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Animals constantly need to evaluate available external and internal information to make appropriate decisions. Identifying, assessing, and acting on relevant cues in contexts such as mate choice, intra-sexual competition, and parental care is particularly important for optimizing individual reproductive success. Several factors can influence decision-making, such as external environmental cues and the animal’s own internal state, yet, we have limited knowledge on how animals integrate available information. Here, we used an entire island population (57 males, 53 females, and 1,109 tadpoles) of the neotropical brilliant-thighed poison frog Allobates femoralisto investigate how 2 factors (olfactory cues and personality traits) influence the ability of males to find and use new resources for tadpole deposition. We experimentally manipulated the location of tadpole deposition sites and their associated olfactory cues, and repeatedly measured exploration and boldness in adult males. We further reconstructed tadpole deposition choices via inferred parent–offspring relationships of adult frogs and tadpoles deposited in our experimental pools using molecular parentage analysis. We found that the discovery and use of new rearing sites were heavily influenced by olfactory cues; however, we did not find an effect of the measured behavioral traits on resource discovery and use. We conclude that in highly dynamic environments such as tropical rainforests, reliable external cues likely take priority over personality traits, helping individuals to discover and make use of reproductive resources.

Gangliosides are glycosphingolipids composed of an oligosaccharide that contains one or more sialic acid residues and is linked to a ceramide, a lipid composed of a long chain base (LCB) that bears an amide-linked fatty acyl group (FA). The ceramide portions of gangliosides are embedded in cell membranes; the exposed glycans interact with the extracellular environment. Gangliosides play a myriad of roles in activities such as cell–cell communication, formation of lipid rafts, cellular adhesion, calcium homeostasis, host-pathogen interaction, and viral invasion. Although the epitopes responsible for the interactions of gangliosides are located in the glycan, the epitope presentation is strongly influenced by the orientation of the attached ceramide within the lipid membrane, a feature that depends on the details of its structure, that is, the specific LCB and FA. Since the identities of both the glycan and the ceramide affect the activity of gangliosides, it is important to characterize the individual intact molecular forms. We report here a mass spectrometry-based method that combines the information gained from low-energy collision-induced dissociation (CID) measurements for the determination of the glycan with tandem mass spectra obtained at stepped higher-energy CID for the detailed characterization of the LCB and FA components of intact gangliosides. We provide results from applications of this method to the analysis of gangliosides present in bovine and human milk in order to demonstrate the assignment of LCB and FA for intact gangliosides and differential detection of isomeric ceramide structures.

We conducted a biophysical study to investigate the self-assembling and albumin-binding propensities of a series of fatty acid-modified locked nucleic acid (LNA) antisense oligonucleotide (ASO) gapmers specific to the MALAT1 gene. To this end, a series of biophysical techniques were applied using label-free ASOs that were covalently modified with saturated fatty acids (FAs) of varying length, branching, and 5′/3′ attachment. Using analytical ultracentrifugation (AUC), we demonstrate that ASOs conjugated with fatty acids longer than C16 exhibit an increasing tendency to form self-assembled vesicular structures. The C16 to C24 conjugates interacted viathe fatty acid chains with mouse and human serum albumin (MSA/HSA) to form stable adducts with near-linear correlation between FA-ASO hydrophobicity and binding strength to mouse albumin. This was not observed for the longer fatty acid chain ASO conjugates (>C24) under the experimental conditions applied. The longer FA-ASO however adopted self-assembled structures with increasing intrinsic stabilities proportional to the fatty acid chain length. For instance, FA chain lengths smaller than C24 readily formed self-assembled structures containing 2 (C16), 6 (C22, bis-C12), and 12 (C24) monomers, as measured by analytical ultracentrifugation (AUC). Incubation with albumin disrupted these supramolecular architectures to form FA-ASO/albumin complexes mostly with 2:1 stoichiometry and binding affinities in the low micromolar range, as determined by isothermal titration calorimetry (ITC) and analytical ultracentrifugation (AUC). Binding of FA-ASOs underwent a biphasic pattern for medium-length FA chain lengths (>C16) with an initial endothermic phase of particulate disruption, followed by an exothermic binding event to the albumin. Conversely, ASO modified with di-palmitic acid (C32) formed a strong, hexameric complex. This structure was not disrupted when incubated with albumin under conditions above the critical nanoparticle concentration (CNC; <0.4 μM). It is noteworthy that the interaction of parent, fatty acid-free malat1 ASO to albumin was below detectability by ITC (KD≫150 μM). This work demonstrates that the nature of mono- vs multimeric structures of hydrophobically modified ASOs is governed by the hydrophobic effect. Consequently, supramolecular assembly to form particulate structures is a direct consequence of the fatty acid chain length. This provides opportunities to exploit the concept of hydrophobic modification to influence pharmacokinetics (PK) and biodistribution for ASOs in two ways: (1) binding of the FA-ASO to albumin as a carrier vehicle and (2) self-assembly resulting in albumin-inert, supramolecular architectures. Both concepts create opportunities to influence biodistribution, receptor interaction, uptake mechanism, and pharmacokinetics/pharmacodynamics (PK/PD) properties in vivo, potentially enabling access to extrahepatic tissues in sufficient concentration to treat disease.

