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Habitat protection is a key component of endangered species conservation, but critical habitat designations are often based on limited data or habitat use during only a portion of a species' life cycle. Protected habitat around breeding pools for the endangered Jefferson Salamander (Ambystoma jeffersonianum (Green, 1827)) and their unisexual dependents (Ambystoma laterale--(2) jeffersonianum) is based upon limited movement data from primarily spring and summer seasons. Furthermore, despite their treatment as distinct species under Canada's Species at Risk Act, differences in habitat use have not been directly compared inareas where they co-occur. We used radiotelemetry to track A. jeffersonianum (JJ) and A. laterale--jeffersonianum (LJJ and LJJJ) during fall migrations to overwintering sites. We used these data and summarized available movement data from past studies that tracked movements in other periods of the annual cycle to estimate year-round critical habitat. Ambystoma jeffersonianum travelled significantly longer distances to overwintering locations than unisexuals. Individuals were more likely to overwinter next to a similar genomotype individual than not. Critical habitat encompassing the entire annual cycle of A. jeffersonianum extends up to 400-450 m from breeding ponds indicating existing regulatory habitat protections in Canada do not currently protect sufficient habitat. Key words: overwintering habitat, Ambystoma laterale--jeffersonianum unisexuals, Ambystoma salamander complex, spatial segregation, radiotelemetry. Si la protection des habitats est un element cle de la conservation des especes menacees, la designation d'habitats essentiels repose souvent sur des donnees limitees ou l'utilisation d'habitats durant une partie seulement du cycle biologique de l'espece. Les habitats proteges autour d'etangs de reproduction de salamandres de Jefferson (Ambystoma jeffersonianum (Green, 1827)) et de leurs dependants unisexues (Ambystoma laterale--(2) jeffersonianum) sont bases sur des donnees limitees sur leurs deplacements principalement pour le printemps et l'ete. En outre, malgre le fait qu'elles soient traitees comme des especes distinctes en vertu de la Loi sur les especes en peril du Canada, les differences d'utilisation de l'habitat des deux especes dans des lieux ou elles cooccurrent n'ont pas ete examinees. Nous avons utilise la radiotelemetrie pour suivre des A. jeffersonianum (JJ) et des A. laterale--jeffersonianum (LJJ et LJJJ) durant des migrations automnales vers des sites d'hivernage. Nous utilisons ces donnees et un condense des donnees sur les deplacements disponibles tirees d'etudes anterieures qui ont suivi les deplacements pendant d'autres periodes du cycle annuel, afin d'estimer les habitats essentiels a l'echelle annuelle. Les A. jeffersonianum parcourent des distances significativement plus longues vers les lieux d'hivernage que les ambystoma unisexues. Les individus sont plus susceptibles d'hiverner a cote d'un individu de genomotype semblable que de genomotype different. L'habitat essentiel qui couvre tout le cycle annuel d'A. jeffersonianum s'etend sur des distances de jusqu'a 400-450 m des etangs de reproduction, ce qui indique que les mesures de protection reglementaires actuellement en place au Canada ne protegent pas des habitats suffisants. [Traduit par la Redaction] Mots-cles : habitat d'hivernage, Ambystoma laterale--jeffersonianum unisexues, complexe des salamandres Ambystoma, segregation spatiale, radiotelemetrie., Introduction Habitat disturbance and destruction are dominant drivers of species endangerment across the globe (Dirzo and Raven 2003; WWF 2016), making habitat protection a key component of recovery for species [...]

Objectives and Study Design: As healthcare evolves, more physicians are taking on administrative roles and pursuing additional graduate education, particularly obtaining a Master's in Business Administration (MBA.) To facilitate a better understanding of these practitioners, we conducted a comparative study of MD/MBA clinicians in multiple surgical fields., Methods: This study aims to compare clinicians with MD/MBAs across multiple surgical subspecialties. Reported metrics include demographics, MBA program structure, salary changes, and professional pursuits. Nine studies were obtained from the PubMed, Cochrane, and Embase databases. Four studies met the inclusion criteria and were analyzed., Results: The majority of MD/MBA degree holders in plastic surgery (95%), orthopedic surgery (89-96%), and ophthalmology (80%) are male. Ophthalmology (37%) demonstrates the highest number of subjects obtaining an MBA via a synchronous MD/MBA. Most clinicians return to clinical practice after degree completion and show high levels of non-clinical pursuits after receiving their MBAs., Conclusions: Though there appear to be differences across surgical subspecialties regarding how an MBA is applied, most maintain clinical duties. Of those that do not, the largest portion transition to administrative duties, consulting, entrepreneurial endeavors, or other professional opportunities. Despite the financial ambiguity of an MBA, physicians value the transformative experience it offers.

Globally, human house types are diverse, varying in shape, size, roof type, building materials, arrangement, decoration and many other features. Here we offer the first rigorous, global evaluation of the factors that influence the construction of traditional (vernacular) houses. We apply macroecological approaches to analyse data describing house features from 1900 to 1950 across 1000 societies. Geographic, social and linguistic descriptors for each society were used to test the extent to which key architectural features may be explained by the biophysical environment, social traits, house features of neighbouring societies or cultural history. We find strong evidence that some aspects of the climate shape house architecture, including floor height, wall material and roof shape. Other features, particularly ground plan, appear to also be influenced by social attributes of societies, such as whether a society is nomadic, polygynous or politically complex. Additional variation in all house features was predicted both by the practices of neighouring societies and by a society's language family. Collectively, the findings from our analyses suggest those conditions under which traditional houses offer solutions to architects seeking to reimagine houses in light of warmer, wetter or more variable climates., (© The Author(s) 2024.)

