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The competitive endothelin receptor antagonists (ERA) bosentan and ambrisentan, which have long been approved for the treatment of pulmonary arterial hypertension, are characterized by very short (1 min) occupancy half-lives at the ET(A) receptor. The novel ERA macitentan, displays a 20-fold increased receptor occupancy half-life, causing insurmountable antagonism of ET-1-induced signaling in pulmonary arterial smooth muscle cells. We show here that the slow ET(A) receptor dissociation rate of macitentan was shared with a set of structural analogs, whereas compounds structurally related to bosentan displayed fast dissociation kinetics. NMR analysis showed that macitentan adopts a compact structure in aqueous solution and molecular modeling suggests that this conformation tightly fits into a well-defined ET(A) receptor binding pocket. In contrast the structurally different and negatively charged bosentan-type molecules only partially filled this pocket and expanded into an extended endothelin binding site. To further investigate these different ET(A) receptor-antagonist interaction modes, we performed functional studies using ET(A) receptor variants harboring amino acid point mutations in the presumed ERA interaction site. Three ET(A) receptor residues significantly and differentially affected ERA activity: Mutation R326Q did not affect the antagonist activity of macitentan, however the potencies of bosentan and ambrisentan were significantly reduced; mutation L322A rendered macitentan less potent, whereas bosentan and ambrisentan were unaffected; mutation I355A significantly reduced bosentan potency, but not ambrisentan and macitentan potencies. This suggests that--in contrast to bosentan and ambrisentan--macitentan-ET(A) receptor binding is not dependent on strong charge-charge interactions, but depends predominantly on hydrophobic interactions. This different binding mode could be the reason for macitentan's sustained target occupancy and insurmountable antagonism.

Different techniques can be applied for the automated production of small and large compound collections. Large libraries that are often generated and tested during the lead-finding stage of a project are typically produced by solid-phase chemistry. Libraries that are significantly smaller in size are often synthesized in solution. Chemistry in solution is rather versatile, offers numerous advantages and is therefore often the method of choice for generating small libraries during a lead optimization process. Fast and reliable purification procedures are required to yield compounds of high quality that can be immediately used in biological as well as pharmacological assays. Solution-phase chemistry combined with automated purification was applied to optimize initial lead inhibitors for the two human orexin receptors OX1 and OX2. Starting from a submicro-molar OX1 selective lead compound, low nanomolar analogues with improved physico-chemical properties were synthesized that antagonize either one or both orexin receptors.

Amphiphilic compounds play crucial roles in biology. They represent molecules with an inherent tendency to orient themselves in a suitable environment (e.g. a lipid bilayer). The driving force behind this effect is probably one of the crucial reasons for structural organization in living matter. An amphiphile typically comprises a hydrophilic as well as a hydrophobic part. The prediction of amphiphilic properties of charged small molecules by means of our in-house developed program CAFCA is presented in this work. An experimentally derived quantification of amphiphilic properties of a compound, expressed in terms of free energy of amphiphilicity (??GAM), can be deduced from surface activity measurements. Amphiphilic moments are obtained by vector addition of individual atom/fragment contribution values. Calculated amphiphilic moments were subsequently calibrated with known free energies of amphiphilicity (??GAM) of a homologous series of small charged amphiphiles (n-alkylsulfonic acids). The influence of conformational effects of molecules on calculated amphiphilic moments were further investigated for a set of eight structurally diverse commercially available drugs with known free energies of amphiphilicity. It turned out that conformations with maximal distance between charged group and center of gravity of the non-charged residue of the molecule yielded best results. Our calculated data and molecular modeling studies are in good accordance with experimentally derived published values. Our program CAFCA (CAlculated Free energy of amphiphilicity of small Charged Amphiphiles) can be used to estimate preferred conformations as well as orientations of molecules in biological membranes and to quantify amphiphilic properties of molecules.

Since its discovery, endothelin-1 has attracted considerable scientific interest for its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. The endothelins appear to be part of a functional regulatory system in the circulation and strong evidence has accumulated for their involvement in clinical disorders associated with vasoconstriction (e.g. renal failure, congestive heart failure).In a program aimed at identifying nonpeptide ET receptor antagonists, a distinct class of substituted arylsulfonamido pyrimidines was discovered from a chemical substance library. Lead optimization led to orally active antagonists of ETA and ETB receptors possessing mixed or receptor-subtype-selective profiles in the low nanomolar range. From these compounds, the mixed antagonist bosentan was selected for development; it shows efficacy in several pathophysiological models of local and systemic vasoconstriction and promising clinical results in patients suffering from congestive heart failure.Chemical modifications in this structural class in combination with X-ray crystal data analysis for key compounds led to more in-depth understanding of antagonist-receptor interaction. Structural determinants of bosentan binding to the ETA receptor were defined on the molecular level by site-directed mutagenesis experiments. This led to a 3D model of the antagonist binding domain which proved valuable to rationalize structure-activity relationships.

In a survey of the arthropod fauna of 33 Urban Green Spaces (UGS) in Bogotá, Colombia, between 2017 and 2019, 21 species (3,825 specimens) of Psylloidea were collected. These represent all seven recognised families of jumping plant-lice and include seven species identified only to genus. The specimens, all adults, were collected on 30 plant species used for arborization in the UGS. Two species are described as new (Mastigimas longicaudatus Rendón-Mera, Burckhardt & Vargas-Fonseca, sp. nov. and Leuronota albilinea Rendón-Mera, Burckhardt & Vargas-Fonseca, sp. nov.), one species is redescribed (Mastigimas colombianus Burckhardt, Queiroz & Drohojowska) and one species is recorded for the first time from Colombia (Calinda trinervis Olivares & Burckhardt). Among the seven species identified only to genus is an undescribed species of Melanastera, representing a genus not previously known from Colombia. Fourteen species found during the survey are probably native (66%) and seven (33%) adventive. Our findings highlight the significance of UGS for preservation of biological diversity and stress the importance of using native plants in urban landscape planning for the conservation of the native entomofauna.

Melanastera sinica He & Burckhardt, sp. nov., a new psylloid species developing on Grewia sp., is described from Hainan, China. It is the first Melanastera species reported from Asia and China, and the second species from the Old World. While New World species of Melanastera are mostly associated with the plant families Melastomataceae and Annonaceae, the two Old World species develop on the malvaceous Grewia, a host otherwise used in psylloids by two Haplaphalara species. The new species is described, diagnosed and illustrated, and its host plant and biogeographic ranges are discussed.

The product of two unitaries can normally be expressed as a single exponential through the famous Baker-Campbell-Hausdorff formula. We present here a counterexample in quantum optics, by showing that an expression in terms of a single exponential is possible only at the expense of the introduction of a new element (a central extension of the algebra), implying that there will be unitaries, generated by a sequence of gates, that cannot be generated by any time-independent quadratic Hamiltonian. A quantum-optical experiment is proposed that brings to light this phenomenon.