There is growing recognition that water insecurity – the inability to reliably access sufficient water for all household uses – is commonly experienced globally and has myriad adverse consequences for human well-being. The role of water insecurity in food insecurity and diet quality, however, has received minimal attention. Data are from panel surveys conducted during 2020–21 among adults involved in smallholder agriculture in Niger (n = 364, 3 rounds), Nigeria (n = 501, 5 rounds), Senegal (n = 501, 5 rounds), and Ghana (n = 543, 5 rounds). We hypothesized that household water insecurity (measured using the brief Household Water Insecurity Experiences Scale) would be associated with greater individual food insecurity (using 5 of the 8 Food Insecurity Experiences Scale items) and lower dietary diversity (using the Minimum Dietary Diversity Score for Women). At baseline, 37.1% of individuals were living in water-insecure households and of these, 90.6% had some experience of food insecurity. In multilevel mixed-effects regressions, individuals living in water-insecure households had 1.67 (95% CI: 1.47, 1.89) times higher odds of reporting any food insecurity experience and were estimated to consume 0.38-fewer food groups (95% CI: -0.50, -0.27) than those living in water-secure households. Experiences with suboptimal water access and use are associated with poor nutrition. The pathways by which water insecurity impacts nutrition should be identified. Global and national food and nutrition security policies could be strengthened by monitoring and developing strategies to address household water insecurity.

The global effects of the Ukraine war hit girls and women the hardest, exacerbating inequalities. Aid programmes must adapt.

Background Flow diverters (FDs) are an effective treatment for intracranial aneurysms, though not free from hemorrhagic complications. A previous study demonstrated increased vascular contractility after FD-implantation as a potential mechanism of distal complications. Our study aimed to investigate whether L-arginine medication affects vascular contractility following FD deployment in a rabbit model.Methods FDs were implanted in the aorta of normal rabbits (+FD, n = 10), with sham-operated aorta as controls (n = 5). L-Arginine was given in the drinking water (2.25% L-arginine hydrochloride) of half of the +FD animals (+FD/+Arg). Force contraction vascular contractility studies were performed on the aortic rings proximal and distal to the FD using an organ bath. Total eNOS, eNOS(pS1177), eNOS(pT495), COX-2, and S100A4 were quantified by western analysis on total protein lysates from aortic segments, normalizing to GAPDH.Results Mean vascular contractility was 53% higher in distal relative to proximal aortic segments (P = 0.0038) in +FD animals, but were not significantly different in +FD/+Arg animals, or in sham-operated controls. The +FD animals expressed significantly reduced levels of eNOS(pS1177) than sham-operated controls (P = 0.0335), while both the +FD and +FD/+Arg groups had reduced levels of eNOS(pT495) relative to sham-operated controls (P = 0.0331 and P = 0.0311, respectively).Conclusion These results suggest that L-arginine medication reduces distal vascular contractility after FD treatment via nitric oxide production and thus might mitigate risk for downstream complications.

Erysipelothrix rhusiopathiaeinfection and septicemia occurred in a 5-d old Boer goat found dead on a farm in western Pennsylvania. On autopsy, there was moderate, focally extensive hemorrhage along the remnants of the urachus and umbilical arteries and the apex of the urinary bladder. Microscopic examination of immunohistochemical stained tissues revealed abundant intracellular and extracellular E. rhusiopathiaeantigen–positive bacilli in all tissues stained, including lung, heart, liver, skeletal muscle, kidney, and thymus. Bacteria isolated from liver and urachus were identified as E. rhusiopathiaeby MALDI-TOF mass spectrometry and further confirmed by a PCR assay. An epidemiologic investigation was conducted via an on-farm questionnaire after the owners noted a 70% mortality rate from the 2019 kidding season. The epidemiologic investigation showed that E. rhusiopathiae, an opportunistic zoonotic organism, was introduced to the farm through a breach in biosecurity and was likely perpetuated among the resident poultry species.

There was no evidence of differences in clinical or histopathologic neurotoxicity parameters between rats exposed to supradiagnostic human dose equivalents of commercially available gadolinium-based contrast agents and saline-exposed rats.

Peripheral neuropathies are a recognized complication of labor in the post-partum period. Herein, we describe an uncommon presentation of sciatic mononeuropathy due to ischiofemoral impingement during labor. A 29-year-old, gravida 4 para 2, female presented post-partum with acute left lower limb paresthesia and left foot drop, following spontaneous vaginal delivery of twins. Neurological examination demonstrated no activation of the left sciatic-innervated muscles and sensory loss in the same distribution. Electromyography (EMG) demonstrated an acute complete left sciatic mononeuropathy. MRI of the lumbosacral plexus and sciatic nerve showed a narrowed quadratus femoris space with mild edema of the muscle, consistent with ischiofemoral impingement syndrome. In addition, there was flattening of the sciatic nerve as it passed through the ischiofemoral space. She was treated conservatively, and at 7-month follow-up, there was marked improvement in muscle strength with ongoing sensory impairment. Repeat EMG demonstrated reinnervation in all sciatic-innervated muscles. This case highlights the risk of a sciatic mononeuropathy secondary to ischiofemoral impingement in the peripartum setting. Future studies are needed to determine if women with a narrow ischiofemoral space at baseline are at increased risk for peripheral nerve injury during labor.

AbstractProlonged and complex courtship behaviors, involving tactile, acoustic, and visual signals, are common in Neotropical poison frogs (Dendrobatidae). Courtship is an important precursor to mating, but courtship components vary across species. In Brilliant-Thighed Poison Frogs (Allobates femoralis[Boulenger 1883]), males guide females to oviposition sites in a so-called “courtship march.” The courtship duration in A. femoralisis among the longest known in poison frogs. To gain insights into the functions of courtship, we observed 29 courtship events in an A. femoralispopulation in French Guiana. In addition, we observed multiple courtships of 7 males to assess intra- and interindividual variations in courtship behavior. We recorded temporal, spatial, and behavioral characteristics of courtship and searched for previously deposited clutches in the males' territories. Courtships started in the afternoon and ended on the following morning. During courtship, pairs moved an average of 19 m within an area of about 6 m2. Twenty-seven out of 29 courtships (93.1%) resulted in successful oviposition, indicating that females rarely reject males once engaged in courtship. Contrary to previous studies of A. femoralis, the spatial and temporal extent of the courtship march did not correlate with the size of a male's territory. Our results indicate that females do not evaluate male quality during courtship but might need an extended courtship phase to verify territory ownership of the courting male and to stimulate ovulation. The prolonged courtship might also be beneficial for spatial learning by females, allowing them to find clutches again in cases of mate loss. Temporal and spatial characteristics vary considerably within and among individuals, and males do not use the same routes in consecutive courtships. However, they probably show females previous clutches. Several courtship traits in our study population differ from A. femoraliscourtship previously described from Peru and Brazil, indicating that dendrobatid courtship is variable among populations.