Arthropod-borne viruses are major causes of human and animal disease, especially in endemic low- and middle-income countries. Mosquito-borne pathogen surveillance is essential for risk assessment and vector control responses. Sentinel chicken serosurveillance (antibody testing) and mosquito pool screening (by RT-qPCR or virus isolation) are currently used to monitor arbovirus transmission, however substantial time lags of seroconversion and/or laborious mosquito identification and RNA extraction steps sacrifice their early warning value. As a consequence, timely vector control responses are compromised. Here, we report on development of a rapid arbovirus detection system whereby adding sucrose to reagents of loop-mediated isothermal amplification with displaced probes (DP-LAMP) elicits infectious mosquitoes to feed directly upon the reagent mix and expectorate viruses into the reagents during feeding. We demonstrate that RNA from pathogenic arboviruses (West Nile and Dengue viruses) transmitted in the infectious mosquito saliva was detectable rapidly (within 45 minutes) without RNA extraction. Sucrose stabilized viral RNA at field temperatures for at least 48 hours, important for transition of this system to practical use. After thermal treatment, the DP-LAMP could be reliably visualized by a simple optical image sensor to distinguish between positive and negative samples based on fluorescence intensity. Field application of this technology could fundamentally change conventional arbovirus surveillance methods by eliminating laborious RNA extraction steps, permitting arbovirus monitoring from additional sites, and substantially reducing time needed to detect circulating pathogens., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: O.Y., S.A.B., and their institutions own intellectual property associated with DP-LAMP assay., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The field of plastic surgery remains at the forefront of technological and surgical innovation. However, the promising applications of robotics in plastic surgery must be thoughtfully balanced with hospital finances and reimbursements. Robotic systems have been studied extensively across multiple surgical disciplines and across diverse health care systems. The results show that there may be equal or better patient outcomes than alternatives. In an era where fiscal responsibility in health care is a top priority, thoughtful budgeting and spending must be considered and revisited frequently to attain sustainable organizational models that ensure appropriate use of robotic technology., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Recently reported "displaceable probe" loop amplification (DP-LAMP) architecture has shown to amplify viral RNA from SARS-CoV-2 with little sample processing. The architecture allows signals indicating the presence of target nucleic acids to be spatially separated, and independent in sequence, from the complicated concatemer that LAMP processes create as part of their amplification process. This makes DP-LAMP an attractive molecular strategy to integrate with trap and sampling innovations to detect RNA from arboviruses carried by mosquitoes in the field. These innovations include (a) development of organically produced carbon dioxide with ethylene carbonate as a bait deployable in mosquito trap, avoiding the need for dry ice, propane tanks, or inorganic carbonates and (b) a process that induces mosquitoes to lay virus-infected saliva on a quaternary ammonium-functionalized paper (Q-paper) matrix, where (c) the matrix (i) inactivates the deposited viruses, (ii) releases their RNA, and (iii) captures viral RNA in a form that keeps it stable for days at ambient temperatures. We report this integration here, with a surprisingly simple workflow. DP-LAMP with a reverse transcriptase was found to amplify arboviral RNA directly from Q-paper, without requiring a separate elution step. This capture-amplification-detection architecture can be multiplexed, with the entire system integrated into a device that can support a campaign of surveillance, in the wild outdoors, that reports the prevalence of arboviruses from field-captured mosquitoes.

Background: Fluid resuscitation plays a prominent role in stabilizing trauma patients with hemorrhagic shock yet there remains uncertainty with regard to optimal administration time, volume, and fluid composition (e.g., whole blood, component, colloids) leading to complications such as trauma-induced coagulopathies (TIC), acidosis, and poor oxygen transport. Synthetic fluids in combination with antioxidants (e.g., vitamin C) may resolve some of these problems., Objectives: We applied quantitative mass spectrometry-based proteomics [liquid chromatography-mass spectrometry (LC-MS/MS)] to map the effects of fluid resuscitation and intravenous vitamin C (VitC) in a pig model of polytrauma (hemorrhagic shock, tissue injury, liver reperfusion, hypothermia, and comminuted bone fracture). The goal was to determine the effects of VitC on plasma protein expression, with respect to changes associated with coagulation and trauma-induced coagulopathy (TIC)., Methods: Longitudinal blood samples were drawn from nine male Sinclair pigs at baseline, 2 h post trauma, and 0.25, 2, and 4 h post fluid resuscitation with 500 mL hydroxyethyl starch. Pigs were treated intravenously (N = 3/treatment group) with saline, 50 mg VitC/kg (Lo-VitC), or 200 mg VitC/kg (Hi-VitC) during fluid resuscitation., Results: A total of 436 plasma proteins were quantified of which 136 changed following trauma and resuscitation; 34 were associated with coagulation, complement cascade, and glycolysis. Unexpectedly, Lo-VitC and Hi-VitC treatments stabilized ADAMTS13 levels by ~4-fold (P = .056) relative to saline and enhanced ADAMTS13/von Willebrand factor (VWF) cleavage efficiency based on LC-MS/MS evidence for the semitryptic VWF cleavage product (VWF 1275-1286 )., Conclusions: This study provides the first comprehensive map of trauma-induced changes to the plasma proteome, especially with respect to proteins driving the development of TIC., (© 2019 International Society on Thrombosis and Haemostasis.)

