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Time-resolved x-ray crystallography (TR-X) at synchrotrons and free electron lasers is a promising technique for recording dynamics of molecules at atomic resolution. While experimental methods for TR-X have proliferated and matured, data analysis is often difficult. Extracting small, time-dependent changes in signal is frequently a bottleneck for practitioners. Recent work demonstrated this challenge can be addressed when merging redundant observations by a statistical technique known as variational inference (VI). However, the variational approach to time-resolved data analysis requires identification of successful hyperparameters in order to optimally extract signal. In this case study, we present a successful application of VI to time-resolved changes in an enzyme, DJ-1, upon mixing with a substrate molecule, methylglyoxal. We present a strategy to extract high signal-to-noise changes in electron density from these data. Furthermore, we conduct an ablation study, in which we systematically remove one hyperparameter at a time to demonstrate the impact of each hyperparameter choice on the success of our model. We expect this case study will serve as a practical example for how others may deploy VI in order to analyze their time-resolved diffraction data.

Most x-ray sources are inherently polychromatic. Polychromatic (“pink”) x-rays provide an efficient way to conduct diffraction experiments as many more photons can be used and large regions of reciprocal space can be probed without sample rotation during exposure—ideal conditions for time-resolved applications. Analysis of such data is complicated, however, causing most x-ray facilities to discard >99% of x-ray photons to obtain monochromatic data. Key challenges in analyzing polychromatic diffraction data include lattice searching, indexing and wavelength assignment, correction of measured intensities for wavelength-dependent effects, and deconvolution of harmonics. We recently described an algorithm, Careless, that can perform harmonic deconvolution and correct measured intensities for variation in wavelength when presented with integrated diffraction intensities and assigned wavelengths. Here, we present Laue-DIALS, an open-source software pipeline that indexes and integrates polychromatic diffraction data. Laue-DIALS is based on the dxtbx toolbox, which supports the DIALS software commonly used to process monochromatic data. As such, Laue-DIALS provides many of the same advantages: an open-source, modular, and extensible architecture, providing a robust basis for future development. We present benchmark results showing that Laue-DIALS, together with Careless, provides a suitable approach to the analysis of polychromatic diffraction data, including for time-resolved applications.

Organic photovoltaics (OPVs) show great promise for both outdoor and indoor applications. However, there remains a lack of understanding around the stability of OPVs, particularly for indoor applications. In this work, the photostability of the poly[(thiophene)‐alt‐(6,7‐difluoro‐2‐(2‐hexyldecyloxy)quinoxaline)]:2,2′‐((2Z,2′Z)‐((4,4,9,9‐tetrahexyl‐4,9‐dihydro‐s‐indaceno[1,2‐b:5,6‐b′]dithiophene‐2,7‐diyl)bis(methanylylidene))bis(3‐oxo‐2,3‐dihydro‐1H‐indene‐2,1‐diylidene))dimalononitrile blend is investigated for both outdoor and indoor applications. Photostability is found to vary drastically with illumination intensity. Devices under high‐intensity white light‐emitting diode (LED) illumination, with their short‐circuit current density (JSC) matching JSC–EQE for AM1.5 G illumination, lose 42% of their initial performance after 30 days of illumination. Contrastingly, after almost 47 days of illumination devices under 1000 lux white LED illumination show no loss in performance. The poor photostability under 1 sun illumination is linked to the poor photostability of IDIC. Through Raman spectroscopy and mass spectrometry, IDIC is found to suffer from photoisomerization, which detrimentally impacts light absorption and carrier extraction. In this work, it is highlighted that under low light levels, the requirement of intrinsic material photostability may be less stringent.