Water security is a powerful concept that is still in its early days in the field of nutrition. Given the prevalence and severity of water issues and the many interconnections between water and nutrition, we argue that water security deserves attention commensurate with its importance to human nutrition and health. To this end, we first give a brief introduction to water insecurity and discuss its conceptualization in terms of availability, access, use, and stability. We then lay out the empirical grounding for its assessment. Parallels to the food-security literature are drawn throughout, both because the concepts are analogous and food security is familiar to the nutrition community. Specifically, we review the evolution of scales to measure water and food security and compare select characteristics. We then review the burgeoning evidence for the causes and consequences of water insecurity and conclude with 4 recommendations: 1) collect more water-insecurity data (i.e., on prevalence, causes, consequences, and intervention impacts); 2) collect better data on water insecurity (i.e., measure it concurrently with food security and other nutritional indicators, measure intrahousehold variation, and establish baseline indicators of both water and nutrition before interventions are implemented); 3) consider food and water issues jointly in policy and practice (e.g., establish linkages and possibilities for joint interventions, recognize the environmental footprint of nutritional guidelines, strengthen the nutrition sensitivity of water-management practices, and use experience-based scales for improving governance and regulation across food and water systems); and 4) make findings easily available so that they can be used by the media, community organizations, and other scientists for advocacy and in governance (e.g., tracking progress towards development goals and holding implementers accountable). As recognition of the importance of water security grows, we hope that so too will the prioritization of water in nutrition research, funding, and policy.

Water security is a powerful concept that is still in its early days in the field of nutrition. Given the prevalence and severity of water issues and the many interconnections between water and nutrition, we argue that water security deserves attention commensurate with its importance to human nutrition and health. To this end, we first give a brief introduction to water insecurity and discuss its conceptualization in terms of availability, access, use, and stability. We then lay out the empirical grounding for its assessment. Parallels to the food-security literature are drawn throughout, both because the concepts are analogous and food security is familiar to the nutrition community. Specifically, we review the evolution of scales to measure water and food security and compare select characteristics. We then review the burgeoning evidence for the causes and consequences of water insecurity and conclude with 4 recommendations: 1) collect more water-insecurity data (i.e., on prevalence, causes, consequences, and intervention impacts); 2) collect better data on water insecurity (i.e., measure it concurrently with food security and other nutritional indicators, measure intrahousehold variation, and establish baseline indicators of both water and nutrition before interventions are implemented); 3) consider food and water issues jointly in policy and practice (e.g., establish linkages and possibilities for joint interventions, recognize the environmental footprint of nutritional guidelines, strengthen the nutrition sensitivity of water-management practices, and use experience-based scales for improving governance and regulation across food and water systems); and 4) make findings easily available so that they can be used by the media, community organizations, and other scientists for advocacy and in governance (e.g., tracking progress towards development goals and holding implementers accountable). As recognition of the importance of water security grows, we hope that so too will the prioritization of water in nutrition research, funding, and policy.

Climate change affects every aspect of the food system, including all nodes along agri-food value chains from production to consumption, the food environments in which people live, and outcomes, such as diets and livelihoods. Men and women often have specific roles and responsibilities within food systems, yet structural inequalities (formal and informal) limit women's access to resources, services, and agency. These inequalities affect the ways in which men and women experience and are affected by climate change. In addition to gender, other social factors are at play, such as age, education, marital status, and health and economic conditions. To date, most climate change policies, investments, and interventions do not adequately integrate gender. If climate-smart and climate-resilient interventions do not adequately take gender differences into account, they might exacerbate gender inequalities in food systems by, for instance, increasing women's labor burden and time poverty, reducing their access to and control over income and assets, and reducing their decision-making power. At the same time, women's contributions are critical to make food systems more resilient to the negative impacts of climate change, given their specialized knowledge, skills and roles in agri-food systems, within the household, at work and in their communities. Increasing the resilience of food systems requires going beyond addressing gendered vulnerabilities to climate change to create an enabling environment that supports gender equality and women's empowerment, by removing structural barriers and rigid gender norms, and building equal power dynamics, as part of a process of gender transformative change. For this to happen, more research is needed to prioritize structural barriers that need to be removed and to identify effective gender transformative approaches.

AbstractDespite rising interest among scientists for over two centuries, parental care behavior has not been as thoroughly studied in amphibians as it has in other taxa. The first reports of amphibian parental care date from the early 18th century, when Maria Sibylla Merian went on a field expedition in Suriname and reported frog metamorphs emerging from their mother's dorsal skin. Reports of this and other parental behaviors in amphibians remained descriptive for decades, often as side notes during expeditions with another purpose. However, since the 1980s, experimental approaches have proliferated, providing detailed knowledge about the adaptive value of observed behaviors. Today, we recognize more than 30 types of parental care in amphibians, but most studies focus on just a few families and have favored anurans over urodeles and caecilians. Here, we provide a synthesis of the last three centuries of parental care research in the three orders comprising the amphibians. We draw attention to the progress from the very first descriptions to the most recent experimental studies, and highlight the importance of natural history observations as a source of new hypotheses and necessary context to interpret experimental findings. We encourage amphibian parental care researchers to diversify their study systems to allow for a more comprehensive perspective of the behaviors that amphibians exhibit. Finally, we uncover knowledge gaps and suggest new avenues of research using a variety of disciplines and approaches that will allow us to better understand the function and evolution of parental care behaviors in this diverse group of animals.