Interactions between the inhibitor of apoptosis protein antagonist LCL161 and the histone deacetylase inhibitor panobinostat (LBH589) were examined in human multiple myeloma (MM) cells. LCL161 and panobinostat interacted synergistically to induce apoptosis in diverse MM cell lines, including those resistant to bortezomib (PS-R). Similar interactions were observed with other histone deacetylase inhibitors (MS-275) or inhibitors of apoptosis protein antagonists (birinapant). These events were associated with downregulation of the noncanonical (but not the canonical) NF-κB pathway and activation of the extrinsic, caspase-8-related apoptotic cascade. Coexposure of MM cells to LCL161/LBH589 induced TRAF3 upregulation and led to TRAF2 and NIK downregulation, diminished expression of BCL-XL, and induction of γH2A.X. Ectopic expression of TRAF2, NIK, or BCL-XL, or short hairpin RNA TRAF3 knock-down, significantly reduced LCL161/LBH589 lethality, as did ectopic expression of dominant-negative FADD. Stromal/microenvironmental factors failed to diminish LCL161/LBH589-induced cell death. The LCL161/LBH589 regimen significantly increased cell killing in primary CD138+ cells (N = 31) and was particularly effective in diminishing the primitive progenitor cell-enriched CD138-/19+/20+/27+ population (N = 23) but was nontoxic to normal CD34+ cells. Finally, combined LCL161/LBH589 treatment significantly increased survival compared with single-agent treatment in an immunocompetent 5TGM1 murine MM model. Together, these findings argue that LCL161 interacts synergistically with LBH589 in MM cells through a process involving inactivation of the noncanonical NF-κB pathway and activation of the extrinsic apoptotic pathway, upregulation of TRAF3, and downregulation of TRAF2/BCL-XL. Notably, this regimen overcomes various forms of resistance, is active against primary MM cells, and displays significant in vivo activity. This strategy warrants further consideration in MM., (© 2021 by The American Society of Hematology.)

Managing the pandemic caused by SARS-CoV-2 requires new capabilities in testing, including the possibility of identifying, in minutes, infected individuals as they enter spaces where they must congregate in a functioning society, including workspaces, schools, points of entry, and commercial business establishments. Here, the only useful tests (a) require no sample transport, (b) require minimal sample manipulation, (c) can be performed by unlicensed individuals, (d) return results on the spot in much less than one hour, and (e) cost no more than a few dollars. The sensitivity need not be as high as normally required by the FDA for screening asymptomatic carriers (as few as 10 virions per sample), as these viral loads are almost certainly not high enough for an individual to present a risk for forward infection. This allows tests specifically useful for this pandemic to trade-off unneeded sensitivity for necessary speed, simplicity, and frugality. In some studies, it was shown that viral load that creates forward-infection risk may exceed 105 virions per milliliter, easily within the sensitivity of an RNA amplification architecture, but unattainable by antibody-based architectures that simply target viral antigens. Here, we describe such a test based on a displaceable probe loop amplification architecture., Competing Interests: Firebird Biomolecular Sciences, LLC, GenePath Diagnostics, Inc., and GenePath Diagnostics India Pvt. Ltd. employ the indicated authors and the specific roles of these authors are articulated in the ‘author contributions’ section. OY, ZY, SAB and their institutions own intellectual property associated with the assay. Some of the items mentioned here are sold by Firebird Biomolecular Sciences, LLC, which employs the indicated authors and is owned by SAB. This does not alter the authors’ and institutions’ adherence to PLOS ONE policies on sharing data and materials.

This study analyzes the trade-off between net present value (NPV) of timber resources, and carbon sequestration and storage for a working forest, the Hofmann Forest in North Carolina, USA. Multi-objective optimization is used to determine the production possibility curves showing the relationship between NPV and carbon. We then perform a sensitivity analysis to explore alternative management strategies. For carbon yields we used aboveground pools: branches, leaves, tops and bole as estimated by the Forest Vegetation Simulator (FVS) and LOBDSS using the California Carbon Market Protocols, including product carbon. Timber yields of sawtimber, chip-n-saw and pulpwood were estimated by LOBDSS for planted stands less than 49 years of age, and FVS was used for all natural stands and planted stands 49 years and over. Our results reveal that NPV opportunity costs associated with increasing carbon sequestration at Hofmann Forest are less than the current California carbon market price. [ABSTRACT FROM AUTHOR]

Solomon Islands, like many Pacific Island nations, suffer from the burden of malnutrition. External drivers including population growth, declining agriculture and fisheries productivity and global food trade have contributed to the transition to greater reliance on imported foods. Globally, diets are recognized as both a cause of and solution to the burden of malnutrition. Using a mixed-method approach this study assessed nutritional status and key determinants of malnutrition among women and young children in rural Solomon Island communities. Quantitative 24-hour recall surveys identified diets of women and young children in these communities to be very limited in diversity. Typical daily diets comprised of fish, sweet potato (and/or rice) and slippery cabbage (a leafy green) usually boiled in coconut milk or baked. Participatory research using problem tree and biocultural approaches identified basic determinants of poor diets and opportunities to address these challenges. We highlight three domains of opportunity to improve diets across multiple scales; 1) improve nutrition-sensitive agriculture and fisheries to produce and distribute diverse, productive and nutrient rich foods; 2) nutrition education and empowerment, focusing on the first 1000 days of life, to influence and inform choices regarding food consumption; and 3) reducing the consumption of imported, energy-rich nutrient poor foods through national and regional policies. These multi-scale domains highlight that food system approaches that strengthen integrated policy and empower people are essential for healthy and sustainable diets in Solomon Islands and more broadly in the Pacific region., (© 2020 The Authors. Maternal & Child Nutrition published by John Wiley & Sons, Ltd.)

KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. KRAS p.G12C , which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRAS G12C identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRAS G12C with submicromolar inhibition of downstream signaling in a KRAS G12C -specific manner., Competing Interests: The authors declare no competing financial interest.

Poor quality data in preclinical trials can result from inconsistent and unstandardized experimental processes. Unpredictable pre-intervention variability generates unreliable data, biases outcomes and results in needless waste of animals and resources. We applied Define-Measure-Analyse-Improve-Control (DMAIC) quality improvement processes to pilot development of a swine model of trauma, haemorrhagic shock and coagulopathy. The goal was to reduce variability through protocol standardization and error reduction. Six male Sinclair swine were sequentially anesthetized, intubated, mechanically ventilated and instrumented, then subjected to multiple-hit injury, followed by fluid resuscitation monitoring and coagulation testing. Experimental tasks were defined and mapped. Performance measures were task performance times, subject stabilization time and number of task execution errors. Process improvement was assessed by reduced times and errors, and subject stability at target physiological values. Previously-overlooked performance errors and deficiencies were identified. 'Mistake-proofing' actions included personnel retraining, revisions of standard operating procedures and use of checklists. The quality improvement pilot trial produced a stable model with reduced protocol deviations. Data quality can be improved and animal waste minimized, if experimental planning incorporates strategies to ensure protocol adherence and reduced operator performance variation and errors. Properly designed pilot trials can be essential components of refinement and reduction strategies in animal-based research.

Remote island nations face a number of challenges in addressing concerns about shark population status, including access to rigorously collected data and resources to manage fisheries. At present, very little data are available on shark populations in the Solomon Islands and scientific surveys to document shark and ray diversity and distribution have not been completed. We aimed to provide a baseline of the relative abundance and diversity of reef sharks and rays and assess the major drivers of reef shark abundance/biomass in the Western Province of the Solomon Islands using stereo baited remote underwater video. On average reef sharks were more abundant than in surrounding countries such as Fiji and Indonesia, yet below that of remote islands without historical fishing pressure, suggesting populations are relatively healthy but not pristine. We also assessed the influence of location, habitat type/complexity, depth and prey biomass on reef shark abundance and biomass. Location was the most important factor driving reef shark abundance and biomass with two times the abundance and a 43% greater biomass of reef sharks in the more remote locations, suggesting fishing may be impacting sharks in some areas. Our results give a much needed baseline and suggest that reef shark populations are still relatively unexploited, providing an opportunity for improved management of sharks and rays in the Solomon Islands., Competing Interests: The authors have declared that no competing interests exist.

Background: Coagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the proinflammatory and procoagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of multiple injuries and hemorrhage., Methods: Male Sinclair swine (n = 24; mean body weight, 27 kg) were anesthetized, intubated, mechanically ventilated, and instrumented for physiologic monitoring. Following stabilization, swine were subjected to shock/traumatic injury (hypothermia, liver ischemia and reperfusion, comminuted femur fracture, hemorrhagic hypotension), resuscitated with 500 mL of hydroxyethyl starch, and randomized to receive either intravenous normal saline (NS), low-dose VitC (50 mg/kg; LO), or high-dose VitC (200 mg/kg; HI). Hemodynamics, blood chemistry, hematology, and coagulation function (ROTEM) were monitored to 4 hours postresuscitation. Histological and molecular analyses were obtained for liver, kidney, and lung., Results: Compared with VitC animals, NS swine showed significant histological end-organ damage, elevated acute lung injury scores, and increased mRNA expression of tissue proinflammatory mediators (IL-1β, IL-8, TNFα), plasminogen activation inhibitor-1 and tissue factor. There were no statistically significant differences between treatment groups on mean arterial pressure or univariate measures of coagulation function; however, NS showed impaired multivariate clotting function at 4 hours., Conclusion: Although correction of coagulation dysfunction was modest, intravenous high-dose VitC may mitigate the proinflammatory/procoagulant response that contributes to multiple organ failure following acute severe multiple injuries., Level of Evidence: Prospective randomized controlled blinded trial study, Preclinical (animal-based).

Monitoring and evaluation are central to ensuring that innovative, multi-scale, and interdisciplinary approaches to sustainability are effective. The development of relevant indicators for local sustainable management outcomes, and the ability to link these to broader national and international policy targets, are key challenges for resource managers, policymakers, and scientists. Sets of indicators that capture both ecological and social-cultural factors, and the feedbacks between them, can underpin cross-scale linkages that help bridge local and global scale initiatives to increase resilience of both humans and ecosystems. Here we argue that biocultural approaches, in combination with methods for synthesizing across evidence from multiple sources, are critical to developing metrics that facilitate linkages across scales and dimensions. Biocultural approaches explicitly start with and build on local cultural perspectives - encompassing values, knowledges, and needs - and recognize feedbacks between ecosystems and human well-being. Adoption of these approaches can encourage exchange between local and global actors, and facilitate identification of crucial problems and solutions that are missing from many regional and international framings of sustainability. Resource managers, scientists, and policymakers need to be thoughtful about not only what kinds of indicators are measured, but also how indicators are designed, implemented, measured, and ultimately combined to evaluate resource use and well-being. We conclude by providing suggestions for translating between local and global indicator efforts.

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.