ABSTRACT The limited temporal completeness and taxonomic accuracy of species lists, made available in a traditional manner in scientific publications, has always represented a problem. These lists are invariably limited to a few taxonomic groups and do not represent up-to-date knowledge of all species and classifications. In this context, the Brazilian megadiverse fauna is no exception, and the Catálogo Taxonômico da Fauna do Brasil (CTFB) (http://fauna.jbrj.gov.br/), made public in 2015, represents a database on biodiversity anchored on a list of valid and expertly recognized scientific names of animals in Brazil. The CTFB is updated in near real time by a team of more than 800 specialists. By January 1, 2024, the CTFB compiled 133,691 nominal species, with 125,138 that were considered valid. Most of the valid species were arthropods (82.3%, with more than 102,000 species) and chordates (7.69%, with over 11,000 species). These taxa were followed by a cluster composed of Mollusca (3,567 species), Platyhelminthes (2,292 species), Annelida (1,833 species), and Nematoda (1,447 species). All remaining groups had less than 1,000 species reported in Brazil, with Cnidaria (831 species), Porifera (628 species), Rotifera (606 species), and Bryozoa (520 species) representing those with more than 500 species. Analysis of the CTFB database can facilitate and direct efforts towards the discovery of new species in Brazil, but it is also fundamental in providing the best available list of valid nominal species to users, including those in science, health, conservation efforts, and any initiative involving animals. The importance of the CTFB is evidenced by the elevated number of citations in the scientific literature in diverse areas of biology, law, anthropology, education, forensic science, and veterinary science, among others.

Abstract To survive, cells must respond to changing environmental conditions. One way that eukaryotic cells react to harsh stimuli is by forming physiological, RNA-seeded subnuclear condensates, termed amyloid bodies (A-bodies). The molecular constituents of A-bodies induced by different stressors vary significantly, suggesting this pathway can tailor the cellular response by selectively aggregating a subset of proteins under a given condition. Here, we identify critical structural elements that regulate heat shock-specific amyloid aggregation. Our data demonstrates that manipulating structural pockets in constituent proteins can either induce or restrict their A-body targeting at elevated temperatures. We propose a model where selective aggregation within A-bodies is mediated by the thermal stability of a protein, with temperature-sensitive structural regions acting as an intrinsic form of post-translational regulation. This system would provide cells with a rapid and stress-specific response mechanism, to tightly control physiological amyloid aggregation or other cellular stress response pathways.

Various excitation-induced loss mechanisms have been identified during the development of direct-gap semiconductor lasers. Recently, indirect-gap laser sources, particularly germanium (Ge) or GeSn based, have emerged due to silicon industry compatibility. Tensile strain is crucial for optical gain or low-threshold room-temperature operation in such media. This study investigates an excitation-induced optical loss mechanism of mechanical origin in Ge-based micro-cavities with all-around stressor layers, a popular platform for strain-engineered laser sources. Using Raman spectroscopy, photoluminescence, and simulations, we find that excitation lowers the optical gain by altering the strain profile. Heating causes Ge micro-cavities to expand within a constraining stressor layer, inducing compressive strain, which is explained by the mismatch in thermal expansion coefficients.

Background Hypertension affects 28.5% of Indians aged 18–69. Real-time registration and follow-up of persons with hypertension are possible with point-of-care digital information systems. We intend to describe herein the experiences of discovering, developing, and deploying a point-of-care digital information system for public health facilities under the India Hypertension Control Initiative. Methods We have adopted an agile and user-centered approach in each phase in selected states of India since 2017. A multidisciplinary team adopted a hybrid approach with quantitative and qualitative methods, such as contextual inquiries, usability testing, and semi-structured interviews with healthcare workers, to document and monitor utility and usability. Results During the discovery phase, we adopted a storyboard technique to understand the requirement of a digital information system. The participatory approach in discovery phase co-designed the information system with the nurses and doctors at Punjab state of India. Simple, which is the developed information system, has a front-end Android mobile application for healthcare workers and a backend dashboard for program managers. As of October 2022, over 24,31,962 patients of hypertension and 8,99,829 diabetes were registered in the information system of 10,017 health facilities. The median duration of registering a new patient was 50 seconds, and for recording a follow-up visit was 14 seconds in the app. High satisfaction was reported in 100 app users’ quarterly interviews. Conclusion Simple was implemented by administering a user-centered approach and agile techniques. It demonstrated high utility and usability among users, highlighting the benefits of a user-centered approach for effective digital health solutions.

Five species of Psyllinae are recognised from Gunung Kinabalu, all previously unknown, and are formally described and named: Cacopsylla graciliforceps sp. nov., C. kinabaluensis sp. nov., C. myrsines sp. nov., C. photiniae sp. nov. and Psylla cirrita sp. nov. Another species similar to P. cirrita remains undescribed due to lack of sufficient material. Two Philippine species closely related to C. kinabaluensis are transferred to Cacopsylla as Cacopsylla aranetae (Miyatake, 1972), comb. nov. and Cacopsylla bakeri (Crawford, 1919), comb. nov. (both from Psylla). Three of the Cacopsylla species probably represent Palaearctic faunal elements (Cacopsylla graciliforceps, C. myrsines and C. photiniae). Host information is available only for Cacopsylla myrsines and C. photiniae, viz. Myrsine dasyphylla (Primulaceae) and Photinia davidiana (Rosaceae), respectively. Myrsine has not been previously reported as host genus of Psylloidea. The five new species bring the number of known Psylloidea species from Gunung Kinabalu to 22. The biogeographic relationships found in the flora, i.e. Oriental elements predominate at lower altitudes, and Himalayan and Australian elements are dominant at altitudes above 2500 m, are reflected in the psyllid fauna (Oriental 4 spp.; Australian 13 spp., Himalayan 3 spp.; unknown 2 spp.). Of the 22 species known from Gunung Kinabalu, 18 are only known from there. This high number is probably only partly due to endemism and is partly due to insufficient knowledge of the psyllid fauna of Borneo and of the tropics in general.

Psyllids (Hemiptera: Psylloidea) are plant sap-sucking insects whose identification is often difficult for non-experts. Despite the rapid development of DNA barcoding techniques and their widespread use, only a limited number of sequences of psyllids are available in the public databases, and those that are available are often misidentified. Here, we provide 80 sequences of two mitochondrial genes, cytochrome c oxidase I (COI) and cytochrome b (Cytb), for 25 species of Aphalaridae, mainly from Bulgaria. The DNA barcodes for 15 of these species are published for the first time. In cases where standard primers failed to amplify the target gene fragment, we designed new primers that can be used in future studies. The distance-based thresholds for the analysed species were between 0.0015 and 0.3415 for COI and 0.0771 and 0.4721 for Cytb, indicating that the Cytb gene has a higher interspecific divergence, compared to COI, and therefore allows for more accurate species identification. The species delimitation based on DNA barcodes is largely consistent with the differences resulting from morphological and host plant data, demonstrating that the use of DNA barcodes is suitable for successful identification of most aphalarid species studied. The phylogenetic reconstruction based on maximum likelihood and Bayesian inference analyses, while showing similar results at high taxonomic levels to previously published phylogenies, provides additional information on the placement of aphalarids at the species level. The following five species represent new records for Bulgaria: Agonoscena targionii, Aphalara affinis, Colposcenia aliena, Co. bidentata, and Craspedolepta malachitica. Craspedolepta conspersa is reported for the first time from the Czech Republic, while Agonoscena cisti is reported for the first time from Albania.