Soil organic amendments (OAs) are used to replenish carbon and nutrients in the soil to prevent its degradation and increase its fertility. While soil can be an important carbon sink, it can also release significant amounts of greenhouse gases (GHGs). Different OA pre-treatment technologies indirectly affect soil aggregate formation and carbon stabilisation even when the same initial substrate is used. However, little is known about the long-term effects of OA pre-treatment on the soil carbon and nitrogen associated with macroaggregates, which are known to disintegrate faster than microaggregates. In this study, we studied the effect of OA-pre-treatment on the soil carbon and nitrogen in relation to aggregate formation and GHG emission using five different OAs (i.e., compost, digestate, fermented product, raw substrate, and a 1:1 mix of compost and fermented product) made of the same type of initial substrate. We monitored the changes in a soil column experiment after 6 and 12 months. Our results indicated that the OA pre-treatment can indirectly affect the GHG emission from soil (i.e., carbon dioxide, nitrous oxide and methane). Compost and the mix released less GHG but had no positive impact on macroaggregates, while digestate induced long-lasting macroaggregation and occluded particulate organic matter formation, emitting intermediate levels of GHGs. The raw material exhibited the highest GHG emissions, similar to fermented products, albeit without benefiting macroaggregation. This research demonstrated that OA pre-treatment has a long-lasting indirect effect on soil carbon and nitrogen, influencing total GHG emissions, N2O formation mechanisms and soil macroaggregate formation.

Irrigation expansion is critical for agricultural and rural development, food and nutrition security, and climate change adaptation in Sub-Saharan Africa (SSA). Lack of accessible energy for irrigation development due to limited off- and on-grid infrastructure and the resulting dependence on costly fuel-based irrigation have been key inhibiting factors for irrigation expansion in the region. Off-grid solar-powered irrigation pumps (SIPs) can overcome many of the energy access and other challenges in the region, but their uptake has been slow. Given the nascent development of the solar irrigation sector in SSA, this paper combines a review of the peer-reviewed and grey literature with key informant interviews to identify systemic barriers to the adoption and growth of solar-powered irrigation. We identify uncovered risks, lack of incentives, and lack of capacity as the key factors limiting the adoption of solar-powered irrigation. Moreover, despite significant global cost reductions, solar-powered irrigation systems remain costly in SSA due to limited market development and geographical constraints. Lack of regulation and low investment in building local institutions and value chains further affect uptake and inhibit leveraging the energy transition for ensuring food security and agriculture-led poverty alleviation in SSA. We propose a move away from thinking of SIPs as “silver bullets” and towards a systems approach and the design of context-specific solutions to address risks, incentives and capacity challenges.

ABSTRACTHigh specificity accompanied with the ability to recruit immune cells has made recombinant therapeutic antibodies an integral part of drug development. Here we present a generic approach to generate two novel IgG-derived antibody formats that are based on a modification of the CrossMab technology. MoAbs harbor two heavy chains (HCs) resulting in one binding entity and one fragment crystallizable region (Fc), whereas DuoMabs are composed of four HCs harboring two binding entities and two Fc regions linked at a disulfide-bridged hinge. The latter bivalent format is characterized by avidity-enhanced target cell binding while simultaneously increasing the ‘Fc-load’ on the surface. DuoMabs were shown to be producible in high yield and purity and bind to surface cells with affinities comparable to IgGs. The increased Fc load directed at the surface of target cells by DuoMabs modulates their antibody-dependent cell-mediated cytotoxicity competency toward target cells, making them attractive for applications that require or are modulated by FcR interactions.

Aberrations in genes coding for subunits of the BRG1/BRM associated factor (BAF) chromatin remodeling complexes are highly abundant in human cancers. Currently, it is not understood how these mostly loss-of-function mutations contribute to cancer development and how they can be targeted therapeutically. The cancer-type-specific occurrence patterns of certain subunit mutations suggest subunit-specific effects on BAF complex function, possibly by the formation of aberrant residual complexes. Here, we systematically characterize the effects of individual subunit loss on complex composition, chromatin accessibility and gene expression in a panel of knockout cell lines deficient for 22 BAF subunits. We observe strong, specific and sometimes discordant alterations dependent on the targeted subunit and show that these explain intracomplex codependencies, including the synthetic lethal interactions SMARCA4–ARID2, SMARCA4–ACTB and SMARCC1–SMARCC2. These data provide insights into the role of different BAF subcomplexes in genome-wide chromatin organization and suggest approaches to therapeutically target BAF-mutant cancers. The authors generate cell lines deficient for 22 BAF subunits, studying effects on complex composition, chromatin accessibility and gene expression. They identify synthetic lethal interactions between SMARCA4–ARID2, SMARCA4–ACTB and SMARCC1–SMARCC2.

The histone acetyl reader bromodomain-containing protein 4 (BRD4) is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1 (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1). We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression; pharmacological inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin associated suggests a direct role for nuclear metabolism in the control of gene expression.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.