From the foods we eat and the houses we construct, to our religious practices and political organization, to who we can marry and the types of games we teach our children, the diversity of cultural practices in the world is astounding. Yet, our ability to visualize and understand this diversity is limited by the ways it has been documented and shared: on a culture-by-culture basis, in locally-told stories or difficult-to-access repositories. In this paper we introduce D-PLACE, the Database of Places, Language, Culture, and Environment. This expandable and open-access database (accessible at https://d-place.org) brings together a dispersed corpus of information on the geography, language, culture, and environment of over 1400 human societies. We aim to enable researchers to investigate the extent to which patterns in cultural diversity are shaped by different forces, including shared history, demographics, migration/diffusion, cultural innovations, and environmental and ecological conditions. We detail how D-PLACE helps to overcome four common barriers to understanding these forces: i) location of relevant cultural data, (ii) linking data from distinct sources using diverse ethnonyms, (iii) variable time and place foci for data, and (iv) spatial and historical dependencies among cultural groups that present challenges for analysis. D-PLACE facilitates the visualisation of relationships among cultural groups and between people and their environments, with results downloadable as tables, on a map, or on a linguistic tree. We also describe how D-PLACE can be used for exploratory, predictive, and evolutionary analyses of cultural diversity by a range of users, from members of the worldwide public interested in contrasting their own cultural practices with those of other societies, to researchers using large-scale computational phylogenetic analyses to study cultural evolution. In summary, we hope that D-PLACE will enable new lines of investigation into the major drivers of cultural change and global patterns of cultural diversity.

Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.

Success in the design of targeted covalent inhibitors depends in part on a knowledge of the factors influencing electrophile reactivity. In an effort to further develop an understanding of structure-reactivity relationships among N-arylacrylamides, we determined glutathione (GSH) reaction rates for a family of N-arylacrylamides independently substituted at ortho-, meta-, and para-positions with 11 different groups common to inhibitor design. We find that substituent effects on reaction rates show a linear Hammett correlation for ortho-, meta-, and para-substitution. In addition, we note a correlation between (1)H and (13)C NMR chemical shifts of the acrylamide with GSH reaction rates, suggesting that NMR chemical shifts may be a convenient surrogate measure of relative acrylamide reactivity. Density functional theory calculations reveal a correlation between computed activation parameters and experimentally determined reaction rates, validating the use of such methodology for the screening of synthetic candidates in a prospective fashion.

Analysis of nucleotide sugars, nucleoside di- and triphosphates and sugar-phosphates is an essential step in the process of understanding enzymatic pathways. A facile and rapid separation method was developed to analyze these compounds present in an enzymatic reaction mixture utilized to produce nucleotide sugars. The Primesep SB column explored in this study utilizes hydrophobic interactions as well as electrostatic interactions with the phosphoric portion of the nucleotide sugars. Ammonium formate buffer was selected due to its compatibility with mass spectrometry. Negative ion mode mass spectrometry was adopted for detection of the sugar phosphate (fucose-1-phophate), as the compound is not amenable to UV detection. Various mobile phase conditions such as pH, buffer concentration and organic modifier were explored. The semi-preparative separation method was developed to prepare 30mg of the nucleotide sugar. (19)F NMR was utilized to determine purity of the purified fluorinated nucleotide sugar. The collected nucleotide sugar was found to be 99% pure., (Published by Elsevier B.V.)

Based on lead compound 1, which was discovered from a high-throughput screen, a series of PI3Kα/mTOR inhibitors were evaluated that contained an imidazo[1,2-a]pyridine as a core replacement for the benzimidazole contained in 1. By exploring various ring systems that occupy the affinity pocket, two fragments containing a methoxypyridine were identified that gave <100 nM potency toward PI3Kα in enzyme and cellular assays with moderate stability in rat and human liver microsomes. With the two methoxypyridine groups selected to occupy the affinity pocket, analogs were prepared with various fragments intended to occupy the ribose pocket of PI3Kα and mTOR. From these analogs, tertiary alcohol 18 was chosen for in vivo pharmacodynamic evaluation based on its potency in the PI3Kα cellular assay, microsomal stability, and in vivo pharmacokinetic properties. In a mouse liver pharmacodynamic assay, compound 18 showed 56% inhibition of HFG-induced AKT (Ser473) phosphorylation at a 30 mg/kg dose., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We contend that biocultural approaches to conservation can achieve effective and just conservation outcomes while addressing erosion of both cultural and biological diversity. Here, we propose a set of guidelines for the adoption of biocultural approaches to conservation. First, we draw lessons from work on biocultural diversity and heritage, social-ecological systems theory, integrated conservation and development, co-management, and community-based conservation to define biocultural approaches to conservation. Second, we describe eight principles that characterize such approaches. Third, we discuss reasons for adopting biocultural approaches and challenges. If used well, biocultural approaches to conservation can be a powerful tool for reducing the global loss of both biological and cultural diversity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

With rising concerns over the failed outcomes of global conservation strategies and the militarization of environmental monitoring and enforcement, there is an urgent need for decolonizing nature conservation. This article examines the position of Indigenous peoples as rights-and-knowledge-holders in this discourse and the vital role they play in biodiversity conservation globally. I present a 2018 case study of the Kogui Indigenous peoples of Sierra Nevada de Santa Marta, Colombia, one of the last remaining examples of a sustainable biocultural system. My results demonstrate that the success of the Kogui is largely defined by their: (a) nature-based cosmovision, (b) strong cultural identity related to that cosmovision, and (c) functioning governance system ordered by Natural Law. These findings stand as beacons to reframe the nature conservation paradigm and help humanity re-find and re-connect with our place in, and relationship with, both the material and non-material worlds. [ABSTRACT FROM AUTHOR]