The voltage-dependent anion channel (VDAC) is a crucial mitochondrial protein that facilitates ion and metabolite exchange between mitochondria and the cytosol. Initially characterized over three decades ago, the structure of VDAC-1 was resolved in 2008, revealing a novel β-barrel protein architecture. This study presents the first room-temperature crystal structure of mouse VDAC-1 (mVDAC-1), which is a significant step toward understanding the channel’s gating mechanism. The new structure, obtained at a 3.3 Å resolution, demonstrates notable differences from the previously determined cryogenic structure, particularly in the loop regions, which may be critical for the transition between the ‘open’ and ‘closed’ states of VDAC-1. Comparative analysis of the root-mean-square deviation (R.M.S.D.) and B-factors between the cryogenic and room-temperature structures suggests that these conformational differences, although subtle, are important for VDAC’s functional transitions. The application of electric field-stimulated X-ray crystallography (EF-X) is proposed as a future direction to resolve the ‘closed’ state of VDAC-1 by inducing voltage-driven conformational changes in order to elucidate the dynamic gating mechanism of VDAC-1. Our findings have profound implications for understanding the molecular basis of VDAC’s role in mitochondrial function and its regulation under physiological conditions.

Abstract Ship present‐weather reports from 1950 to 2019 are used to assess trends in the reporting of precipitation occurrence over the global oceans. Annual reported precipitation frequency shows statistically significant positive trends of up to ∼15% per decade throughout most ocean areas equatorward of 45°. However, latitudes poleward of 45° are dominated by negative trends, some areas of which meet the 95% confidence threshold. Nine smaller regions were subjectively selected for further investigation, revealing that the observed trends, both positive and negative, are often but not always nearly linear, with the amplitude of interannual fluctuations usually being much larger than that expected from random sampling error alone. The annual time series reveal that four comparatively dry areas are associated with the largest overall positive trends, ranging from 8.3% to 12.8% (relative) per decade. Trends were also computed separately for each season, revealing remarkable overall consistency in trends across seasons.

IKZF1 encodes the transcription factor IKAROS, a zinc finger DNA-binding protein with a key role in lymphoid lineage development. IKAROS plays a critical role in the development of lineage-restricted mature lymphocytes. Deletions within IKZF1 in B-cell acute lymphoblastic leukemia (B-ALL) lead to a loss of normal IKAROS function, conferring leukemic stem cell properties, including self-renewal and subsequent uncontrolled growth. IKZF1 deletions are associated with treatment resistance and inferior outcomes. Early identification of IKZF1 deletions in B-ALL may inform the intensification of therapy and other potential treatment strategies to improve outcomes in this high-risk leukemia.

Most x-ray sources are inherently polychromatic. Polychromatic ("pink") x-rays provide an efficient way to conduct diffraction experiments as many more photons can be used and large regions of reciprocal space can be probed without sample rotation during exposure-ideal conditions for time-resolved applications. Analysis of such data is complicated, however, causing most x-ray facilities to discard >99% of x-ray photons to obtain monochromatic data. Key challenges in analyzing polychromatic diffraction data include lattice searching, indexing and wavelength assignment, correction of measured intensities for wavelength-dependent effects, and deconvolution of harmonics. We recently described an algorithm, Careless, that can perform harmonic deconvolution and correct measured intensities for variation in wavelength when presented with integrated diffraction intensities and assigned wavelengths. Here, we present Laue-DIALS, an open-source software pipeline that indexes and integrates polychromatic diffraction data. Laue-DIALS is based on the dxtbx toolbox, which supports the DIALS software commonly used to process monochromatic data. As such, Laue-DIALS provides many of the same advantages: an open-source, modular, and extensible architecture, providing a robust basis for future development. We present benchmark results showing that Laue-DIALS, together with Careless, provides a suitable approach to the analysis of polychromatic diffraction data, including for time-resolved applications.

