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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.

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.

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.)

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.)

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.)

Traditional ecological knowledge (TEK) is a critical global resource that may be eroding amid social and environmental change. Here, we present data on local perceptions of TEK change from three communities on Malekula Island in Vanuatu. Utilizing a structured interview (n = 120), we find a common perception of TEK loss. Participants defined two key periods of TEK erosion (roughly 1940-1960 and 1980-present), and noted that TEK decline was driven both external (e.g., church) and internal (e.g., shifting values) processes. Erosion was perceived to more comprehensive in the worldview domain than in aspects of ethnobiological knowledge and practice. These data indicate the perceived fragility of TEK systems and the complexity of TEK change. TEK systems are critical to natural resource management, and data such as these will assist in designing nuanced responses to the ongoing loss of cultural knowledge and practice.

Background: The integration of traditional ecological knowledge (TEK) into formal school curricula may be a key tool for the revitalisation of biocultural diversity, and has the potential to improve the delivery of educational objectives. This paper explores perceptions of the value of TEK to formal education curricula on Malekula Island, Vanuatu. We conducted 49 interviews with key stakeholders (local TEK experts, educators, and officials) regarding the use of the formal school system to transmit, maintain, and revitalise TEK. Interviews also gathered information on the areas where TEK might add value to school curricula and on the perceived barriers to maintaining and revitalising TEK via formal education programs., Results: Participants reported that TEK had eroded on Malekula, and identified the formal school system as a principal driver. Most interviewees believed that if an appropriate format could be developed, TEK could be included in the formal education system. Such an approach has potential to maintain customary knowledge and practice in the focus communities. Participants identified several specific domains of TEK for inclusion in school curricula, including ethnomedical knowledge, agricultural knowledge and practice, and the reinforcement of respect for traditional authority and values. However, interviewees also noted a number of practical and epistemological barriers to teaching TEK in school. These included the cultural diversity of Malekula, tensions between public and private forms of knowledge, and multiple values of TEK within the community., Conclusions: TEK has potential to add value to formal education systems in Vanuatu by contextualising the content and process of curricular delivery, and by facilitating character development and self-awareness in students. These benefits are congruent with UNESCO-mandated goals for curricular reform and provide a strong argument for the inclusion of TEK in formal school systems. Such approaches may also assist in the maintenance and revitalisation of at-risk systems of ethnobiological knowledge. However, we urge further research attention to the significant epistemological challenges inherent in including TEK in formal school, particularly as participants noted the potential for such approaches to have negative consequences.

Despite the prevalence of KRAS mutations in human cancers, there remain no targeted therapies for treatment. The serine-threonine kinase STK33 has been proposed to be required for the survival of mutant KRAS-dependent cell lines, suggesting that small molecule kinase inhibitors of STK33 may be useful to treat KRAS-dependent tumors. In this study, we investigated the role of STK33 in mutant KRAS human cancer cells using RNA interference, dominant mutant overexpression, and small molecule inhibitors. As expected, KRAS downregulation decreased the survival of KRAS-dependent cells. In contrast, STK33 downregulation or dominant mutant overexpression had no effect on KRAS signaling or survival of these cells. Similarly, a synthetic lethal siRNA screen conducted in a broad panel of KRAS wild-type or mutant cells identified KRAS but not STK33 as essential for survival. We also obtained similar negative results using small molecule inhibitors of the STK33 kinase identified by high-throughput screening. Taken together, our findings refute earlier proposals that STK33 inhibition may be a useful therapeutic approach to target human KRAS mutant tumors., (©2011 AACR.)

N-(6-(6-Chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (1) is a potent and efficacious inhibitor of PI3Kα and mTOR in vitro and in vivo. However, in hepatocyte and in vivo metabolism studies, 1 was found to undergo deacetylation on the 2-amino substituent of the benzothiazole. As an approach to reduce or eliminate this metabolic deacetylation, a variety of 6,5-heterocyclic analogues were examined as an alternative to the benzothiazole ring. Imidazopyridazine 10 was found to have similar in vitro potency and in vivo efficacy relative to 1, while only minimal amounts of the corresponding deacetylated metabolite of 10 were observed in hepatocytes.