Sensory processing includes perception, organization, and reaction to sensory stimuli. Research has shown that deaf and hard-of-hearing children have unique sensory processing characteristics. The aim of this study was to identify these characteristics and examine the contributions of factors such as type of amplification, chronological age, hearing age, and frequency of rehabilitation to sensory processing features. Parents of 52 children, aged 3 to 10 years old, completed the Sensory Profile questionnaire. Results showed that most children were within the typical performance range in most subscales, however, children with cochlear implants had better scores in several domains compared to children with hearing aids. Chronological age, hearing age, and frequency of rehabilitation did not contribute to overall sensory processing. These results indicate that children with cochlear implants have a more successful integration of sensory processing abilities. Early intervention and consistent rehabilitation are needed to optimize sensory outcomes in deaf and hard-of-hearing children. [ABSTRACT FROM AUTHOR]

This study investigates the integration of geoheritage into geoconservation strategies, with a specific emphasis on the Khowai Badlands in West Bengal, India. Recognizing the importance of preserving geological, ecological, and cultural heritage, this research aims to address the challenges and opportunities associated with holistic conservation approaches. Methodologically, the study employs a combination of literature review, case study analysis, and policy evaluations. The findings underscore the critical role of geological formations in supporting biodiversity and the cultural heritage embedded within these landscapes. Moreover, the study emphasizes the need for sustainable tourism practices and community involvement in conservation efforts, ensuring the long-term sustainability of our planet’s natural and cultural heritage for future generations. [ABSTRACT FROM AUTHOR]

Introduction: Since 1990, there has been a global decline in forest areas. Between 2010 and 2020, the greatest annual net loss of forests was on the African continent. Despite South African indigenous forests and trees being protected under the National Forests Act of 1998 (Act No. 84 of 1998), the country has also shown an increased annual net loss of forests. Although the Vhembe District Municipality in South Africa has lost forest owing to humaninduced deforestation and other land use activities, sacred forests have not been affected. According to traditional beliefs, exploitation of such indigenous patches of sacred forests is taboo. This study aims to explore the role of taboos in the protection of the remaining patches of sacred forest. Methods: The study relies on data collected between December 2022 and December 2023. Semi-structured interviewswere conductedwith key informants (n = 61) and local communities in Tshidzivhe and Duthuni villages (n = 60). Observations were used as a further data collection tool. The interview questions were prepared to assess the role of taboos in the protection and management of sacred forests. Data collected through interviews were analysed using thematic content analysis, while field observations helped to corroborate the results from the interviews. Results and discussion: The study identified two main taboos - one that restricts entry into the sacred forests (i.e. preventing entry into the sacred forests, and harvesting, hunting and hiking in these areas), and another that prohibits noise or activities that disrespect sacred forests. The study found that believers and nonbelievers alike, for fear of retribution by the spirits, still obey these taboos and their relatedmyths. This has allowed these areas to develop dense stands of closed-canopy evergreen forest that support more diverse flora and fauna than found in surrounding areas. Although sacred forests are not meant for biodiversity conservation, they offer opportunities to be integrated into global conservation targets of "30x30" and "Half-Earth" by 2030. They also offer the opportunity of serving as carbon sinks which is key to climate change mitigation. Recommendations for protecting sacred forests and associated taboos are drawn up based on these results. [ABSTRACT FROM AUTHOR]

Sex determination in the nematode C. elegans is controlled by the master regulator XOL-1 during embryogenesis. Expression of xol-1 is dependent on the ratio of X chromosomes and autosomes, which differs between XX hermaphrodites and XO males. In males, xol-1 is highly expressed and in hermaphrodites, xol-1 is expressed at very low levels. XOL-1 activity is known to be critical for the proper development of C. elegans males, but its low expression was considered to be of minimal importance in the development of hermaphrodite embryos. Our study reveals that XOL-1 plays an important role as a regulator of developmental timing during hermaphrodite embryogenesis. Using a combination of imaging and bioinformatics techniques, we found that hermaphrodite embryos have an accelerated rate of cell division, as well as a more developmentally advanced transcriptional program when xol-1 is lost. Further analyses reveal that XOL-1 is responsible for regulating the timing of initiation of dosage compensation on the X chromosomes, and the appropriate expression of sex-biased transcriptional programs in hermaphrodites. We found that xol-1 mutant embryos overexpress the H3K9 methyltransferase MET-2 and have an altered H3K9me landscape. Some of these effects of the loss of xol-1 gene were reversed by the loss of met-2. These findings demonstrate that XOL-1 plays an important role as a developmental regulator in embryos of both sexes, and that MET-2 acts as a downstream effector of XOL-1 activity in hermaphrodites. Author summary: Various organisms have differing ways of determining, at a molecular level, what the sex of a developing embryo is supposed to be. The two sexes in the nematode C. elegans, hermaphrodite and male, have different numbers of X chromosomes. Hermaphrodites have two X chromosomes and males only have one. This mismatch raises an additional problem as hermaphrodites will have twice the amount of genes expressed from the X compared to males. This is solved by a process called dosage compensation, which equalizes gene expression between the sexes. A molecular sensor called XOL-1 detects the number of X chromosomes in an embryo and kick-starts the process of proper sexual development and/or dosage compensation. XOL-1 was known to be very important for activating male development but was believed to not have any role in the development of the hermaphrodite sex. We show that XOL-1 has some crucial roles in hermaphrodite embryos in controlling the rate of development of the embryo, and regulating the timing of dosage compensation. We also show that MET-2, a protein that deposits repressive methyl marks on DNA-bound histone proteins, is involved in this process. [ABSTRACT FROM AUTHOR]