Abstract Background At the centre of smallholders’ adaptation is a need to understand their perceptions on key climatic scenarios so as to glean helpful information for key decision-making processes. In Kenya at the moment, downstream information regarding these circumstances remain scanty, with many smallholders being ‘on their own’, in spite of the imminent threats from shifting precipitation patterns, rising temperatures, and intensifying droughts. At the sub-national levels, potential impacts of these situations are likely to deepen due to extensive cases of land use transformations, habitat degradation, plummeting water resources capacity and common inter-ethnic conflicts, among other negative externalities. The study examined current climatic situations in Trans-Mara East sub-County, to the south-western part of Kenya, as well as the smallholders’ perceptions about the situations, their adaptation levels and constraints thereof. Results Pearson correlation coefficient, indicated a weak positive association between smallholder’s perceptions and either their age, marital status, level of education, or livelihood streams (r ≤ 0.1; p ≥ 0.05, for all), unlike their climatic perceptions and farm sizes which showed a strong positive association (r = 0.430; p ≤ 0.01). Key desired adaptation options, improving crop varieties, livestock feeding techniques and crop diversification, topped their options, with destocking being least desired. Education levels (r = 0.229; p ≤ 0.05) and farm sizes (r = 0.534; p ≤ 0.01) had a positively significant association with adaptive capacity, in addition to a significantly weak, association between their adaptive capacity and both their individual’s marital status (r = 0.154; p ≥ 0.05) and diversity of livelihood streams (r = 0.034; p ≥ 0.05). The analysis also showed a weak negative association between their adaptive capacity and age (r = − 0.026; p ≥ 0.05). Amid the key constraints which emerged include high cost of farm inputs, limited access to credit and market uncertainties, among others. Pearson correlation coefficient showed a significantly strong negative association between smallholders’ constraints and both (r ≥ − 0.3; p ≤ 0.01) their level of education, and diversity of livelihood streams. A significantly strong positive association (r = 0.280; p ≤ 0.01) was identified between smallholder’s age and constraints, while marital status and farm sizes both (r ≤ − 0.01; p ≥ 0.05) revealed weak non-significant negative association with the constraints. Conclusions Trans-Mara East sub-County has been grappling with a number of climate-related challenges. These were manifested through increased rainfall uncertainties, intensifying droughts, and rising temperatures, with effects on crop and livestock performances in the area, accompanied by plummeting household food security and income positions. Besides, smallholders’ perceptions intersected with various intervening subtleties. Smallholders' adaptive capacity in the area, was largely not associated with their socioeconomic characteristics as most of the respective components such as education, and livelihood streams, were barely fully-fledged. Moreover, the constraints against their adaptive capacity were mainly related to the existing policies and their respective implementations at the downstream levels with limited attribution to the farm-level interventions. It is thus incumbent upon the decision-makers, and other key stakeholders to explore avenues for amplifying the smallholders’ desired adaptation schemes while down-sizing the existing adaptation bottlenecks in the area.

Abstract Background Neuroendocrine prostate cancer (NEPC) may be rising in prevalence as patients with advanced prostate cancer potentially develop resistance to contemporary anti-androgen treatment through a neuroendocrine phenotype. While prior studies comparing NEPC and prostatic adenocarcinoma have identified important candidates for targeted therapy, most have relied on few NEPC patients due to disease rarity, resulting in thousands of differentially expressed genes collectively and offering an opportunity for meta-analysis. Moreover, past studies have focused on prototypical NEPC samples with classic immunohistochemistry profiles, whereas there is increasing recognition of atypical phenotypes. In the primary setting, small cell prostatic carcinoma (SCPC) is frequently admixed with adenocarcinomas that may be clonally related, and a minority of SCPCs express markers typical of prostatic adenocarcinoma while rare cases do not express neuroendocrine markers. We derived a meta-signature of prototypical high-grade NEPC, then applied it to develop a classifier of primary SCPC incorporating disease heterogeneity. Methods Prototypical NEPC samples from 15 patients across 6 frozen tissue microarray datasets were assessed for genes with consistent outlier expression relative to adenocarcinomas. Resulting genes were used to determine subgroups of primary SCPCs (N=16) and high-grade adenocarcinomas (N=16) profiled by exon arrays using formalin-fixed paraffin-embedded (FFPE) material from our institutional archives. A subgroup classifier was developed using differential expression for feature selection, and applied to radical prostatectomy cohorts. Results Sixty nine and 375 genes demonstrated consistent outlier expression in at least 80% and 60% of NEPC patients, with close resemblance in expression between NEPC and small cell lung cancer. Clustering by these genes generated 3 subgroups among primary samples from our institution. Nearest centroid classification based on the predominant phenotype from each subgroup (9 prototypical SCPCs, 9 prototypical adenocarcinomas, and 4 atypical SCPCs) achieved a 4.5% error rate by leave-one-out cross-validation. The classifier identified SCPC-like expression in 40% (2/5) of mixed adenocarcinomas and 0.3-0.6% of adenocarcinomas from prospective (4/2293) and retrospective (2/355) radical prostatectomy cohorts, where both SCPC-like retrospective cases subsequently developed metastases. Conclusions Meta-analysis generates a robust signature of prototypical high-grade NEPC, and may facilitate development of a primary SCPC classifier based on FFPE material with potential prognostic implications.