Many species of herbaceous perennials now have numerous cultivars, with growth habits and flower colors unique to each cultivar. Vegetative propagation is required so that resulting plants are genetically identical to the parent plant. Although many cultivars are selected for precocious and vigorous flowering, it is often difficult to collect adequate vegetative cuttings from such cultivars for commercial production because juvenile (vegetative) growth is preferred for high-quality cuttings. Cuttings that are reproductive (with flower buds or flowers) can have reduced or delayed rooting and increased occurrences of fungal pathogens (especially Botrytis species), resulting in lack of crop uniformity. We sought to answer the question, can growing stock plants of herbaceous perennials under defined photoperiods extend the length of the vegetative period and enhance the rooting of cuttings harvested from these stock plants? In this study, stock plants of ‘P009S’ twinspur (Diascia integerrima), ‘Furman's Red’ sage (Salvia greggii), and ‘Wild Thing’ sage (Salvia greggii) were grown under ambient, 12-hour light, 10-hour light, and 8-hour light to determine if a particular photoperiod could be used to suppress reproductive growth by promoting vegetative growth, thereby enhancing cutting rooting success. Effects of photoperiod treatments varied among the plant cultivars studied. Plants grown under 8-hour photoperiod had longer duration of vegetative growth, smaller growth rates, and lower dry weights when compared with plants grown under 12-hour or 10-hour photoperiod. Plants grown under 12-hour photoperiod had shorter duration of vegetative growth, larger growth rates, and higher dry weights when compared with plants grown under 10-hour and 8-hour photoperiods. The probability of rooting of cuttings harvested from stock plants of ‘P009S’ twinspur, ‘Furman’s Red’ sage, and ‘Wild Thing’ sage grown under 12-hour and 10-hour photoperiods was greater when compared with cuttings harvested from stock plants grown under 8 h photoperiod.

Learners who learn from OER often cannot have their learning assessed or receive a credential. Open credentials offer a potential solution to this problem, combining badges or micro-credentials with competence frameworks and digital seals. This study identified the current situation of open credentials in post-secondary education in Europe, the main themes of the discourse, and the points of agreement and divergence surrounding them. The data comprised a corpus of transcriptions from 12 expert interviews and a focus group. Qualitative text analysis identified the principal themes. Findings included the following: (a) few assessments are available as open content; (b) linking OER and credentials requires detailed and expensive work on learning outcomes and assessment; (c) the aggregation of open credentials to create higher-level qualifications is a widely accepted ambition; (d) the European Union’s infrastructure to support open credentials is appropriate and effective and can foster trust; (e) the outstanding challenges are organisational and practical, not technological; (f) assessment and content provisions should belong to separate organisational functions; and finally, (g) funding and support for open credentials in professional accreditation are essential for further progress.

The efficient and effective use of land that agriPV, or agrivoltaic, systems offer is especially appealing for Aotearoa-New Zealand, since more than a third of its land area serves agricultural purposes. However, several factors might constrain the implementation of agriPV systems, and different values and preferences need consideration from a community acceptance perspective. As a first step, a high-level investigation into the potential suitability of agriPV systems in Aotearoa–New Zealand was undertaken. The different factors that influence performance of agriPV systems were considered. Then a GIS analysis was undertaken using the analytical hierarchy process – a multicriteria decision-making technique. The spatial data analysis provided insight to identify the regions in Aotearoa–New Zealand best suited to agriPV systems. Overall, it is estimated that 80 percent of the farmland in the country is either good or fairly suitable for agriPV developments with a number of regions identified as potential areas for further investigations.

Background The Breakthrough Devices Program of the US Food and Drug Administration has accelerated the development and evaluation of medical devices for patients with heart failure. One such device is the Optimizer Smart System, which the US Food and Drug Administration approved in 2019. Methods and Results The Optimizer device was evaluated in a pivotal randomized clinical trial (FIX‐HF‐5C [Confirmatory Randomized Trial Evaluating the Optimizer System]) that leveraged Bayesian borrowing of external data to reduce the sample size and determine therapeutic device benefit versus continued medical therapy. Bayesian borrowing is explained in the context of the FIX‐HF‐5C trial, including an overview of the statistical methodologies, regulatory considerations, and interpretations of trial results. Conclusions The US Food and Drug Administration Breakthrough Devices Program and novel Bayesian statistical methodology accelerated the path to regulatory approval and patient access to a potentially lifesaving device and may serve as a model for future clinical trials.

Background The Society for Cardiovascular Angiography and Interventions proposed a staging system (A–E) to predict prognosis in cardiogenic shock. Herein, we report clinical outcomes of the RECOVER III study for the first time, according to Society for Cardiovascular Angiography and Interventions shock classification. Methods and Results The RECOVER III study is an observational, prospective, multicenter, single‐arm, postapproval study of patients with acute myocardial infarction with cardiogenic shock undergoing percutaneous coronary intervention with Impella support. Patients enrolled in the RECOVER III study were assigned a baseline Society for Cardiovascular Angiography and Interventions shock stage. Staging was then repeated within 24 hours after initiation of Impella. Kaplan‐Meier survival curve analyses were conducted to assess survival across Society for Cardiovascular Angiography and Interventions shock stages at both time points. At baseline assessment, 16.5%, 11.4%, and 72.2% were classified as stage C, D, and E, respectively. At ≤24‐hour assessment, 26.4%, 33.2%, and 40.0% were classified as stage C, D, and E, respectively. Thirty‐day survival among patients with stage C, D, and E shock at baseline was 59.7%, 56.5%, and 42.9%, respectively (P=0.003). Survival among patients with stage C, D, and E shock at ≤24 hours was 65.7%, 52.1%, and 29.5%, respectively (P

Abstract While several studies have investigated the various effects of open educational resources (OER) and open educational practices (OEP), few have focused on its connection to learning achievement. The related scientific literature is divided about the effects of OER and OEP with regards to their contribution to learning achievement. To address this tension, a meta-analysis and research synthesis of 25 studies (N = 119,840 participants) was conducted to quantitatively investigate the effects of OER and OEP on students’ learning achievement. The analysis included course subject, level of education, intervention duration, sample size, geographical distribution, and research design as moderating variables of the obtained effects. The findings revealed that OER and OEP have a significant yet negligible (g = 0.07, p