The frequency-dependent electrical properties and strain self-sensing behaviour of ultra-high performance concrete (UHPC) as cement-based stress/strain self-sensing (CBSS) smart materials were investigated in the frequency range from 100 Hz to 300 kHz. By using the electrical parameters of the equivalent electric circuit model, the quantitative relations of capacitance and conductance of CBSS with the measurement frequency were derived. The capacitance and the conductance exhibit power-law type dependence on the measurement frequency. The calculated capacitance values at frequencies beyond 2 kHz and conductance values are consistent with the experimental results. The sweep-frequency test and the fixed-frequency test were performed to examine effects of the excitation frequencies on strain self-sensing properties of CBSS. The fractional change in capacitance (FCC) and resistance (FCR) of CBSS are frequency-dependent in the frequency range from 100 Hz to the fB, but frequency-independent in the frequency range from the fB to 300 kHz. The fA and the fB are 1.7–4.0 kHz and 11–78 kHz depending on the fiber dosages, respectively. FCC and FCR reach their maximum at the fA and 100 Hz, respectively. The responses of capacitance and resistance of CBSS to strain show good repeatability during cyclic loading. As the fiber dosage increases, capacitance-based sensitivity to strain increases initially and then decreases at the fA, and resistance-based sensitivity to strain of CBSS increases with increasing fiber contents. [ABSTRACT FROM AUTHOR]

Determinants of farmer well-being can be derived from objective and subjective measures of social components, environmental sustainability indicators, and quality of life indices, as well as the multiple scales that farms and farmers operate. Yet, despite multiple frameworks on farmer well-being, the extent to which farmer-expressed values are used in the development of farmer well-being indicators is unclear. Challenges can arise from extracting indicators that are insufficiently grounded in place, or that inadequately incorporate context and biocultural relations and practices. Here in this scoping review, we synthesize the methodologies in the literature on assessing farmer well-being and identify the extent to which farmer well-being domains are derived from values expressed directly by farmers. We consolidated and coded 92 papers to respond to the following questions: (1) What are the most frequent farmer well-being domains in published studies? (2) What methods are used to elicit multidimensional farmer well-being domains? (3) Do well-being domains used in the literature adequately reflect a biocultural context, including place-based influences on well-being? Our results show that economics and social relationships are frequent domains of how farmer well-being is identified and assessed. These domains tend to be measured simultaneously, while less common domains, such as governance and place, are rather isolated. A suite of methods was used to assess well-being domains, ranging from basic surveys to in-depth participant observation. Yet, we identify gaps in the methods for deriving farmer well-being indicators. Specifically, methods that refer to farmer-expressed values were rare and domains identified through a place-based approach were often not recorded, but, arguably, critical in developing multidimensionality of farmer well-being. We show that while the translocal approach is well represented in established well-being frameworks, farmer expression is not foundational in well-being assessments but is needed in order to center farmer values when generating indicators of well-being. [ABSTRACT FROM AUTHOR]

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Coordinated activation and inhibition of F-actin supports the movements of morphogenesis. Understanding the proteins that regulate F-actin is important, since these proteins are mis-regulated in diseases like cancer. Our studies of C. elegans embryonic epidermal morphogenesis identified the GTPase CED-10/Rac1 as an essential activator of F-actin. However, we need to identify the GEF, or Guanine-nucleotide Exchange Factor, that activates CED-10/Rac1 during embryonic cell migrations. The two-component GEF, CED-5/CED-12, is known to activate CED-10/Rac1 to promote cell movements that result in the engulfment of dying cells during embryogenesis, and a later cell migration of the larval Distal Tip Cell. It is believed that CED-5/CED-12 powers cellular movements of corpse engulfment and DTC migration by promoting F-actin formation. Therefore, we tested if CED-5/CED-12 was involved in embryonic migrations, and got a contradictory result. CED-5/CED-12 definitely support embryonic migrations, since their loss led to embryos that died due to failed epidermal cell migrations. However, CED-5/CED-12 inhibited F-actin in the migrating epidermis, the opposite of what was expected for a CED-10 GEF. To address how CED-12/CED-5 could have two opposing effects on F-actin, during corpse engulfment and cell migration, we investigated if CED-12 harbors GAP (GTPase Activating Protein) functions. A candidate GAP region in CED-12 faces away from the CED-5 GEF catalytic region. Mutating a candidate catalytic Arginine in the CED-12 GAP region (R537A) altered the epidermal cell migration function, and not the corpse engulfment function. We interfered with GEF function by interfering with CED-5's ability to bind Rac1/CED-10. Mutating Serine-Arginine in CED-5/DOCK predicted to bind and stabilize Rac1 for catalysis, resulted in loss of both ventral enclosure and corpse engulfment. Genetic and expression studies strongly support that the GAP function likely acts on different GTPases. Thus, we propose CED-5/CED-12 support the cycling of multiple GTPases, by using distinct domains, to both promote and inhibit F-actin nucleation. Author summary: GTPases in their active state promote actin nucleation that drives cellular events, from cell migrations, to cell shape changes, to cell-cell interactions. To function correctly, GTPases need to cycle from the active, GTP-bound state, to the inactive, GDP-bound state. This cycle is supported by Guanine-nucleotide Exchange Factors, or GEFs, that support activation as GDP is switched for GTP, and GTPase-Activating Proteins, or GAPs that support hydrolysis back to the GDP bound state. The Rac1/CED-10 GTPase has a well-studied GEF, CED-5/CED-12, that promotes Rac1 activation during cell engulfment of dying cells. Here we tested if CED-5/CED-12 also functioned as the activator, or GEF for Rac1 during embryonic epidermal cell migrations. Surprisingly, CED-5/CED-12 behaved completely opposite to what was expected during epidermal cell migration. Therefore, we investigated if CED-5/CED-12 could harbor a GAP function. Comparing models of human and C. elegans protein structures suggested a putative GAP region, which we mutated to show that CED-12 likely functions as a GAP. Genetic and gene expression tests identify other GTPases, CDC-42 and RHO-1, as likely targets of this newly uncovered CED-12 GAP function. These findings suggest CED-5/CED-12 can support the cycling of multiple GTPases, and either promote or inhibit F-actin nucleation, using its GEF or GAP functions. [ABSTRACT FROM AUTHOR]