Appropriate agricultural water management (AWM) is crucial not only for alleviating water scarcity but also for food and nutrition security and healthy ecosystems. The multidimensional nature of AWM and inherently complex feedbacks between its components necessitate a systems approach. This paper proposes six dimensions of AWM and illustrates the importance of a systems approach using six separate, but linked, classical AWM topics. By emphasizing the whole picture of AWM and interactions among its subsystems at multiple levels, a systems approach offers the opportunity to holistically scrutinize the pros and cons of proposed AWM interventions beyond their direct effects at the locus that a single‐dimensional approach foretells. Six dimensions for agricultural water management are proposedA systems perspective is a sine qua non for identifying interventions and formulating successful agricultural water policiesSuccess stories reconfirm the importance of taking a systems approach

Interventions that aim to increase water availability for agriculture hold great potential for improving nutrition through increasing food production, generating income, enhancing water access and sanitation and hygiene conditions, and through strengthening women’s empowerment. Yet there is scarce evidence on the linkages between small-scale irrigation and the pathways through which nutrition outcomes can be achieved. Using data from a cross-sectional household survey collected in Ethiopia and Tanzania, we explored the potential for small-scale irrigation to contribute to improved diets, and identify the pathways through which irrigation affects dietary diversity as measured by the Household Dietary Diversity Score. Unadjusted comparisons show that irrigating households in both countries produced more vegetables, fruits and cash crops, are less food insecure, have a higher value of production, and have higher production diversity and dietary diversity compared to non-irrigating households. Econometric results of a simultaneous equation (3SLS) model showed that irrigation leads to better household dietary diversity mainly through the pathway of increasing household incomes. However, these results are statistically significant only in the case of Ethiopia, and not in Tanzania. While irrigation increased production diversity in Ethiopia, the benefits of increased dietary diversity cannot be attributed to these changes in production after controlling for the effect of income. Other factors, such as gender of the household head and having off-farm income, also influence dietary diversity in Ethiopia. These findings suggest that the potential for irrigation to influence diets is highly context-specific. Understanding the particular pathways and entry points for nutrition-sensitive agriculture approaches could help to improve their benefits for nutrition.

During the winter of 2014, a weak polar vortex brought record cold temperatures to the north‐central (“Midwest”) United States, and the Great Lakes reached the highest extent of ice coverage (92.5%) since 1979. This event shut down the generation of seismic signals caused by wind‐driven wave action within the lakes (termed “lake microseisms”), giving an unprecedented opportunity to isolate and characterize these novel signals through comparison with nonfrozen time periods. Using seismic records at 72 broadband stations, we observe Great Lakes microseism signals at distances >300 km from the lakes. In contrast to conventional oceanic microseisms, there is no clear relationship between the frequency content of the seismic signals (observed from ~0.5–5‐s period) and the dominant swell period or resonance periods of the lakes based on their bathymetric profiles. Thus, the exact generation mechanism is not readily explained by conventional microseism theory and warrants further investigation. Besides earthquakes, a large range of signals are recorded by seismic instruments, including cultural activity, wind, and ocean waves. Although these signals are often a hindrance to earthquake studies, they have recently been used as a tool for seismic imaging as well as for studying near‐surface processes. Here we explore the characteristics and spatial area impacted by novel signals arising from wind‐driven wave activity within the Great Lakes of North America. As these signals often blend in to other noise sources (such as ocean waves) they have been difficult to understand and fully characterize. We overcome this difficulty by utilizing seismic records from 2014, when a meandering jet stream led to anomalously high concentrations of ice coverage (92.5% coverage) over the Great Lakes during the early spring. As a consequence of this event, seismic signals generated by the lakes vanished. By comparing seismic records during this time period to previous and subsequent nonfrozen years, we are able to isolate the contribution of lake microseisms and show that they significantly impact seismic recordings across the Midwestern United States. Anomalously high ice extent on the North American Great Lakes during the winter of 2014 shut down the generation of lake microseismsSeismic signals from the Great Lakes occur between 0.5 and 5‐s period and are observable at distances >300 km from lake shorelinesThe Michigan Upper Peninsula observes the strongest signals; these peak at ~1.5‐s period regardless of the swell period in Lake Superior

Zusammenfassung.Ethylenglykol ist ein süsslich schmeckender Alkohol (einfachster zweiwertiger Alkohol, Synonym «Glykol»), der in handelsüblichen Frostschutzmitteln und anderen industriellen Lösungen verwendet wird. Ohne adäquate Therapiemassnahmen kann eine Intoxikation mit Ethylenglykol zu einer schweren metabolischen Azidose, zum akuten Nierenversagen und zum Tod führen. Nach gastrointestinaler Resorption findet die Metabolisierung überwiegend hepatisch, unter anderem durch die Alkoholdehydrogenase, statt und resultiert in einer schweren metabolischen Azidose mit Anionenlücke und der Bildung von Kalziumoxalat-Kristallen, die sich in verschiedenen Geweben ablagern können. In der Niere führt dies zur akuten Tubulusnekrose mit potenziell reversiblem Nierenversagen. Therapeutisch entscheidend ist die schnellstmögliche Inhibition der Alkoholdehydrogenase durch Fomepizol oder Ethanol, um die Bildung toxischer Metaboliten zu verhindern. Die Hämodialyse bietet die effektivste Methode der sekundären Dekontamination. Bei frühem Therapiebeginn ist die Prognose günstig.

Patients with refractory or relapsed haematological malignancies have few treatment options and short survival times. Identification of effective therapies with genomic-based precision medicine is hampered by intratumour heterogeneity and incomplete understanding of the contribution of various mutations within specific cancer phenotypes. Ex-vivo drug-response profiling in patient biopsies might aid effective treatment identification; however, proof of its clinical utility is limited.

A calibrated deep learning model for analyzing medical images that outputs an uncertainty level for each prediction provides better understanding and trust in stand-alone artificial intelligence models deployed in the clinical workflow.

Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for γ-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.

