An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013-2023).

This Perspective is a continuation of our analysis of U.S. FDA-approved small-molecule drugs (1938-2012) containing nitrogen heterocycles. In this study we report drug structure and property analyses of 321 unique new small-molecule drugs approved from January 2013 to December 2023 as well as information about frequency of important heteroatoms such as sulfur and fluorine and key small nitrogen substituents (CN and NO2). The most notable change is an incredible increase in drugs containing at least one nitrogen heterocycle─82%, compared to 59% from preceding decades─as well as a significant increase in the number of nitrogen heterocycles per drug. Pyridine has claimed the #1 high-frequency nitrogen heterocycle occurrence spot from piperidine (#2), with pyrimidine (#5), pyrazole (#6), and morpholine (#9) being the big top 10 climbers. Also notable is high number of fused nitrogen heterocycles, apparently driven largely by newly approved cancer drugs.

Cystic fibrosis pathogens persist in the upper respiratory tract following initiation of elexacaftor/tezacaftor/ivacaftor therapy.

Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has revolutionized the treatment of cystic fibrosis (CF) for most affected individuals but the effects of treatment on sinus microbiota are still unknown. Changes to the airway microbiota in CF are associated with disease state and alterations to the bacterial community after ETI initiation may require changes to clinical management regimens. We collected sinus swab samples from the middle meatus in an observational study of 38 adults with CF and chronic rhinosinusitis (CRS) from 2017 to 2021 and captured the initiation of ETI therapy. We performed 16S and custom amplicon sequencing to characterize the sinus microbiota pre- and post-ETI. Real-time quantitative PCR (RT-qPCR) was performed to estimate total bacterial abundance. Sinus samples from people with CF (pwCF) clustered into three community types, dependent on the dominant bacterial organism: a Pseudomonas-dominant, Staphylococcus-dominant, and mixed dominance cluster. Shannon's diversity index was low and not significantly altered post-ETI. Total bacterial load was not significantly lowered post-ETI. Pseudomonas spp. abundance was significantly reduced post-ETI, but eradication was not observed. Staphylococcus spp. became the dominant organism in most individuals post-ETI and we showed the presence of methicillin-resistant Staphylococcus aureus (MRSA) in the sinus both pre- and post-ETI. We also demonstrated that the sinus microbiome is predictive of the presence of Pseudomonas spp., Staphylococcus spp., and Serratia spp. in the sputum. Pseudomonas spp. and Staphylococcus spp., including MRSA, persist in the sinuses of pwCF after ETI therapy, indicating that these pathogens will continue to be important in CF airway disease management in the era of highly effective modulator therapies (HEMT).IMPORTANCEHighly effective modulator therapies (HEMT), such as elexacaftor/tezacaftor/ivacaftor (ETI), for cystic fibrosis (CF) have revolutionized patient care and quality of life for most affected individuals. The effects of these therapies on the microbiota of the airways are still unclear, though work has already been published on changes to microbiota in the sputum. Our study presents evidence for reduced relative abundance of Pseudomonas spp. in the sinuses following ETI therapy. We also show that Staphylococcus spp. becomes the dominant organism in the sinus communities of most individuals in this cohort after ETI therapy. We identified methicillin-resistant Staphylococcus aureus (MRSA) in the sinus microbiota both pre- and post-therapy. These findings demonstrate that pathogen monitoring and treatment will remain a vital part of airway disease management for people with cystic fibrosis (pwCF) in the era of HEMT.

Reconstitution and characterization of BRAF in complex with 14-3-3 and KRAS4B on nanodiscs.