The phosphoinositide 3-kinase (PI3K) family catalyzes the ATP-dependent phosphorylation of the 3'-hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. There is abundant evidence demonstrating that PI3K signaling is dysregulated in many human cancers, suggesting that therapeutics targeting the PI3K pathway may have utility for the treatment of cancer. Our efforts to identify potent, efficacious, and orally available PI3K/mammalian target of rapamycin (mTOR) dual inhibitors resulted in the discovery of a series of substituted quinolines and quinoxalines derivatives. In this report, we describe the structure-activity relationships, selectivity, and pharmacokinetic data of this series and illustrate the in vivo pharmacodynamic and efficacy data for a representative compound.

Plant-parasitic nematodes are the most destructive group of plant pathogens worldwide and are extremely challenging to control. The recent completion of two root-knot nematode genomes opens the way for a comparative genomics approach to elucidate the success of these parasites. Sequencing revealed that Meloidogyne hapla, a diploid that reproduces by facultative, meiotic parthenogenesis, encodes approximately 14,200 genes in a compact, 54 Mpb genome. Indeed, this is the smallest metazoan genome completed to date. By contrast, the 86 Mbp Meloidogyne incognita genome encodes approximately 19,200 genes. This species reproduces by obligate mitotic parthenogenesis and exhibits a complex pattern of aneuploidy. The genome includes triplicated regions and contains allelic pairs with exceptionally high degrees of sequence divergence, presumably reflecting adaptations to the strictly asexual reproductive mode. Both root-knot nematode genomes have compacted gene families compared with the free-living nematode Caenorhabditis elegans, and both encode large suites of enzymes that uniquely target the host plant. Acquisition of these genes, apparently via horizontal gene transfer, and their subsequent expansion and diversification point to the evolutionary history of these parasites. It also suggests new routes to their control.

We have prepared a series of cathepsin K inhibitors bearing the keto-1,3,4-oxadiazole warhead capable of forming a hemithioketal complex with the target enzyme. By modifying binding moieties at the P1, P2, and prime side positions of the inhibitors, we have achieved selectivity over cathepsins B, L, and S, and have achieved sub-nanomolar potency against cathepsin K. This series thus represents a promising chemotype that could be used in diseases implicated by imbalances in cathepsin K activity such as osteoporosis.

Three outreach activities by a school of nursing, in partnership with community agencies, provided learning experiences in primary and secondary preventive health care for graduate and undergraduate nursing students while addressing health needs in the community. The activities included administration of immunizations to a newly arrived Somali Bantu refugee population, targeted screening of an African-American population at risk for diabetic retinopathy, and general health screening for an underserved Hispanic immigrant population. These activities lend insight and depth to a community health curriculum by allowing students to provide needed services while engaging with culturally diverse clients of varying socioeconomic status. Learner objectives, resources, processes and outcomes are provided for each example.

A novel series of 3,4-disubstituted azetidinones based inhibitors of the cysteine protease cathepsin K (Cat K) has been identified. Although not optimized, some of these compounds show at least 100-fold selectivity against other cathepsins. The use of cyclic moieties as P2 elements has proven to be crucial to achieve a high degree of selectivity.

The structures of a series of complexes designed to mimic intermediates along the reaction coordinate for beta-galactosidase are presented. These complexes clarify and enhance previous proposals regarding the catalytic mechanism. The nucleophile, Glu537, is seen to covalently bind to the galactosyl moiety. Of the two potential acids, Mg(2+) and Glu461, the latter is in better position to directly assist in leaving group departure, suggesting that the metal ion acts in a secondary role. A sodium ion plays a part in substrate binding by directly ligating the galactosyl 6-hydroxyl. The proposed reaction coordinate involves the movement of the galactosyl moiety deep into the active site pocket. For those ligands that do bind deeply there is an associated conformational change in which residues within loop 794-804 move up to 10 A closer to the site of binding. In some cases this can be inhibited by the binding of additional ligands. The resulting restricted access to the intermediate helps to explain why allolactose, the natural inducer for the lac operon, is the preferred product of transglycosylation.