Research teams working with indigenous people or local communities in the field of global environmental change represent local knowledge and concerns related to climate or environmental issues in the resulting scientific texts. However, by highlighting some aspects in particular ways and fading others to the background, every representation simultaneously reveals, conceals, and distorts aspects of what is represented. This paper aims to analytically highlight how frames in scientific texts are at work in emphasizing some aspects of local knowledge and concerns while fading other aspects into the background, which inevitably has micro and macro consequences through how local knowledge is incorporated, represented, and added to the body of knowledge of a given field. I have adapted a widely used frame concept from media studies to make it suitable for the analysis of scientific texts. The proposed method identifies main frames of a paper, maps how devices for achieving selective emphases, such as repetitive formulations and strong words, are at work in the text, and elicits how the frame's key functions occur in papers: (1) identify problems, (2) diagnose causes, (3) make moral judgments, (4) suggest solutions or offer a path toward solutions, and (5) attribute roles. Points (4) and (5) are specifically designed for the analysis of scientific texts. In addition, I have added a step that shows how frames shape representations of local knowledge and concerns in scientific texts. This method is meant to develop reflexive awareness among the scholarly community about their writing practices and promote critical thinking about the unintended impacts that uncritical reproduction of taken-for-granted frames may have through their shaping of representations of local and indigenous knowledge and concerns. To illustrate the potential of the frame concept for analyzing scientific texts, I applied the new method to two papers. Further, the paper discusses the potential of frame analysis as a tool for reflexivity among research teams that work with and within local communities. [ABSTRACT FROM AUTHOR]

Conservation biology is a mission-driven discipline that must navigate a new relationship between conservation and science. Because conservation is a social and political as well as an ecological project, conservation biologists must practice interdisciplinarity and collaboration. In a comparative study of 7 cases (Jaguars in the Chaco, Grevy's zebra in Kenya, Beekeeping in Tanzania, Andean cats in Argentina, Jaguars in Mexico, Lobster fishing, and Black bears in Mexico), we examined motivations for collaboration in conservation, who can collaborate in conservation, and how conservation professionals can work well together. In 5 case studies, successful conservation outcomes were prioritized over livelihood benefits. In the other 2 cases, livelihoods were prioritized. All case studies employed participatory approaches. There were multiple external actors, including local and Indigenous communities, nongovernmental organizations, agencies, regional and national governments, and international organizations, which enhanced conservation and wider sustainability outcomes. Key collaboration aspects considered across the case studies were time (mismatch between relationship building and project schedules), trust required for meaningful partnerships, tools employed, and transformative potential for people, nature, and the discipline of conservation biology. We developed guidelines for successful collaboration, including long-term commitment, knowledge integration, multiscalar and plural approaches, cultivation of trust, appropriate engagement, evaluation, supporting students, and efforts for transformation., (© 2022 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Aphelenchoides besseyi is a plant-parasitic nematode (PPN) in the family Aphelenchoididae capable of infecting more than 200 plant species. A. besseyi is also a species complex with strains exhibiting varying pathogenicity to plants. We present the genome and annotations of six Aphelenchoides species, four of which belonged to the A. besseyi species complex. Most Aphelenchoides genomes have a size of 44.7-47.4 Mb and are among the smallest in clade IV, with the exception of A. fujianensis, which has a size of 143.8 Mb and is one of the largest. Phylogenomic analysis successfully delimited the species complex into A. oryzae and A. pseudobesseyi and revealed a reduction of transposon elements in the last common ancestor of Aphelenchoides. Synteny analyses between reference genomes indicated that three chromosomes in A. besseyi were derived from fission and fusion events. A systematic identification of horizontal gene transfer (HGT) genes across 27 representative nematodes allowed us to identify two major episodes of acquisition corresponding to the last common ancestor of clade IV or major PPNs, respectively. These genes were mostly lost and differentially retained between clades or strains. Most HGT events were acquired from bacteria, followed by fungi, and also from plants; plant HGT was especially prevalent in Bursaphelenchus mucronatus. Our results comprehensively improve the understanding of HGT in nematodes., (© 2023 The Authors. Molecular Ecology Resources published by John Wiley & Sons Ltd.)

Interspecies hybrid sterility has been extensively studied, especially in the genus Drosophila. Hybrid sterility is more often found in the heterogametic (XY or ZW) sex, a trend called Haldane's rule. Although this phenomenon is pervasive, identification of a common genetic mechanism remains elusive, with modest support found for a range of potential theories. Here, we identify a single precise morphological phenotype, which we call 'needle-eye sperm', that is associated with hybrid sterility in three separate species pairs that span the Drosophila genus. The nature of the phenotype indicates a common point of meiotic failure in sterile hybrid males. We used 10 generations of backcross selection paired with whole-genome pooled sequencing to genetically map the regions underlying the needle-eye (NE) sperm phenotype. Surprisingly, the sterility phenotype was present in ~50% of males even after 10 generations of backcrossing, and only a single region of the X chromosome was associated with sterility in one direction of backcross. Owing to the common phenotype among sterile male hybrids, and the strong effect of individual loci, further exploration of these findings may identify a universal mechanism for the evolution of hybrid sterility. [ABSTRACT FROM AUTHOR]