RAF kinases are key components of the RAS-MAPK signaling pathway, which drives cell growth and is frequently overactivated in cancer. Upstream signaling activates the small GTPase RAS, which recruits RAF to the cell membrane, driving a transition of the latter from an auto-inhibited monomeric conformation to an active dimer. Despite recent progress, mechanistic details underlying RAF activation remain unclear, particularly the role of RAS and the membrane in mediating this conformational rearrangement of RAF together with 14-3-3 to permit RAF kinase domain dimerization. Here, we reconstituted an active complex of dimeric BRAF, a 14-3-3 dimer and two KRAS4B on a nanodisc bilayer and verified that its assembly is GTP-dependent. Biolayer interferometry (BLI) was used to compare the binding affinities of monomeric versus dimeric full-length BRAF:14-3-3 complexes for KRAS4B-conjugated nanodiscs (RAS-ND) and to investigate the effects of membrane lipid composition and spatial density of KRAS4B on binding. 1,2-Dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) and higher KRAS4B density enhanced the interaction of BRAF:14-3-3 with RAS-ND to different degrees depending on BRAF oligomeric state. We utilized our reconstituted system to dissect the effects of KRAS4B and the membrane on the kinase activity of monomeric and dimeric BRAF:14-3-3 complexes, finding that KRAS4B or nanodiscs alone were insufficient to stimulate activity, whereas RAS-ND increased activity of both states of BRAF. The reconstituted assembly of full-length BRAF with 14-3-3 and KRAS on a cell-free, defined lipid bilayer offers a more holistic biophysical perspective to probe regulation of this multimeric signaling complex at the membrane surface.

Crystal structure of NRAS Q61K with a ligand-induced pocket near switch II.

The RAS isoforms (KRAS, HRAS and NRAS) have distinct cancer type-specific profiles. NRAS mutations are the second most prevalent RAS mutations in skin and hematological malignancies. Although RAS proteins were considered undruggable for decades, isoform and mutation-specific investigations have produced successful RAS inhibitors that are either specific to certain mutants, isoforms (pan-KRAS) or target all RAS proteins (pan-RAS). While extensive structural and biochemical investigations have focused mainly on K- and H-RAS mutations, NRAS mutations have received less attention, and the most prevalent NRAS mutations in human cancers, Q61K and Q61R, are rare in K- and H-RAS. This manuscript presents a crystal structure of the NRAS Q61K mutant in the GTP-bound form. Our structure reveals a previously unseen pocket near switch II induced by the binding of a ligand to the active form of the protein. This observation reveals a binding site that can potentially be exploited for development of inhibitors against mutant NRAS. Furthermore, the well-resolved catalytic site of this GTPase bound to native GTP provides insight into the stalled GTP hydrolysis observed for NRAS-Q61K.

Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis.

Today, more than 90% of people with cystic fibrosis (pwCF) are eligible for the highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy called elexacaftor/tezacaftor/ivacaftor (ETI) and its use is widespread. Given the drastic respiratory symptom improvement experienced by many post-ETI, clinical studies are already underway to reduce the number of respiratory therapies, including antibiotic regimens, that pwCF historically relied on to combat lung disease progression. Early studies suggest that bacterial burden in the lungs is reduced post-ETI, yet it is unknown how chronic Pseudomonas aeruginosa populations are impacted by ETI. We found that pwCF remain infected throughout their upper and lower respiratory tract with their same strain of P. aeruginosa post-ETI, and these strains continue to evolve in response to the newly CFTR-corrected airway. Our work underscores the continued importance of CF airway microbiology in the new era of highly effective CFTR modulator therapy. IMPORTANCE: The highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.

Engineered dityrosine-bonding of the RSV prefusion F protein imparts stability and potency advantages.

Viral fusion proteins facilitate cellular infection by fusing viral and cellular membranes, which involves dramatic transitions from their pre- to postfusion conformations. These proteins are among the most protective viral immunogens, but they are metastable which often makes them intractable as subunit vaccine targets. Adapting a natural enzymatic reaction, we harness the structural rigidity that targeted dityrosine crosslinks impart to covalently stabilize fusion proteins in their native conformations. We show that the prefusion conformation of respiratory syncytial virus fusion protein can be stabilized with two engineered dityrosine crosslinks (DT-preF), markedly improving its stability and shelf-life. Furthermore, it has 11X greater potency as compared with the DS-Cav1 stabilized prefusion F protein in immunogenicity studies and overcomes immunosenescence in mice with simply a high-dose formulation on alum.