Small-molecule drugs may complement antibody-based therapies in an immune-oncology setting, yet systematic methods for the identification and characterization of the immunomodulatory properties of these entities are lacking. We surveyed the immumomodulatory potential of 1,402 small chemical molecules, as defined by their ability to alter the cell-cell interactions among peripheral mononuclear leukocytes ex vivo, using automated microscopy and population-wide single-cell image analysis. Unexpectedly, ∼10% of the agents tested affected these cell-cell interactions differentially. The results accurately recapitulated known immunomodulatory drug classes and revealed several clinically approved drugs that unexpectedly harbor the ability to modulate the immune system, which could potentially contribute to their physiological mechanism of action. For instance, the kinase inhibitor crizotinib promoted T cell interactions with monocytes, as well as with cancer cells, through inhibition of the receptor tyrosine kinase MSTR1 and subsequent upregulation of the expression of major histocompatibility complex molecules. The approach offers an attractive platform for the personalized identification and characterization of immunomodulatory therapeutics.

Reoperation rates are high after surgery for hip fractures. We investigated the effect of a sliding hip screw versus cancellous screws on the risk of reoperation and other key outcomes.

Letter to the Editor

mRNA LNPs can experience a decline in activity over short periods (ranging from weeks to months). As a result, they require frozen storage and transportation conditions to maintain their full functionality when utilized. Currently approved commercially available mRNA LNP vaccines also necessitate frozen storage and supply chain management. Overcoming this significant inconvenience in the future is crucial to reducing unnecessary costs and challenges associated with storage and transport. In this study, our objective was to illuminate the potential time frame for nonfrozen storage and transportation conditions of mRNA LNPs without compromising their activity. To achieve this goal, we conducted a stability assessment and an in vitro cell culture delivery study involving five mRNA LNPs. These LNPs were constructed by using a standard formulation similar to that employed in the three commercially available LNP formulations. Among these formulations, we selected five structurally diverse ionizable lipids─C12–200, CKK-E12, MC3, SM-102, and lipid 23─from the existing literature. We incorporated these lipids into a standard LNP formulation, keeping all other components identical. The LNPs, carrying mRNA payloads, were synthesized by using microfluidic mixing technology. We evaluated the shelf life stability of these LNPs over a span of 9 weeks at temperatures of 2–8, 25, and 40 °C, utilizing an array of analytical techniques. Our findings indicated minimal impact on the hydrodynamic diameter, zeta potential, encapsulation efficiency, and polydispersity of all LNPs across the various temperatures over the studied period. The RiboGreen assay analysis of LNPs showed consistent mRNA contents over several weeks at various nonfrozen storage temperatures, leading to the incorrect assumption of intact and functional LNPs. This misunderstanding was rectified by the significant differences observed in EGFP protein expression in an in vitro cell culture (using HEK293 cells) across the five LNPs. Specifically, only LNP 1 (C12–200) and LNP 4 (SM-102) exhibited high levels of EGFP expression at the start (T0), with over 90% of HEK293 cells transfected and mean fluorescence intensity (MFI) levels exceeding 1. Interestingly, LNP 1 (C12–200) maintained largely unchanged levels of in vitro activity over 11 weeks when stored at both 2–8 and 25 °C. In contrast, LNP 4 (SM-102) retained its functionality when stored at 2–8 °C over 11 weeks but experienced a gradual decline of in vitro activity when stored at room temperature over the same period. Importantly, we observed distinct LNP architectures for the five formulations through cryo-EM imaging. This highlights the necessity for a deeper comprehension of structure–activity relationships within these complex nanoparticle structures. Enhancing our understanding in this regard is vital for overcoming storage and stability limitations, ultimately facilitating the broader application of this technology beyond vaccines.

•Water resilient food systems will be critical for meeting future food demands under changing climates.•Six foundational elements of good governance are proposed that could reduce future water insecurity in food systems.•Greater understanding of the role of working with nature will be central to achieving water resilient food systems.•Incentives, innovations in institutions, and technology will be critical to address trade-offs, make difficult decisions and make sound investments.

For animals to survive until reproduction, it is crucial that juveniles successfully detect potential predators and respond with appropriate behavior. The recognition of cues originating from predators can be innate or learned. Cues of various modalities might be used alone or in multi-modal combinations to detect and distinguish predators but studies investigating multi-modal integration in predator avoidance are scarce. Here, we used wild, naive tadpoles of the Neotropical poison frog Allobates femoralis ( Boulenger, 1884) to test their reaction to cues with two modalities from two different sympatrically occurring potential predators: heterospecific predatory Dendrobates tinctorius tadpoles and dragonfly larvae. We presented A. femoralis tadpoles with olfactory or visual cues, or a combination of the two, and compared their reaction to a water control in a between-individual design. In our trials, A. femoralis tadpoles reacted to multi-modal stimuli (a combination of visual and chemical information) originating from dragonfly larvae with avoidance but showed no reaction to uni-modal cues or cues from heterospecific tadpoles. In addition, visual cues from conspecifics increased swimming activity while cues from predators had no effect on tadpole activity. Our results show that A. femoralis tadpoles can innately recognize some predators and probably need both visual and chemical information to effectively avoid them. This is the first study looking at anti-predator behavior in poison frog tadpoles. We discuss how parental care might influence the expression of predator avoidance responses in tadpoles.

ABSTRACTThe formation of undesired high molecular weight species such as dimers is an important quality attribute for therapeutic monoclonal antibody formulations. Therefore, the thorough understanding of mAb dimerization and the detailed characterization mAb dimers is of great interest for future pharmaceutical development of therapeutic antibodies. In this work, we focused on the analyses of different mAb dimers regarding size, surface properties, chemical identity, overall structure and localization of possible dimerization sites. Dimer fractions of different mAbs were isolated to a satisfactory purity from bulk material and revealed 2 predominant overall structures, namely elongated and compact dimer forms. The elongated dimers displayed one dimerization site involving the tip of the Fab domain. Depending on the stress applied, these elongated dimers are connected either covalently or non-covalently. In contrast, the compact dimers exhibited non-covalent association. Several interaction points were detected for the compact dimers involving the hinge region or the base of the Fab domain. These results indicate that mAb dimer fractions are rather complex and may contain more than one kind of dimer. Nevertheless, the overall appearance of mAb dimers suggests the existence of 2 predominant dimeric structures, elongated and compact, which are commonly present in preparations of therapeutic mAbs.

