of the bulk perovskite and reducing its stability against halide segregation. Our work elucidates links between composition, ionic pathways, and halide segregation, and it facilitates the future engineering of phase-stable mixed-halide perovskites.
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IJS, KILJ, NUK, PNG, UL, UM
CD4
T cells are at the nexus of the innate and adaptive arms of the immune system. However, little is known about the evolutionary history of CD4
T cells, and it is unclear whether their ...differentiation into specialized subsets is conserved in early vertebrates. In this study, we have created transgenic zebrafish with vibrantly labeled CD4
cells allowing us to scrutinize the development and specialization of teleost CD4
leukocytes in vivo. We provide further evidence that CD4
macrophages have an ancient origin and had already emerged in bony fish. We demonstrate the utility of this zebrafish resource for interrogating the complex behavior of immune cells at cellular resolution by the imaging of intimate contacts between teleost CD4
T cells and mononuclear phagocytes. Most importantly, we reveal the conserved subspecialization of teleost CD4
T cells in vivo. We demonstrate that the ancient and specialized tissues of the gills contain a resident population of il-4/13b-expressing Th2-like cells, which do not coexpress il-4/13a Additionally, we identify a contrasting population of regulatory T cell-like cells resident in the zebrafish gut mucosa, in marked similarity to that found in the intestine of mammals. Finally, we show that, as in mammals, zebrafish CD4
T cells will infiltrate melanoma tumors and obtain a phenotype consistent with a type 2 immune microenvironment. We anticipate that this unique resource will prove invaluable for future investigation of T cell function in biomedical research, the development of vaccination and health management in aquaculture, and for further research into the evolution of adaptive immunity.
Peatlands are expected to experience sustained yet fluctuating higher temperatures due to climate change, leading to increased microbial activity and greenhouse gas emissions. Despite mounting ...evidence for viral contributions to these processes in peatlands underlain with permafrost, little is known about viruses in other peatlands. More generally, soil viral biogeography and its potential drivers are poorly understood at both local and global scales. Here, 87 metagenomes and five viral size-fraction metagenomes (viromes) from a boreal peatland in northern Minnesota (the SPRUCE whole-ecosystem warming experiment and surrounding bog) were analyzed for dsDNA viral community ecological patterns, and the recovered viral populations (vOTUs) were compared with our curated PIGEON database of 266,125 vOTUs from diverse ecosystems.
Within the SPRUCE experiment, viral community composition was significantly correlated with peat depth, water content, and carbon chemistry, including CH
and CO
concentrations, but not with temperature during the first 2 years of warming treatments. Peat vOTUs with aquatic-like signatures (shared predicted protein content with marine and/or freshwater vOTUs) were significantly enriched in more waterlogged surface peat depths. Predicted host ranges for SPRUCE vOTUs were relatively narrow, generally within a single bacterial genus. Of the 4326 SPRUCE vOTUs, 164 were previously detected in other soils, mostly peatlands. None of the previously identified 202,371 marine and freshwater vOTUs in our PIGEON database were detected in SPRUCE peat, but 0.4% of 80,714 viral clusters (VCs, grouped by predicted protein content) were shared between soil and aquatic environments. On a per-sample basis, vOTU recovery was 32 times higher from viromes compared with total metagenomes.
Results suggest strong viral "species" boundaries between terrestrial and aquatic ecosystems and to some extent between peat and other soils, with differences less pronounced at higher taxonomic levels. The significant enrichment of aquatic-like vOTUs in more waterlogged peat suggests that viruses may also exhibit niche partitioning on more local scales. These patterns are presumably driven in part by host ecology, consistent with the predicted narrow host ranges. Although more samples and increased sequencing depth improved vOTU recovery from total metagenomes, the substantially higher per-sample vOTU recovery after viral particle enrichment highlights the utility of soil viromics. Video abstract The importance of Minnesota peat viromes in revealing terrestrial and aquatic niche partitioning for viral populations.
Anhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK ...Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson's Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h
SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson's Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.
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