The voltage-dependent anion channel (VDAC) is a crucial mitochondrial protein that facilitates ion and metabolite exchange between mitochondria and the cytosol. Initially characterized over three decades ago, the structure of VDAC-1 was resolved in 2008, revealing a novel β-barrel protein architecture. This study presents the first room-temperature crystal structure of mouse VDAC-1 (mVDAC-1), which is a significant step toward understanding the channel's gating mechanism. The new structure, obtained at a 3.3 Å resolution, demonstrates notable differences from the previously determined cryogenic structure, particularly in the loop regions, which may be critical for the transition between the 'open' and 'closed' states of VDAC-1. Comparative analysis of the root-mean-square deviation (R.M.S.D.) and B-factors between the cryogenic and room-temperature structures suggests that these conformational differences, although subtle, are important for VDAC's functional transitions. The application of electric field-stimulated X-ray crystallography (EF-X) is proposed as a future direction to resolve the 'closed' state of VDAC-1 by inducing voltage-driven conformational changes in order to elucidate the dynamic gating mechanism of VDAC-1. Our findings have profound implications for understanding the molecular basis of VDAC's role in mitochondrial function and its regulation under physiological conditions.

Carotid blowout syndrome (CBS) is a rare and fatal complication which arises from patients who have been treated for head and neck cancer. The incidence of CBS is rare and not commonly seen by emergency physicians. We review a case of a 68-year-old woman with a history of laryngectomy and chemo-radiation therapy presenting with massive oral bleeding and hypotension. Her course and treatments are highlighted, literature referring to CBS are described and we reintroduce the approach of managing such a patient in the emergency department.

Schistosomiasis is a disease of major public health importance in sub-Saharan Africa. Immunoregulation begins early in schistosome infection and is characterized by hyporesponsiveness to parasite and bystander antigens, suggesting that a schistosome infection at the time of immunization could negatively impact the induction of protective vaccine responses. This study examined whether having a Schistosoma mansoni infection at the time of immunization with hepatitis B and tetanus toxoid (TT) vaccines impacts an individual's ability to achieve and maintain protective antibody levels against hepatitis B surface antigen or TT.Adults were recruited from Kisumu Polytechnic College in Western Kenya. At enrollment, participants were screened for schistosomiasis and soil transmitted helminths (STHs) and assigned to groups based on helminth status. The vaccines were then administered and helminth infections treated a week after the first hepatitis B boost. Over an 8 month period, 3 blood specimens were obtained for the evaluation of humoral and cytokine responses to the vaccine antigens and for immunophenotyping.146 individuals were available for final analysis and 26% were S. mansoni positive (Sm+). Schistosomiasis did not impede the generation of initial minimum protective antibody levels to either hepatitis B or TT vaccines. However, median hepatitis B surface antibody levels were significantly lower in the Sm+ group after the first boost and remained lower, but not significantly lower, following praziquantel (PZQ) treatment and final boost. In addition, 8 months following TT boost and 7 months following PZQ treatment, Sm+ individuals were more likely to have anti-TT antibody levels fall below levels considered optimal for long term protection. IL-5 levels in response to in vitro TT stimulation of whole blood were significantly higher in the Sm+ group at the 8 month time period as well.Individuals with schistosomiasis at the start the immunizations were capable of responding appropriately to the vaccines as measured by antibody responses. However, they may be at risk of a more rapid decline in antibody levels over time, suggesting that treating schistosome infections with praziquantel before immunizations could be beneficial. The timing of the treatment as well as its full impact on the maintenance of antibodies against vaccine antigens remains to be elucidated.