(1) Background: The rise in electronic cigarette (E-cigarette) popularity, especially among adolescents, has prompted research to investigate potential effects on health. Although much research has been carried out on the effect on lung health, the first site exposed to vaping—the oral cavity—has received relatively little attention. The aims of this study were twofold: to examine the effects of E-liquids on the viability and hydrophobicity of oral commensal streptococci, and the effects of E-cigarette-generated aerosols on the biomass and viability of oral commensal streptococci. (2) Methods: Quantitative and confocal biofilm analysis, live–dead staining, and hydrophobicity assays were used to determine the effect on oral commensal streptococci after exposure to E-liquids and/or E-cigarette-generated aerosols. (3) Results: E-liquids and flavors have a bactericidal effect on multispecies oral commensal biofilms and increase the hydrophobicity of oral commensal streptococci. Flavorless and some flavored E-liquid aerosols have a bactericidal effect on oral commensal biofilms while having no effect on overall biomass. (4) Conclusions: These results indicate that E-liquids/E-cigarette-generated aerosols alter the chemical interactions and viability of oral commensal streptococci. Consequently, the use of E-cigarettes has the potential to alter the status of disease and health in the oral cavity and, by extension, affect systemic health.

Accurate measurement of testicular volume (TV) in boys is an important tool in clinical practice, e.g., in varicocele treatment. This study aims to assess the degree of intra- and interobserver variability of testicular volume measurements. In a prospective study, boys between 11 and 17 years of age without testicular pathology were enrolled. Testicular ultrasound was performed by three investigators (A: pediatric radiologist; B: pediatric surgery/urology resident; C: pediatric urologist). Intraobserver variability was calculated in investigators B and C and interobserver variability between all three investigators. A total of 30 boys were enrolled. Mean intraobserver variability in both observers was +0.3% with a range of −39.6 to 51.5%. The proportion of measurements with a difference >20% was 18.6%. The mean interobserver variability was −1.0% (range: −74.1% to 62.8%). The overall proportion of measurements with a difference >20% was 35%. A lower testicular size of < 4 mL showed a significantly higher rate of >20% difference in both the intraobserver group (31.1% vs. 14.4%; p = 0.035) and the interobserver group (63.2% vs. 26.2%; p = 0.000031). Furthermore, the rate of >20% difference was significantly lower in obese compared to non-obese patients in both the intraobserver (2.8% vs. 22.4%; p = 0.0084) and the interobserver group (24% vs. 40.8%, p = 0.0427). Both intraobserver and interobserver variability in ultrasound-based TV measurements in pubertal boys contain a relevant degree of uncertainty that renders them unsuitable for individualized follow-up care. At the cohort level, however, mean differences in ultrasound-based TV measurements are low enough to make ultrasound comparisons reasonable.

Visits to forests can improve human health and well-being through various mechanisms. They can support the immune system, promote physical activity, and restore stress and attention fatigue. Questions remain about how perceived qualities in forests important to support such salutogenic, i.e., health-promoting, benefits can be represented in forest simulation tools to allow quantitative analyses, e.g., long-term projections or trade-off analyses with other forest functions, such as biodiversity conservation, wood production, etc. Questions also remain about how different forest management regimes might impact such perceived qualities in forests. Here, we defined three types of salutogenic forest characteristics (SFCs), referred to as Deep, Spacious, and Mixed forest characteristics, respectively. We did so by using the perceived sensory dimension (PSD) model, which describes and interrelates more fundamental perceived qualities of recreational outdoor environments that are important to support people’s health and well-being. We identified proxy variables for the selected PSD models in boreal forest stands and compared the effect of five different management regimes on both individual PSD models and the derived SFCs when projecting a forest landscape 100 years into the future. Our results suggest combinations of protection (set-aside) and variations of continuous cover forestry as the most promising strategies to achieve these salutogenic properties in the long-term future. Depending on the SFC in focus and the specific management regime used, between 20% and 50% of the landscape could support associated properties in the long term (100 years). This might impact how forests should be managed when salutogenic outcomes are considered alongside, e.g., wood production and other forest contributions.

Fossils can document the morphological diversification through time and date lineages, providing relevant characters are preserved. Primascena Klimaszewsi, 1997 was erected for P. subita Klimaszewsi, 1997 on the basis of a single, partly damaged male from Dominican amber. Originally assigned to Rhinocolidae: Paurocephalinae, the genus was subsequently transferred to Psyllidae: Aphalaroidinae. Recently, two undescribed species resembling the fossil species were discovered in Brazil (Mato Grosso do Sul), allowing a detailed morphological study of adults and immatures. Based on the morphological study, a revised diagnosis of the genus is provided, including the previously unknown female and fifth instar immatures. Primascena subita is redescribed and P. empsycha n. spec. and P. ruprechtiae n. spec. are formally described and illustrated. An identification key is provided for the species of Primascena. A cladistic morphological analysis supports the placement of the two new species in Primascena, and of this genus in the Aphalaroidinae. It is sister to all but Aphalaroida, though with little support. The two Brazilian species develop on Ruprechtia spp. (Polygonaceae: Eriogonoideae), an unusual psyllid host. Immatures of P. ruprechtiae are free-living on the lower leaf face and do not induce galls.

Abstract Nanowires are promising platforms for realizing ultra-compact light sources for photonic integrated circuits. In contrast to impressive progress on light confinement and stimulated emission in III-V and II-VI semiconductor nanowires, there has been no experimental demonstration showing the potential to achieve strong cavity effects in a bottom-up grown single group-IV nanowire, which is a prerequisite for realizing silicon-compatible infrared nanolasers. Herein, we address this limitation and present an experimental observation of cavity-enhanced strong photoluminescence from a single Ge/GeSn core/shell nanowire. A sufficiently large Sn content ( ~ 10 at%) in the GeSn shell leads to a direct bandgap gain medium, allowing a strong reduction in material loss upon optical pumping. Efficient optical confinement in a single nanowire enables many round trips of emitted photons between two facets of a nanowire, achieving a narrow width of 3.3 nm. Our demonstration opens new possibilities for ultrasmall on-chip light sources towards realizing photonic-integrated circuits in the underexplored range of short-wave infrared (SWIR).