AbstractSince 2012, a multi-agency initiative to restore these native forage species has been under way. Evaluating the restoration success of Cisco Coregonus artediand Bloater C. hoyiin Lake Ontario waters requires methods to identify stocked fish. However, juvenile Cisco and Bloater are fragile; thus, mass marking techniques that reduce the handling of individual fish are required and have not previously been evaluated. In 2014–2015 we evaluated the usefulness of calcein (SE-MARK) as a marker on bony structures, including the otolith. Juvenile Bloater and Cisco (14, 100, 128 d old) were immersed in a calcein bath at 5,000 mg/L of water for 4 min to apply the chemical marker. Observations of the marking retention were evaluated 8 d following the treatment. All fish immersed in calcein had strong brilliant marks (rating scale 3) on all bony structures including scales, fin rays, jaw bones, and vertebrate. The otolith was the only hard structure that did not show a brilliant marking due to the opaque nature of the structure. Our results suggest that calcein produces a strong discernable mark on hard bony structures of Cisco and Bloater; however, long-term retention needs further study.Received October 30, 2015; accepted January 9, 2016

Since 2012, a multi-agency initiative to restore these native forage species has been under way. Evaluating the restoration success of Cisco Coregonus artediand Bloater C. hoyiin Lake Ontario waters requires methods to identify stocked fish. However, juvenile Cisco and Bloater are fragile; thus, mass marking techniques that reduce the handling of individual fish are required and have not previously been evaluated. In 2014–2015 we evaluated the usefulness of calcein (SE-MARK) as a marker on bony structures, including the otolith. Juvenile Bloater and Cisco (14, 100, 128 d old) were immersed in a calcein bath at 5,000 mg/L of water for 4 min to apply the chemical marker. Observations of the marking retention were evaluated 8 d following the treatment. All fish immersed in calcein had strong brilliant marks (rating scale 3) on all bony structures including scales, fin rays, jaw bones, and vertebrate. The otolith was the only hard structure that did not show a brilliant marking due to the opaque nature of the structure. Our results suggest that calcein produces a strong discernable mark on hard bony structures of Cisco and Bloater; however, long-term retention needs further study.

The resolution adopted by the General Assembly of the United Nations on 25 September 2015 is symptomatic of the water-energy-food (WEF) nexus. It postulates goals and related targets for 2030 that include (1) End hunger, achieve food security and improved nutrition, and promote sustainable agriculture (SDG2); (2) Ensure availability and sustainable management of water and sanitation for all (SDG6); and (3) Ensure access to affordable, reliable, sustainable, and modern energy for all (SDG7). There will be tradeoffs between achieving these goals particularly in the wake of changing consumption patterns and rising demands from a growing population expected to reach more than nine billion by 2050. This paper uses global economic analysis tools to assess the impacts of long-term changes in fossil fuel prices, for example, as a result of a carbon tax under the UNFCCC or in response to new, large findings of fossil energy sources, on water and food outcomes. We find that a fossil fuel tax would not adversely affect food security and could be a boon to global food security if it reduces adverse climate change impacts.

Self-assembly refers to the spontaneous organization of individual building blocks into higher order structures. It occurs in biological systems such as spherical viruses, which utilize icosahedral symmetry as a guiding principle for the assembly of coat proteins into a capsid shell. In this study, we characterize the self-assembling protein nanoparticle (SAPN) system, which was inspired by such viruses. To facilitate self-assembly, monomeric building blocks have been designed to contain two oligomerization domains. An N-terminal pentameric coiled-coil domain is linked to a C-terminal coiled-coil trimer by two glycine residues. By combining monomers with inherent propensity to form five- and threefold symmetries in higher order agglomerates, the supposition is that nanoparticles will form that exhibit local and global symmetry axes of order 3 and 5. This article explores the principles that govern the assembly of such a system. Specifically, we show that the system predominantly forms according to a spherical core-shell morphology using a combination of scanning transmission electron microscopy and small angle neutron scattering. We introduce a mathematical toolkit to provide a specific description of the possible SAPN morphologies, and we apply it to characterize all particles with maximal symmetry. In particular, we present schematics that define the relative positions of all individual chains in the symmetric SAPN particles, and provide a guide of how this approach can be generalized to nonspherical morphologies, hence providing unprecedented insights into their geometries that can be exploited in future applications.