Early life conditions reduce similarity between reproductive partners in HPA axis response to stress.

Social environments modulate endocrine function, yet it is unclear whether individuals can become like their social partners in how they physiologically respond to stressors. This social transmission of hypothalamic-pituitary-adrenal (HPA) axis reactivity could have long-term consequences for health and lifespan of individuals if their social partners react to stressors with an exaggerated HPA axis response. We tested whether glucocorticoid levels in response to stress of breeding partners changes after breeding depending on whether partners had similar or dissimilar postnatal conditions. We manipulated postnatal conditions by mimicking early life stress in zebra finch chicks (Taeniopygia guttata) via postnatal corticosterone exposure. When they reached adulthood, we created breeding pairs where the female and male had experienced either the same or different early life hormonal treatment (corticosterone or control). Before and after breeding, we obtained blood samples within 3 min and after 10 min or 30 min of restraint stress (baseline, cort10, cort30). We found that corticosterone levels of individuals in response to restraint were affected by their own and their partner's early life conditions, but did not change after breeding. However, across all pairs, partners became more similar in cort30 levels after breeding, although differences between partners in cort10 remained greater in pairs with a corticosterone-treated female. Thus, we show that HPA axis response to stressors in adulthood can be modulated by reproductive partners and that similarity between partners is reduced when females are postnatally exposed to elevated glucocorticoids.

Environmental drivers impact the accumulation and diversity of antibiotic resistance in green stormwater infrastructure.

Antibiotic resistance poses an urgent public health concern, with the environment playing a crucial role in the development and dissemination of resistant bacteria. There is a growing body of research indicating that stormwater is a significant source and transport vector of resistance elements. This research sought to characterize the role of green stormwater infrastructure (GSI), designed for stormwater infiltration, in accumulating and propagating antibiotic resistance in the urban water cycle. Sampling included 24 full-scale GSI systems representing three distinct types of GSI - bioswales, bioretention cells, and constructed wetlands. The results indicated that GSI soils accumulate antibiotic resistance genes (ARGs) at elevated concentrations compared to nonengineered soils. Bioretention cells specifically harbored higher abundances of ARGs, suggesting that the type of GSI influences ARG accumulation. Interestingly, ARG diversity in GSI soils was not impacted by the type of GSI design or the diversity of the microbial community and mobile genetic elements. Instead, environmental factors (catchment imperviousness, metals, nutrients, and salts) were identified as significant drivers of ARG diversity. These findings highlight how environmental selective pressures in GSI promote ARG persistence and proliferation independently of the microbial community. Therefore, GSI systems have the potential to be a substantial contributor of abundant and diverse ARGs to the urban water cycle.

Prolactin Mediates Long-Term, Seasonal Rheostatic Regulation of Body Mass in Female Mammals.

A series of well-described anabolic and catabolic neuropeptides are known to provide short-term, homeostatic control of energy balance. The mechanisms that govern long-term, rheostatic control of regulated changes in energy balance are less well characterized. Using the robust and repeatable seasonal changes in body mass observed in Siberian hamsters, this report examined the role of prolactin in providing long-term rheostatic control of body mass and photoinduced changes in organ mass (ie, kidney, brown adipose tissue, uterine, and spleen). Endogenous circannual interval timing was observed after 4 months in a short photoperiod, indicated by a significant increase in body mass and prolactin mRNA expression in the pituitary gland. There was an inverse relationship between body mass and the expression of somatostatin (Sst) and cocaine- and amphetamine-regulated transcript (Cart). Pharmacological inhibition of prolactin release (via bromocriptine injection), reduced body mass of animals maintained in long photoperiods to winter-short photoperiod levels and was associated with a significant increase in hypothalamic Cart expression. Administration of ovine prolactin significantly increased body mass 24 hours after a single injection and the effect persisted after 3 consecutive daily injections. The data indicate that prolactin has pleiotropic effects on homeostatic sensors of energy balance (ie, Cart) and physiological effectors (ie, kidney, BAT). We propose that prolactin release from the pituitary gland acts as an output signal of the hypothalamic rheostat controller to regulate adaptive changes in body mass.