Biological and cultural diversity are inextricably linked and rapidly eroding worldwide. As a response, many conservation efforts foster synergies between cultural and biological diversity agendas through biocultural approaches. However, such approaches do not always address biocultural conflicts, where certain cultural practices can lead to biodiversity loss and, in turn, threaten the continuance of such practices. In this study, we examined a biocultural conflict in the Dimi ceremony, the most important rite of passage of the Daasanach agro-pastoralists of north Kenya, in which skins from threatened carnivore species are used extensively as traditional ornaments. We quantified the current use of skins in Dimi as well as changes in the cultural ceremony that exacerbate its impacts on wildlife. We collected field-based data on the context of the use of skins through structured interviews, focus-group discussions, participant observation and counts of skins in two Dimi ceremonies. We counted a total of 121 skins of four carnivore species being used in a single ceremony. We also found that Dimi has become environmentally unsustainable, threatening distant cheetah Acinonyx jubatus and leopard Panthera pardus populations and local species with spotted skins (African civet Civettictis civetta, common genet Genetta genetta and serval Leptailurus serval). The young Daasanach are deeply concerned about the lack of availability of skins in their area, as well as the prohibitive prices, and they are calling for alternatives to the use of skins in Dimi. Overall, our study shows that acknowledging biocultural conflicts and opening space for dialogue with local communities are essential for the maintenance of both biological and cultural diversity.

In 2015, the Ethiopian Federal Ministry of Health (FMOH) developed the Saving Lives through Safe Surgery (SaLTS) initiative to improve national surgical care. Previous work led to development and implementation of 15 surgical key performance indicators (KPIs) to standardize surgical data practices. The objective of this project is to investigate current practices of KPI data collection and assess quality to improve data management and strengthen surgical systems. The first portion of the study documented the surgical data collection process including methods, instruments, and effectiveness at 10 hospitals across 2 regions in Ethiopia. Secondly, data for KPIs of focus [1. Surgical Volume, 2. Perioperative Mortality Rate (POMR), 3. Adverse Anesthetic Outcome (AAO), 4. Surgical Site Infection (SSI), and 5. Safe Surgery Checklist (SSC) Utilization] were compared between registries, KPI reporting forms, and the DHIS2 (district health information system) electronic database for a 6-month period (January-June 2022). Quality was assessed based on data completeness and consistency. The data collection process involved hospital staff recording data elements in registries, quality officers calculating KPIs, completing monthly KPI reporting forms, and submitting data into DHIS2 for the national and regional health bureaus. Data quality verifications revealed discrepancies in consistency at all hospitals, ranging from 1-3 indicators. For all hospitals, average monthly surgical volume was 57 cases, POMR was 0.38% (13/3399), inpatient SSI rate was 0.79% (27/3399), AAO rate was 0.15% (5/3399), and mean SSC utilization monthly was 93% (100% median). Half of the hospitals had incomplete data within the registries, ranging from 2-5 indicators. AAO, SSC, and SSI were commonly missing data in registries. Non-standardized KPI reporting forms contributed significantly to the findings. Facilitators to quality data collection included continued use of registries from previous interventions and use of a separate logbook to document specific KPIs. Delayed rollout of these indicators in each region contributed to issues in data quality. Barriers involved variable indicator recording from different personnel, data collection tools that generate false positives (i.e. completeness of SSC defined as paper form filled out prior to patient discharge) or missing data because of reporting time period (i.e. monthly SSI may miss infections outside of one month), inadequate data elements in registries, and lack of standardized monthly KPI reporting forms. As the FMOH introduces new indicators and changes, we recommend continuous and consistent quality checks and data capacity building, including the use of routinely generated health information for quality improvement projects at the department level.

Acetamiprid (ACE) and imidacloprid (IMI) are insecticides of global importance and are used as spray and watering agents for ornamental plants to control biting and sucking insects or as topical medications on pets to remove and control fleas. Human biomonitoring data on ACE and IMI exposures when applying these products are limited. We investigated exposures to ACE and IMI in male volunteers after the domestic application of either an ACE-containing agent or an IMI-containing spot-on medication. Complete and consecutive urine samples were collected for up to 56 h after application. Urine samples were analyzed for ACE, IMI, and their respective metabolites (N-desmethyl-ACE, IMI-olefin, and sum of 4−/5-hydroxy-IMI) by liquid chromatography–tandem mass spectrometry. Fairly uniform concentrations of N-desmethyl-ACE could be observed before and after orchid treatment, so that an ACE exposure associated with orchid treatment can most likely be excluded. In contrast, after the application of the IMI-containing medication, elevated concentrations of IMI, 4−/5-hydroxy-IMI, and IMI-olefin were quantified in urine samples post-20 h with maximum concentrations of 3.1, 14.9, and 8.0 μg/g creatinine, respectively, well above general background levels. Nevertheless, the IMI intake (10.6 μg/kg bw), calculated from the excreted amounts, was around five times below the current European acceptable daily intake. Based on the case results here, household exposures to ACE and IMI after spray treatment of ornamental plants and anti-flea treatment of dogs can be regarded as low and safe. However, people regularly applying neonicotinoid-containing formulations, such as professional gardeners and employees in animal shelters, should be studied in more detail.

Advancement in solid organ transplantation and hematopoietic stem cell transplant continues to improve the health outcomes of patients and widens the number of eligible patients who can benefit from the medical progress. Preserving the effectiveness of antimicrobials remains crucial, as otherwise transplant surgeries would be unsafe due to surgical site infections, and the risk of sepsis with neutropenia would preclude stem cell transplant. In this review, we provide updates on three previously discussed stewardship challenges: febrile neutropenia, Clostridioides difficile infection, and asymptomatic bacteriuria. We also offer insight into four new stewardship challenges: the applicability of the “shorter is better” paradigm shift to antimicrobial duration; antibiotic allergy delabeling and desensitization; colonization with multidrug-resistant gram-negative organisms; and management of cytomegalovirus infections. Specifically, data are accumulating for “shorter is better” and antibiotic allergy delabeling in transplant patients, following successes in the general population. Unique to transplant patients are the impact of multidrug-resistant organism colonization on clinical decision-making of antibiotic prophylaxis in transplant procedure and the need for antiviral stewardship in cytomegalovirus. We highlighted the expansion of antimicrobial stewardship interventions as potential solutions for these challenges, as well as gaps in knowledge and opportunities for further research.