This study was conducted to determine the prevalence and effect of parasitic infection on erythrocyte indices in trade camels slaughtered in Maiduguri, Nigeria. Two hundred adult one humped camels comprised of 87 (43.5 %) males and 113 (56.5 %) females were examined for helminths and hemoparasites at their slaughter time according to the standard procedures. An overall prevalence of 79 % for single and mixed infections was observed. Examination of faecal samples from camels shows 82 (41 %) were harbouring different nematodes, mostly Strongyle, Strongyloides and Hemonchus species. Buffy coat and thin smear examination of blood samples showed Babesia and Anaplasma species. More females (44.5 %) than males (34.5 %) were positive for various parasitic infections. But the percentage was not statistically significant (P > 0.05). Packed cell volume (PCV), mean haemoglobin concentration (MCH), mean corpuscular haemoglobin concentration (MCHC) and red blood cell counts were significantly (P < 0.01) affected in the infected camels compared to the non-infected ones. Parasite infection in camels leads to macrocytic anaemia.

Parasitologic surveys of young adults in college and university settings are not commonly done, even in areas known to be endemic for schistosomiasis and soil-transmitted helminths. We have done a survey of 291 students and staff at the Kisumu National Polytechnic in Kisumu, Kenya, using the stool microscopy Kato-Katz (KK) method and the urine point-of-care circulating cathodic antigen (POC-CCA) test. Based on three stools/two KK slides each, in the 208 participants for whom three consecutive stools were obtained, Schistosoma mansoni prevalence was 17.8%. When all 291 individuals were analyzed based on the first stool, as done by the national neglected tropical disease (NTD) program, and one urine POC-CCA assay (n = 276), the prevalence was 13.7% by KK and 23.2% by POC-CCA. Based on three stools, 2.5% of 208 participants had heavy S. mansoni infections (≥400 eggs/gram feces), with heavy S. mansoni infections making up 13.5% of the S. mansoni cases. The prevalence of the soil-transmitted helminths (STH: Ascaris lumbricoides, Trichuris trichiura and hookworm) by three stools was 1.4%, 3.1%, and 4.1%, respectively, and by the first stool was 1.4%, 2.4% and 1.4%, respectively. This prevalence and intensity of infection with S. mansoni in a college setting warrants mass drug administration with praziquantel. This population of young adults is ‘in school’ and is both approachable and worthy of inclusion in national schistosomiasis control and elimination programs.

Misfolding of the microtubule-binding protein tau into filamentous aggregates is characteristic of many neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Determining the structures and dynamics of these tau fibrils is important for designing inhibitors against tau aggregation. Tau fibrils obtained from patient brains have been found by cryo-electron microscopy to adopt disease-specific molecular conformations. However, in vitro heparin-fibrillized 2N4R tau, which contains all four microtubule-binding repeats (4R), was recently found to adopt polymorphic structures. Here we use solid-state NMR spectroscopy to investigate the global fold and dynamics of heparin-fibrillized 0N4R tau. A single set of 13C and 15N chemical shifts was observed for residues in the four repeats, indicating a single β-sheet conformation for the fibril core. This rigid core spans the R2 and R3 repeats and adopts a hairpin-like fold that has similarities to but also clear differences from any of the polymorphic 2N4R folds. Obtaining a homogeneous fibril sample required careful purification of the protein and removal of any proteolytic fragments. A variety of experiments and polarization transfer from water and mobile side chains indicate that 0N4R tau fibrils exhibit heterogeneous dynamics: Outside the rigid R2-R3 core, the R1 and R4 repeats are semirigid even though they exhibit β-strand character and the proline-rich domains undergo large-amplitude anisotropic motions, whereas the two termini are nearly isotropically flexible. These results have significant implications for the structure and dynamics of 4R tau fibrils in vivo.

Vietnamese Ukrainians are a largely unstudied identity group that has recently attracted attention due to the impacts of the Russo-Ukrainian War. Our study examines Vietnamese-Ukrainian bicultural identity as experienced by 10 university student refugees of the war in 2022–23. Researchers conducted semi-structured ethnographic interviews in which each participant examined identity formation experiences as second-generation Vietnamese Ukrainians. Participants also reflected upon the impacts to ethnic identity self-awareness that resulted from their unexpected return migration to Vietnam as student refugees of war. The cohort of study participants created a tight-knit Vietnamese-Ukrainian return diaspora in an environment conducive to self-reflection and exploration of their ongoing ethnic identity journeys. In our study, we argue that the ethnic identity formation of young Vietnamese Ukrainians relies on the active construction of intercultural personhood as an adaptation to transnational mobility and change. [ABSTRACT FROM AUTHOR]