Efficacy, Feasibility, and Safety of the X-Tack Endoscopic HeliX Tacking System: A Multicenter Experience.

BACKGROUND AND AIMS: The application of endoscopic suturing has revolutionized defect closures. Conventional over-the-scope suturing necessitates removal of the scope, placement of the device, and reinsertion. A single channel, single sequence, through-the-scope suturing device has been developed to improve this process. This study aims to describe the efficacy, feasibility, and safety of a through-the-scope suturing device for gastrointestinal defect closure. METHODS: This was a retrospective multicenter study involving 9 centers of consecutive adult patients who underwent suturing using the X-Tack Endoscopic HeliX Tacking System (Apollo Endosurgery). The primary outcomes were technical success and long-term clinical success. Secondary outcomes included adverse events, recurrence, and reintervention rates. RESULTS: In all, 56 patients (mean age 53.8, 33 women) were included. Suturing indications included fistula repair (n=22), leak repair (n=7), polypectomy defect closure (n=12), peroral endoscopic myotomy (POEM) site closure (n=7), perforation repair (n=6), and ulcers (n=2). Patients were followed at a mean duration of 74 days. Overall technical and long-term clinical success rates were 92.9% and 75%, respectively. Both technical and clinical success rates were 100% for polypectomies, POEM-site closures, and ulcers. Success rates were lower for the repair of fistulas (95.5% technical, 54.5% clinical), leaks (57.1%, 28.6%), and perforations (100%, 66.7%). No immediate adverse events were noted. CONCLUSION: This novel, through-the-scope endoscopic suturing system, is a safe and feasible method to repair defects that are ≤3 cm. The efficacy of this device may be better suited for superficial defects as opposed to full-thickness defects. Larger defects will need more sutures and probably a double closure technique to provide a reinforcement layer.

FSHß links photoperiodic signaling to seasonal reproduction in Japanese quail.

Annual cycles in daylength provide an initial predictive environmental cue that plants and animals use to time seasonal biology. Seasonal changes in photoperiodic information acts to entrain endogenous programs in physiology to optimize an animal's fitness. Attempts to identify the neural and molecular substrates of photoperiodic time measurement in birds have, to date, focused on blunt changes in light exposure during a restricted period of photoinducibility. The objectives of these studies were first to characterize a molecular seasonal clock in Japanese quail and second, to identify the key transcripts involved in endogenously generated interval timing that underlies photosensitivity in birds. We hypothesized that the mediobasal hypothalamus (MBH) provides the neuroendocrine control of photoperiod-induced changes in reproductive physiology, and that the pars distalis of the pituitary gland contains an endogenous internal timer for the short photoperiod-dependent development of reproductive photosensitivity. Here, we report distinct seasonal waveforms of transcript expression in the MBH, and pituitary gland and discovered the patterns were not synchronized across tissues. Follicle-stimulating hormone-ß (FSHß) expression increased during the simulated spring equinox, prior to photoinduced increases in prolactin, thyrotropin-stimulating hormone-ß, and testicular growth. Diurnal analyses of transcript expression showed sustained elevated levels of FSHß under conditions of the spring equinox, compared to autumnal equinox, short (<12L) and long (>12L) photoperiods. FSHß expression increased in quail held in non-stimulatory short photoperiod, indicative of the initiation of an endogenously programmed interval timer. These data identify that FSHß establishes a state of photosensitivity for the external coincidence timing of seasonal physiology. The independent regulation of FSHß expression provides an alternative pathway through which other supplementary environmental cues, such as temperature, can fine tune seasonal reproductive maturation and involution.