Background Heart failure with preserved ejection fraction ≥50% is prevalent with few evidence‐based therapies. In a trial of patients with heart failure with preserved ejection fraction with specialized pacemakers, treatment with accelerated personalized pacing averaging 75 bpm (myPACE) markedly improved quality of life, NT‐proBNP (N‐terminal pro–brain natriuretic peptide), physical activity, and atrial fibrillation burden compared with the standard lower rate setting of 60 bpm (usual care). Methods and Results In this exploratory study, provider‐initiated echocardiographic studies obtained before and after the trial were assessed for changes in left ventricular (LV) structure and function among participants who continued their pacing assignment. The analytic approach aimed to detect differences in standard and advanced echocardiographic parameters within and between study arms. Of the 100 participants, 16 myPACE and 20 usual care arm had a qualifying set of echocardiograms performed a mean (SD) 3 (2.0) years apart. Despite similar baseline echocardiogram measures, sustained exposure to moderately accelerated pacing resulted in reduced septal wall thickness (in cm: myPACE 1.1 [0.2] versus usual care 1.2 [0.2], P=0.008) and lower LV mass to systolic volume ratio (in g/mL: myPACE 4.8 [1.9] versus usual care 6.8 [3.1], P=0.038) accompanied by a minor reduction in LV ejection fraction (in %: myPACE 55 [5] versus usual care 60 [5], P=0.015). These changes were paralleled by improvements in heart failure‐related quality of life (myPACE Minnesota Living with Heart Failure Questionnaire improved by 16.1 [13.9] points, whereas usual care worsened by 6.9 [11.6] points, P

Objectives To evaluate oxygen saturation and vital signs measured in the community by emergency medical services (EMS) as clinical markers of COVID-19-positive patient deterioration.Design A retrospective data analysis.Setting Patients were conveyed by EMS to two hospitals in Hampshire, UK, between 1 March 2020 and 31 July 2020.Participants A total of 1080 patients aged ≥18 years with a COVID-19 diagnosis were conveyed by EMS to the hospital.Primary and secondary outcome measures The primary study outcome was admission to the intensive care unit (ICU) within 30 days of conveyance, with a secondary outcome representing mortality within 30 days of conveyance. Receiver operating characteristic (ROC) analysis was performed to evaluate, in a retrospective fashion, the efficacy of different variables in predicting patient outcomes.Results Vital signs measured by EMS staff at the first point of contact in the community correlated with patient 30-day ICU admission and mortality. Oxygen saturation was comparably predictive of 30-day ICU admission (area under ROC (AUROC) 0.753; 95% CI 0.668 to 0.826) to the National Early Warning Score 2 (AUROC 0.731; 95% CI 0.655 to 0.800), followed by temperature (AUROC 0.720; 95% CI 0.640 to 0.793) and respiration rate (AUROC 0.672; 95% CI 0.586 to 0.756).Conclusions Initial oxygen saturation measurements (on air) for confirmed COVID-19 patients conveyed by EMS correlated with short-term patient outcomes, demonstrating an AUROC of 0.753 (95% CI 0.668 to 0.826) in predicting 30-day ICU admission. We found that the threshold of 93% oxygen saturation is prognostic of adverse events and of value for clinician decision-making with sensitivity (74.2% CI 0.642 to 0.840) and specificity (70.6% CI 0.678 to 0.734).

The UV filters octocrylene (OC) and 2-ethylhexyl salicylate (EHS) are commonly used in sunscreens and frequently detected in environmental media. However, knowledge on human exposures is scarce.In this human biomonitoring (HBM) study, we analyzed concentrations of exposure biomarkers specific to OC (CPAA, DOCCA, 5OH-OC) and EHS (5OH-EHS, 5oxo-EHS, 5cx-EPS) in 24-h urine samples (n = 420) from the German Environmental Specimen Bank (ESB). These samples were collected from German students (20–29 years; 30 males/30 females per year) between 1996 and 2020 (4-year intervals; collection in winter).We found continuously increasing OC and EHS exposures (Jonckheere-Terpstra; p LOQ) and 0.060 µg/L 5cx-EPS (88 %>LOQ). This general trend was confirmed by the other biomarkers, however at lower detection rates. Based on metabolite excretion in the 24-h urine samples and human toxicokinetic data, we calculated maximum daily intakes (DI) of 17 µg/(kg bw * d) OC and 59 µg/(kg bw * d) EHS. Based on a derived no-effect level (DNEL) of 0.8 mg/(kg bw * d), the OC exposures of individuals in our study did not indicate any health risk. Similarly, for EHS all biomarker concentrations were well below the HBM-I values of 12 µg/L 5OH-EHS and 11 µg/L 5cx-EPS.Our data proves the general applicability of specific OC and EHS metabolites for HBM in the general population and shows clearly increasing exposures. Higher (co-)exposures must be expected in populations with increased sunscreen use such as (summer) vacationers, children and outdoor workers.

Abstract The European Union (EU) set clear climate change mitigation targets to reach climate neutrality, accounting for forests and their woody biomass resources. We investigated the consequences of increased harvest demands resulting from EU climate targets. We analysed the impacts on national policy objectives for forest ecosystem services and biodiversity through empirical forest simulation and multi-objective optimization methods. We show that key European timber-producing countries – Finland, Sweden, Germany (Bavaria) – cannot fulfil the increased harvest demands linked to the ambitious 1.5°C target. Potentials for harvest increase only exists in the studied region Norway. However, focusing on EU climate targets conflicts with several national policies and causes adverse effects on multiple ecosystem services and biodiversity. We argue that the role of forests and their timber resources in achieving climate targets and societal decarbonization should not be overstated. Our study provides insight for other European countries challenged by conflicting policies and supports policymakers.

There is an ongoing debate in the literature about the ways of using technology to enhance students’ Computational Thinking (CT). This special issue further enriches this debate by investigating how educational technology could be used, and for which purposes, to facilitate learning CT. It includes six papers demonstrating the innovative design of curricula and the use of various technologies to teach CT for students in different educational levels. Based on these papers, this special issue points out that more research is needed to investigate the best educational practices that could be used to teach CT rather than focusing on the technology itself. It also reveals that future work could cover smart learning analytics and precision education to better model students’ individual differences, hence effectively supporting learning CT.