In this paper, we explore Bahnar perspectives on the agency of plants and forest, and human–forest relations in Vietnam. The Bahnar are among Vietnam's 54 recognized ethnic minority peoples 1 , many of whom live in proximity to the forest, gather its resources, and regard it as a spiritual abode in their cosmology. The Bahnar (Ba Na) people who inhabit the Central Highlands and are the main focus of this article have traditionally relied on the forest for subsistence, practising swidden cultivation, hunting birds and mammals, and gathering plants. Their forest knowledge is transmitted primarily orally; through the lexicon, everyday discourses, stories, and songs. It is acquired through participation in forest-related activities and informal learning of arts such as vernacular architecture, basketry, canoe-building, and textiles. The Bahnar see spirits in things in nature with which they have a connection or routine interactions (stones, streams, and trees) but not in everything. The Bahnar spiritual connection with the forest also guides their husbandry of increasingly scarce forest resources, such as rattan used in basketry, and large trees needed to make canoes. Certain plants and trees are protected by taboos, and certain parts of the forest are considered sacred, inhabited by gods and spirits, and not to be touched. Forests possess animacy for the Bahnar in that they are sensitive and responsive to a wide range of human behaviours, and must be treated with respect and care. This human–forest–spirit relationship is the primary lens through which the Bahnar perceive nature, and guides their daily interactions with it. [ABSTRACT FROM AUTHOR]

Natural river diversion, or avulsion, controls the distribution of channels on a floodplain and channel sandstone bodies within fluvial stratigraphic architecture. Avulsions establish new flow paths and create channels through several recognized processes, or styles. These include reoccupying existing channels, or annexation, downcutting into the floodplain, or incision, and constructing new channels from crevasse‐splay distributary networks, or progradation. Recent remote sensing observations show that avulsion style changes systematically moving downstream along modern fluvial fans but, to date, no studies have assessed the significance of these trends on fluvial fan stratigraphy. Here, spatiotemporal changes in avulsion stratigraphy are investigated within the Salt Wash Member of the Morrison Formation, deposited in the Cordilleran foreland basin during the Late Jurassic epoch. Measured sections and photographic panels were analysed from 23 locations across the Salt Wash extent. Avulsion style was identified in the stratigraphic record by the basal contact of a channel storey with underlying strata: channel–channel contacts indicate annexation, channel–floodplain contacts indicate incision and channel–heterolithic contacts indicate progradation. Contact types change downstream, such that channel–channel and channel–floodplain contacts dominate proximal locations, while channel–heterolithic contacts become increasingly prevalent downstream. Outcrop results were compared to a numerical model of fluvial fan formation and remote‐sensing analysis of avulsions on modern fans. In both additional datasets, channels in proximal fan positions tend to avulse via annexation, reoccupying abandoned channels, while channels in more distal positions tend to avulse via increasingly significant progradation. These findings suggest a relationship between newly recognized downstream changes in avulsion style and well‐established downstream changes in fluvial fan architecture. Furthermore, this suggests that fan architecture can inform interpretations of ancient fluvial dynamics, including avulsion behaviour, and that avulsions can cause stratigraphically significant and measurable changes to fan architecture. [ABSTRACT FROM AUTHOR]

Jewish Community Action (JCA) is a 501(c)(3) organization based in St. Paul, Minnesota, that, in collaboration with Black, Indigenous, and people of color (BIPOC)-led groups, equips Jewish people residing in the state to advocate for racial and economic justice. Community education and outreach are central to this work. JCA's Decriminalizing Communities Campaign, in particular, invites participants to transform the ways we conceive of public safety apart from systems of surveillance, incarceration, and detention. The Education Basebuilding Circles began in 2018, expanding the curriculum developed by Showing Up for Racial Justice (SURJ) in response to the legacy of police violence in the wake of the killing of Philando Castile. The circles use a popular education model to bring together adult learners by implementing a 6-week curriculum that examines the intersections of the criminal justice and immigration enforcement apparatus. This article summarizes that curriculum and provides examples of activities that effectively engage learners in self-reflection, community building, and action planning.