A mapping exercise using automated techniques to develop a search strategy to identify systematic review tools.

The Systematic Review Toolbox aims provide a web-based catalogue of tools that support various tasks within the systematic review and wider evidence synthesis process. Identifying publications surrounding specific systematic review tools is currently challenging, leading to a high screening burden for few eligible records. We aimed to develop a search strategy that could be regularly and automatically run to identify eligible records for the SR Toolbox, thus reducing time on task and burden for those involved. We undertook a mapping exercise to identify the PubMed IDs of papers indexed within the SR Toolbox. We then used the Yale MeSH Analyser and Visualisation of Similarities (VOS) Viewer text-mining software to identify the most commonly used MeSH terms and text words within the eligible records. These MeSH terms and text words were combined using Boolean Operators into a search strategy for Ovid MEDLINE. Prior to the mapping exercise and search strategy development, 81 software tools and 55 'Other' tools were included within the SR Toolbox. Since implementation of the search strategy, 146 tools have been added. There has been an increase in tools added to the toolbox since the search was developed and its corresponding auto-alert in MEDLINE was originally set up. Developing a search strategy based on a mapping exercise is an effective way of identifying new tools to support the systematic review process. Further research could be conducted to help prioritise records for screening to reduce reviewer burden further and to adapt the strategy for disciplines beyond healthcare.

Evaluating ChatGPT Performance on the Orthopaedic In-Training Examination.

Background: Artificial intelligence (AI) holds potential in improving medical education and healthcare delivery. ChatGPT is a state-of-the-art natural language processing AI model which has shown impressive capabilities, scoring in the top percentiles on numerous standardized examinations, including the Uniform Bar Exam and Scholastic Aptitude Test. The goal of this study was to evaluate ChatGPT performance on the Orthopaedic In-Training Examination (OITE), an assessment of medical knowledge for orthopedic residents. Methods: OITE 2020, 2021, and 2022 questions without images were inputted into ChatGPT version 3.5 and version 4 (GPT-4) with zero prompting. The performance of ChatGPT was evaluated as a percentage of correct responses and compared with the national average of orthopedic surgery residents at each postgraduate year (PGY) level. ChatGPT was asked to provide a source for its answer, which was categorized as being a journal article, book, or website, and if the source could be verified. Impact factor for the journal cited was also recorded. Results: ChatGPT answered 196 of 360 answers correctly (54.3%), corresponding to a PGY-1 level. ChatGPT cited a verifiable source in 47.2% of questions, with an average median journal impact factor of 5.4. GPT-4 answered 265 of 360 questions correctly (73.6%), corresponding to the average performance of a PGY-5 and exceeding the corresponding passing score for the American Board of Orthopaedic Surgery Part I Examination of 67%. GPT-4 cited a verifiable source in 87.9% of questions, with an average median journal impact factor of 5.2. Conclusions: ChatGPT performed above the average PGY-1 level and GPT-4 performed better than the average PGY-5 level, showing major improvement. Further investigation is needed to determine how successive versions of ChatGPT would perform and how to optimize this technology to improve medical education. Clinical Relevance: AI has the potential to aid in medical education and healthcare delivery.

Expanding ocean protection and peace: a window for science diplomacy in the Gulf.

The ecological state of the Persian or Arabian Gulf (hereafter 'Gulf') is in sharp decline. Calls for comprehensive ecosystem-based management approaches and transboundary conservation have gone largely unanswered, despite mounting marine threats made worse by climate change. The region's long-standing political tensions add additional complexity, especially now as some Gulf countries will soon adopt ambitious goals to protect their marine environments as part of new global environmental commitments. The recent interest in global commitments comes at a time when diplomatic relations among all Gulf countries are improving. There is a window of opportunity for Gulf countries to meet global marine biodiversity conservation commitments, but only if scientists engage in peer-to-peer diplomacy to build trust, share knowledge and strategize marine conservation options across boundaries. The Gulf region needs more ocean diplomacy and coordination; just as critically, it needs actors at its science-policy interface to find better ways of adapting cooperative models to fit its unique marine environment, political context and culture. We propose a practical agenda for scientist-led diplomacy in the short term and lines of research from which to draw (e.g. co-production, knowledge exchange) to better design future science diplomacy practices and processes suited to the Gulf's setting.