New evaluation of the Mainz/Mogontiacum legionary fortress’ architectural defences includes a total of 25 sites covering some 150 years of research history. The investigation emphasizes consideration of the excavations that took place following the publication of D. Baatz’s 1962 monograph on the legionary fortress. This work may be expected to provide new information on the evolution of the defensive systems, which remained unknown for extended periods. Subsequently, and for the first time since 1962, a complete plan of the legionary fortress has been developed. This digital cadastral plan should provide a foundation for future investigations. The plan was constructed using QGIS (a geographic information system) and by geo-referencing all existing excavation plans, as well as digitally redrawing all structures, and combining these with a database. All available data on the structures are included, as well as the catalogue numbers of the features within the present work, alongside the corresponding relevant finds, included as image files. The maps generated herein are based upon this complete cadastre. Site evaluation resulted in the division of the earth-and-timber fortress and the stone fortress into three distinct structural phases for each. The timber phase 1 of the fortress’ defensive circuit consisted of an earth-and-timber rampart fronted by a V-shaped ditch (defensive ditch I). The ground-plan of this first fortress is different and smaller to what was previously known, and the porta praetoria was situated some 60 m south of the later fortress’ corresponding structure. The connection of the back rampart with the long north-western side remains unclear, but its course was identified for the first time for the early fortress. The north-western side (FS 12b), as well as the rear rampart (FS 03, 06) lie within the scope of the later stone fortress. Based on the defensive ditch (FS 04), it was possible to locate the latter structure within the limits of the later retentura. Its position therein means that the connection between the rear rampart and the fortress’ south-eastern side must have had an unusual outline. Future excavations in the area between Helmholtzweg and Langenbeckstraße should help to clarify the progression of the earth-and-timber fortress’ defences. Furthermore, the early buildings in this site likely lie outside the boundaries of the fortress and belong to the Augustan canabae legionis. Based on the new line of the defences on the rear rampart and along the long northern side, the maximum size of the fortress is reduced to 34 ha, compared with the previously estimated 37 ha. Chronologically, the earliest fortress was erected in connection with the Augustan occupation phase, and a date of 13/12 BC was presumed. More recent findings, however, point to an earlier date, around 17/16 BC. Prior to the end of phase 1, several repair efforts on the earth-and-timber rampart were identified. This would have taken place before the defences on the rear rampart (FS 06), as well as possibly on the northern side (FS 12b), were dismantled and advanced by some 30 m to the position of the later stone fortress. Archaeological finds provided dates for these events, placing them during the late-Augustan or early-Tiberian period. These changes fundamentally altered the fortress at Mainz. Perhaps the increase in size coincided with a completely new concept for large parts of the fortress, including the relocation of the porta praetoria to the main gate site of the later stone fortress. As a result, the fortress’ main axis, the via praetoria, had to be moved, which subsequently resulted in changes to the internal plan of the fortress. This radical new alignment was likely connected with the restructuring of the Rhine frontier by Emperor Tiberius in AD 17, which also coincided with a renunciation of the hitherto offensive policy in Germania. De facto, it is only now that we can assume that the two legions XIV Gemina and XVI Gallica were permanently stationed here. During the occupation period, with its flexibly operating units, there is no historical evidence for a double legionary fortress, nor is one to be expected. Such an edifice would have been conceived from the outset for permanently garrisoned units, the likes of which are known from the Tiberian period onwards. Timber phase 2 of the earth-and-timber defensive circuit is the poorest documented of the archaeological features. On the new rear rampart, which had been moved forward, a new earth-and-timber rampart was constructed, the posts of which were also set into parallel running trenches. To date, it was only possible to locate the presence of this new rampart in the north-western section of the rear rampart. The course of the fortress’ northern side during the second phase remains unknown, but was probably also moved forward. On the south-eastern long side, no changes could be discerned, and in this area, the earth-and-timber rampart continued into phase 2. No corresponding ditch (defensive ditch II) could be identified. It was likely destroyed during construction work for the later V-shaped ditches. For timber phase 3, a new ditch (defensive ditch III) was laid out some 20-25 m in front of the earth-and-timber rampart, which was still standing. It cut several features of Claudian date in the canabae legionis, including a drain, the backfill of which is coin-dated to AD 41. The structural alterations are connected with the arrival of legio IV Macedonica and legio XXII Primigenia. It remains unclear whether there was a subsequent, second defensive ditch. No changes to the earth-and-timber rampart can be identified archaeologically during phase 3 and the north-western long side is also the only one for which the course remains unknown for this phase. Clearly, the modifications to the fortification during this period were incorporated into an overall building programme that reveals a comprehensive master plan. For instance, within the canabae legionis numerous groups of open pits were filled in and a ring road was built around the fortress. The restructuring of the road, which left the porta principalis dextra towards the fort located at present-day Mainz-Weisenau, transforming it into a representative funerary street, is also dated to around the mid-1st c. AD, and was likely part of this reorganisation. The same applies to the road leaving the porta principalis sinistra towards Bingen. The end of phase 3 was initiated by extensive building activities. The beginning of stone phase 1 is marked by the backfilling of defensive ditch III, dated, at the earliest, by coins to the late-Vespasianic period, but more likely to the Domitianic period, following the Chattan wars of AD 84/85. The masonry defensive wall (wall I), measuring 1,70-2,30 m wide at its foundation, was fronted by a V-shaped ditch (defensive ditch IV). During the same period the masonry aqueduct was also constructed. With stone phase I, the fortress’ northern side can, for the first time, be identified. It runs along the slope of the Linsenberg and is thus as much as 70 m further north than had been presumed, meaning that the fortress was larger than previously thought, roughly 37 ha, rather than some 35-36 ha. On this side of the fortress no defensive ditch existed at any time during the stone phases. In stone phase 2 the existing defensive ditch was filled in and a new one (Va) was dug. These measures may have occurred in the middle or in the second half of the 2nd c. AD. A reconstruction of the fortress wall did not accompany this work. Consequently, the garrisoning of legio XXII Primigenia pia fidelis in AD 97, which remained there until its end, had no demonstrable effect on the fortress’ defensive circuit. Moreover, the archaeological findings provide no evidence for a reduction in the size of the fortress, which had until then been used by two legions. The defensive ditch excavated at the beginning of stone phase 2 was renewed at least twice. These efforts are well evidenced by two V-shaped bases in the ditch (defensive ditch Vb-c), demonstrating the clearing of sedimented material from within the ditch. They should not be interpreted as separate phases of the defence system. Stone phase 3 is expressed by a wall-facing, measuring up to 1 m wide, fronting the existing rampart and can be linked to a supra-regional construction programme to reinforce the military bases along the Rhine frontier. It is possible that these operations were preceded by the backfilling of defensive ditch Vc. Date attribution using the archaeological material is difficult, but in conjunction with the results of the present study, stone phase 3 can be narrowed down to the second quarter of the 4th c. AD or shortly thereafter. Presumably, a U-shaped ditch was installed in front of the fortress’ reinforced wall, which, to date, could only be identified at the south-western corner of the stronghold. In contrast, along other segments, defensive ditch Vc was infilled to form a hollow and may have remained in use as a defensive obstacle. Much like efforts to date the beginning of stone phase 3, an end date for the legionary fortress remains uncertain. It is likely that legio XXII Primigenia was heavily decimated during the usurpation of Magnentius in AD 350-353, as well as during the Germanic invasions of AD 352 and 355, with only a few units remaining in Mainz. The final abandonment of the legionary fortress likely took place around AD 364/370, i.e. shortly before the construction of the city wall around AD 369/370-375. Presumably the measures that led to the abandonment of the legionary fortress, the dissolution of the remaining units of legio XXII Primigenia and the reduction of the city wall were part of a decision enacted during the rule of Valentinian I, as part of an effort to strengthen the Rhine frontier. The construction of Mainz’s second city wall, which traversed the legionary fortress from southeast to northwest, was preceded by extensive demolition and levelling operations of all fortress structures, in order to obtain building materials, as well as to establish a glacis in front of the city wall. To what extent the area between the city wall and the old praetorial front served as a reduced space for a garrison of limitanei units of the late-4th c. AD remains unclear. (Traduction : Clive Bridger, Xanten.)