Global seismographic networks (GSNs) emerged during the late nineteenth and early twentieth centuries, facilitated by seminal international developments in theory, technology, instrumentation, and data exchange. The mid‐ to late‐twentieth century saw the creation of the World‐Wide Standardized Seismographic Network (1961) and International Deployment of Accelerometers (1976), which advanced global geographic coverage as seismometer bandwidth increased greatly allowing for the recording of the Earth's principal seismic spectrum. The modern era of global observations and rapid data access began during the 1980s, and notably included the inception of the GEOSCOPE initiative (1982) and GSN (1988). Through continual improvements, GEOSCOPE and the GSN have realized near‐real time recording of ground motion with state‐of‐art data quality, dynamic range, and timing precision to encompass 180 seismic stations, many in very remote locations. Data from GSNs are increasingly integrated with other geophysical data (e.g., space geodesy, infrasound and Interferometric Synthetic Aperture Radar). Globally distributed seismic data are critical to resolving crust, mantle, and core structure; illuminating features of the plate tectonic and mantle convection system; rapid characterization of earthquakes; identification of potential tsunamis; global nuclear test verification; and provide sensitive proxies for environmental changes. As the global geosciences community continues to advance our understanding of Earth structure and processes controlling elastic wave propagation, GSN infrastructure offers a springboard to realize increasingly multi‐instrument geophysical observatories. Here, we review the historical, scientific, and monitoring heritage of GSNs, summarize key discoveries, and discuss future associated opportunities for Earth Science. Global seismographic networks (GSNs) record information‐rich ground motion signals that allow scientists and nations to identify and quantify global earthquakes and other seismic sources, and to rapidly assess their significance and impacts on society. In addition to providing a global standard for the monitoring and assessment of such events, these networks provide unique high‐quality data that are fundamental to revealing Earth's structure and dynamic behavior. Scientific applications of GSNs, supplemented by regional data, include imaging the deep interior of the Earth and its plate tectonic system, modeling the structure and dynamics of the inner core, imaging and understanding the rupture of earthquake faults, detecting, discriminating, and characterizing nuclear and other explosions, and improving our general understanding of Earth's ubiquitous seismic wavefield and the unique information that it conveys from the deep interior to the surface and atmosphere of the planet. Leveraging the extensive and hardened infrastructure at these global observatories facilitates the recording of other signals of geophysical interest, such as the magnetic field, low frequency sound waves, and meteorological observations. We review the heritage of GSNs, including their history and resulting scientific achievements, and summarize future opportunities for these networks to contribute further to improved advancements in Earth science. Long running globally distributed seismographic networks are fundamental to understanding Earth's interior structure and processesNetworks have expanded beyond initial mid‐twentieth century design which were focused on recording signals from earthquakes and explosionsGlobal seismic data combined with data from nearby geophysical instrumentation continue to facilitate new discoveries in Earth science Long running globally distributed seismographic networks are fundamental to understanding Earth's interior structure and processes Networks have expanded beyond initial mid‐twentieth century design which were focused on recording signals from earthquakes and explosions Global seismic data combined with data from nearby geophysical instrumentation continue to facilitate new discoveries in Earth science

AbstractMurphy MH, Gandino CJ, Ringler NH, Kirby L, Johnson S, Smith M, Schroeder S. 2015. Assessment of the Onondaga Lake, New York, fish community following reductions of nutrient inputs from a wastewater treatment plant. Lake Reserv Manage. 31:347–358.Fish surveys have been periodically conducted on Onondaga Lake since 1927; more intensive surveys began in 1989 by the State University of New York, College of Environmental Science and Forestry, and have continued annually. Recent efforts (2000–2012) by the Onondaga County Department of Water Environment Protection documented the fish community prior to and following (post-2005) major reductions in nutrient loading to Onondaga Lake from the wastewater treatment facility in Syracuse, New York. These upgrades have had dramatic effects on the lake fish community; adult species richness has increased from 13 species recorded in 1946 to more than 40 species documented annually since 2008 and more than 50 species documented since 2000. Adult species diversity has varied since 2000, with increasing dominance by largemouth bass, yellow perch, and brown bullhead. Adult fish diversity was significantly higher following wastewater treatment plant upgrades in 2004 and 2005 (F1,18= 5.26, P= 0.03). Dramatic increases in macrophyte coverage and dreissenid mussel densities also have been documented. Rarefaction analysis was conducted to standardize survey results by computing expected species richness values from 2000 to 2012 as well as relative to 1946. Expected species richness was not statistically significant following upgrades compared to prior (F1,23= 3.81; P= 0.075). Linear regression of expected species richness showed a significant increasing trend for the 2002–2012 gillnet data (ES52= 0.391*YEAR + 67.66, r2= 0.59, P< 0.006) and the 1946–2012 trap net data (ES164= 0.203*YEAR + 4.44, r2= 0.81, P< 0.005). The Onondaga Lake fish community is still adapting to the various water quality changes, and continued monitoring is necessary to understand the trophic structure of the lake and how this may affect sportfishing opportunities in the future.

In southern Africa, the connections between climate and the water–energy–food nexus are strong. Physical and socioeconomic exposure to climate is high in many areas and in crucial economic sectors. Spatial interdependence is also high, driven, for example, by the regional extent of many climate anomalies and river basins and aquifers that span national boundaries. There is now strong evidence of the effects of individual climate anomalies, but associations between national rainfall and gross domestic product and crop production remain relatively weak. The majority of climate models project decreases in annual precipitation for southern Africa, typically by as much as 20% by the 2080s. Impact models suggest these changes would propagate into reduced water availability and crop yields. Recognition of spatial and sectoral interdependencies should inform policies, institutions and investments for enhancing water, energy and food security. Three key political and economic instruments could be strengthened for this purpose: the Southern African Development Community, the Southern African Power Pool and trade of agricultural products amounting to significant transfers of embedded water.

Timely diagnosis of carpal fractures is important for optimal treatment outcome. Magnetic resonance (MR) imaging performed early in the workup can provide an accurate and specific diagnosis, as well as uncover developing complications. In the absence of carpal fractures, MR imaging can provide alternative diagnoses such as other unsuspected fractures involving the distal radius/ulna or hand, osseous contusions, and soft-tissue injuries to various ligaments about the wrist. Although MR imaging is the imaging modality of choice to assess the viability of the proximal fragment in scaphoid nonunion, the optimal imaging protocol is not universally agreed upon.

This article discusses the normal anatomy and pathologic appearances of the intrinsic and extrinsic wrist ligaments using MR Imaging. Technological advances in surface coil design and higher magnetic field strengths have improved radiologists’ ability to consistently visualize these small ligaments in their entirety. Wrist ligament anatomy, in the context of proper physiologic function, is emphasized, including common normal variants, and their appearances on MR imaging. The spectrum of disorders, incorporating overlapping appearances of senescent degenerative changes, and destabilizing ligament tears, is outlined. The diagnostic performance of MR imaging to date for various ligament abnormalities is discussed, along with significant limitations.