Biochemical and biophysical characterization of the RAS family small GTPase protein DiRAS3.

DiRAS3, also called ARHI, is a RAS (sub)family small GTPase protein that shares 50-60% sequence identity with H-, K-, and N-RAS, with substitutions in key conserved G-box motifs and a unique 34 amino acid extension at its N-terminus. Unlike the RAS proto-oncogenes, DiRAS3 exhibits tumor suppressor properties. DiRAS3 function has been studied through genetics and cell biology, but there has been a lack of understanding of the biochemical and biophysical properties of the protein, likely due to its instability and poor solubility. To overcome this solubility issue, we engineered a DiRAS3 variant (C75S/C80S), which significantly improved soluble protein expression in E. coli. Recombinant DiRAS3 was purified by Ni-NTA and size exclusion chromatography (SEC). Concentration dependence of the SEC chromatogram indicated that DiRAS3 exists in monomer-dimer equilibrium. We then produced truncations of the N-terminal (ΔN) and both (ΔNC) extensions to the GTPase domain. Unlike full-length DiRAS3, the SEC profiles showed that ΔNC is monomeric while ΔN was monomeric with aggregation, suggesting that the N and/or C-terminal tail(s) contribute to dimerization and aggregation. The 1H-15N HSQC NMR spectrum of ΔNC construct displayed well-dispersed peaks similar to spectra of other GTPase domains, which enabled us to demonstrate that DiRAS3 has a GTPase domain that can bind GDP and GTP. Taken together, we conclude that, despite the substitutions in the G-box motifs, DiRAS3 can switch between nucleotide-bound states and that the N- and C-terminal extensions interact transiently with the GTPase domain in intra- and inter-molecular fashions, mediating weak multimerization of this unique small GTPase.

A narrative review of recent tools and innovations toward automating living systematic reviews and evidence syntheses.

Living reviews are an increasingly popular research paradigm. The purpose of a 'living' approach is to allow rapid collation, appraisal and synthesis of evolving evidence on an important research topic, enabling timely influence on patient care and public health policy. However, living reviews are time- and resource-intensive. The accumulation of new evidence and the possibility of developments within the review's research topic can introduce unique challenges into the living review workflow. To investigate the potential of software tools to support living systematic or rapid reviews, we present a narrative review informed by an examination of tools contained on the Systematic Review Toolbox website. We identified 11 tools with relevant functionalities and discuss the important features of these tools with respect to different steps of the living review workflow. Four tools (NestedKnowledge, SWIFT-ActiveScreener, DistillerSR, EPPI-Reviewer) covered multiple, successive steps of the review process, and the remaining tools addressed specific components of the workflow, including scoping and protocol formulation, reference retrieval, automated data extraction, write-up and dissemination of data. We identify several ways in which living reviews can be made more efficient and practical. Most of these focus on general workflow management, or automation through artificial intelligence and machine-learning, in the screening process. More sophisticated uses of automation mostly target living rapid reviews to increase the speed of production or evidence maps to broaden the scope of the map. We use a case study to highlight some of the barriers and challenges to incorporating tools into the living review workflow and processes. These include increased workload, the need for organisation, ensuring timely dissemination and challenges related to the development of bespoke automation tools to facilitate the review process. We describe how current end-user tools address these challenges, and which knowledge gaps remain that could be addressed by future tool development. Dedicated web presences for automatic dissemination of in-progress evidence updates, rather than solely relying on peer-reviewed journal publications, help to make the effort of a living evidence synthesis worthwhile. Despite offering basic living review functionalities, existing end-user tools could be further developed to be interoperable with other tools to support multiple workflow steps seamlessly, to address broader automatic evidence retrieval from a larger variety of sources, and to improve dissemination of evidence between review updates.

Feeding without teeth: the material properties of rhamphothecae from two species of durophagous sea turtles.

The feeding apparatus of sea turtles comprises cornified keratinous rhamphothecae overlaying a bony rostrum. Although keratin is less stiff than the enamel of toothed animals, certain species of sea turtles are capable of withstanding large forces when feeding on hard prey. We aimed to quantify the mineral density, water content and compressive mechanical properties of rhamphothecae from two durophagous species: loggerhead (Caretta caretta) and Kemp's ridley (Lepidochelys kempii) sea turtles. Since loggerheads theoretically produce the greater bite forces of these two species, we predicted that keratin from their rhamphothecae would have a greater mineral density and be stiffer, stronger and tougher compared with Kemp's ridley sea turtles. We found that total water weight of hydrated specimens (20%) was consistent between species. Rhamphotheca mineral density ranged between 0 and 0.069 g cm-3; loggerheads had significantly greater mineral density compared with Kemp's ridleys, for which several specimens had no mineral detected. Despite the greater mineral density in loggerheads, we found no significant difference in Young's modulus, yield strength or toughness between these species. In addition to mineral density, our findings suggest that other material components, such as sulfur, may be influencing the material properties of keratin from sea turtle rhamphothecae.

Economic evaluations of interventions to prevent and control health-care-associated infections: a systematic review.

Almost 9 million health-care-associated infections have been estimated to occur each year in European hospitals and long-term care facilities, and these lead to an increase in morbidity, mortality, bed occupancy, and duration of hospital stay. The aim of this systematic review was to review the cost-effectiveness of interventions to limit the spread of health-care-associated infections), framed by WHO infection prevention and control core components. The Embase, National Health Service Economic Evaluation Database, Database of Abstracts of Reviews of Effects, Health Technology Assessment, Cinahl, Scopus, Pediatric Economic Database Evaluation, and Global Index Medicus databases, plus grey literature were searched for studies between Jan 1, 2009, and Aug 10, 2022. Studies were included if they reported interventions including hand hygiene, personal protective equipment, national-level or facility-level infection prevention and control programmes, education and training programmes, environmental cleaning, and surveillance. The British Medical Journal checklist was used to assess the quality of economic evaluations. 67 studies were included in the review. 25 studies evaluated methicillin-resistant Staphylococcus aureus outcomes. 31 studies evaluated screening strategies. The assessed studies that met the minimum quality criteria consisted of economic models. There was some evidence that hand hygiene, environmental cleaning, surveillance, and multimodal interventions were cost-effective. There were few or no studies investigating education and training, personal protective equipment or monitoring, and evaluation of interventions. This Review provides a map of cost-effectiveness data, so that policy makers and researchers can identify the relevant data and then assess the quality and generalisability for their setting.

The Self-Association of the KRAS4b Protein is Altered by Lipid-Bilayer Composition and Electrostatics.

KRAS is a peripheral membrane protein that regulates multiple signaling pathways, and is mutated in ≈30 % of cancers. Transient self-association of KRAS is essential for activation of the downstream effector RAF and oncogenicity. The presence of anionic phosphatidylserine (PS) lipids in the membrane was shown to promote KRAS self-assembly, however, the structural mechanisms remain elusive. Here, we employed nanodisc bilayers of defined lipid compositions, and probed the impact of PS concentration on KRAS self-association. Paramagnetic NMR experiments demonstrated the existence of two transient dimer conformations involving alternate electrostatic contacts between R135 and either D153 or E168 on the "α4/5-α4/5" interface, and revealed that lipid composition and salt modulate their dynamic equilibrium. These dimer interfaces were validated by charge-reversal mutants. This plasticity demonstrates how the dynamic KRAS dimerization interface responds to the environment, and likely extends to the assembly of other signaling complexes on the membrane.