Hurricanes Ian and Nicole caused devastating destruction across Florida in September and November 2022, leaving widespread damage in their wakes. This study focuses on the assessment of barrier islands’ shorelines, encompassing natural sand dunes and dune vegetation as well as armored dunes with man-made infrastructure such as seawalls. High-resolution satellite imagery from Planet was used to assess the impacts of these hurricanes on the beach shorelines of Volusia, Flagler, and St. Johns Counties on the Florida Central East Coast. Shorefront vegetation was classified into two classes. Normalized Difference Vegetation Index (NDVI) values were calculated before the hurricanes, one month after Hurricane Ian, one month after Hurricane Nicole, and one-year post landfall. LiDAR (Light Detection and Ranging) was incorporated to calculate vertical changes in the shorelines before and after the hurricanes. The results suggest that natural sand dunes were more resilient as they experienced less impact to vegetation and elevation and more substantial recovery than armored dunes. Moreover, the close timeframe of the storm events suggests a compound effect on the weakened dune systems. This study highlights the importance of understanding natural dune resilience to facilitate future adaptive management efforts because armored dunes may have long-term detrimental effects on hurricane-prone barrier islands.

The interaction between light and matter is one of the oldest research areas of quantum mechanics, and a field that just keeps on delivering new insights and applications. With the arrival of cavity and circuit quantum electrodynamics we can now achieve strong light-matter couplings which form the basis of most implementations of quantum technology. But quantum information processing also has high demands requiring total error rates of fractions of percentage in order to be scalable (fault-tolerant) to useful applications. Since errors can also arise from modelling, this has brought into center stage one of the key approximations of quantum theory, the Rotating Wave Approximation (RWA) of the quantum Rabi model, leading to the Jaynes-Cummings Hamiltonian. While the RWA is often very good and incredibly useful to understand light-matter interactions, there is also growing experimental evidence of regimes where it is a bad approximation. Here, we ask and answer a harder question: for which experimental parameters is the RWA, although perhaps qualitatively adequate, already not good enough to match the demands of scalable quantum technology? For example, when is the error at least, and when at most, 1%? To answer this, we develop rigorous non-perturbative bounds taming the RWA. We find that these bounds not only depend, as expected, on the ratio of the coupling strength and the oscillator frequency, but also on the average number of photons in the initial state. This confirms recent experiments on photon-dressed Bloch-Siegert shifts. We argue that with experiments reporting controllable cavity states with hundreds of photons and with quantum error correcting codes exploring more and more of Fock space, this state-dependency of the RWA is increasingly relevant for the field of quantum computation, and our results pave the way towards a better understanding of those experiments.

TRPV Ion channels are sophisticated molecular sensors designed to respond to distinct temperature thresholds. The recent surge in cryo-EM structures has provided numerous insights into the structural rearrangements accompanying their opening and closing; however, the molecular mechanisms by which TRPV channels establish precise and robust temperature sensing remain elusive. In this work we employ molecular simulations, multi-ensemble contact analysis, graph theory, and machine learning techniques to reveal the temperature-sensitive residue-residue interactions driving allostery in TRPV3. We find that groups of residues exhibiting similar temperature-dependent contact frequency profiles cluster at specific regions of the channel. The dominant mode clusters on the ankyrin repeat domain and displays a linear melting trend while others display non-linear trends. These modes describe the residue-level temperature response patterns that underlie the channel's functional dynamics. With network analysis, we find that the community structure of the channel changes with temperature. And that a network of high centrality contacts connects distant regions of the protomer to the gate, serving as a means for the temperature-sensitive contact modes to allosterically regulate channel gating. Using a random forest model, we show that the contact states of specific temperature-sensitive modes are indeed predictive of the channel gate's state. Supporting the physical validity of these modes and networks are several residues identified with our analyses that are reported in literature to be functionally critical. Our results offer high resolution insight into thermo-TRP channel function and demonstrate the utility of temperature-sensitive contact analysis.

الأهداف: هدفت هذه الدّراسة إلى الكشف عن أثر تدريب المعلّمين المستند إلى أنموذج تصميم تعليم لابتكار مصادر تعليم مفتوحة (أنموذج غوشه) على الكفايات المهنيّة للمعلّمين. المنهجية: استندت الدّراسة إلى التّصميم المتوازي المتقارب الذي تضمّن جمع البيانات الكميّة بالتّزامن مع النّوعيّة، وتحليلهما بشكل منفصل، والاعتماد عليهما معاً في تفسير النّتائج. اعتمد البحث الكمّي على المنهج شبه التّجريبي؛ حيث تمّ تحديد عينة قصديّة تكوّنت من 289 معلّماً ومعلّمة، وإلحاقهم بتدريبات مستندة إلى أنموذج تصميم التّعليم لابتكار مصادر تعليم مفتوحة، وجمع البيانات من خلال استجابات عينة الدّراسة لاستبيان قبلي وبعدي لكفايات المعلّمين المهنيّة، ثمّ فحص الفروق في المتوسّطات الحسابيّة للاستجابات القبليّة والبعديّة. واعتمد البحث الكيفي على مقابلات المجموعات البؤريّة. النتائج: أظهرت نتائج الدّراسة أنّ استناد تدريب المعلّمين إلى أنموذج تصميم تعليم يدمج مجموعة من النّظريّات الواعدة، والتي تندرج منها عدّة استراتيجيّات تعليميّة متمركزة حول المتعلّم، أدّى إلى تعاضد نقاط قوى تلك النّظريّات، والاستراتيجيّات؛ لتسهم معاً في تطوير كفايات المعلّمين المهنيّة من معارف ومهارات واتّجاهات، مع وجود تحدّيات في تطبيق الأنموذج الذي تمّ التّدريب عليه نتيجة ضيق الوقت، والعبء الوظيفي، وضعف البنية التّكنولوجيّة، ومقاومة التّغيير. الخلاصة: خلصت الدّراسة إلى أنّ التّدريب المستند إلى أنموذج تصميم التّعليم لابتكار مصادر تعليم مفتوحة أثّر إيجاباً على كفايات المعلّمين المهنيّة في كل من المجالات المرتبطة بتصميم التّعليم، وتنفيذه، وإدارة العمليّة التّعليميّة، ومتابعتها وتقييمها، وبذلك أوصت الدّراسة بتبنّي أنموذج تصميم التّعليم لابتكار مصادر تعليم مفتوحة في برامج تدريب المعلّمين، وفي العمليّة التّعليميّة، وتبنّي سياسات تقلّل من التّحدّيات التي تواجه المعلّمين عند تطبيقه.

الأهداف: هدفت هذه الدراسة إلى معرفة دور الألعاب التعليمية في تعويض الفاقد التعليمي في الأزمات في فلسطين وسوريا، والتحديات التي تواجه توظيفها، وسبل التغلب عليها. المنهجية: اعتمدت الدراسة على إجراء مقابلات شبه مبنية مفتوحة مع عينة الدراسة التي تكونت من عشرين شخصا تم اختيارهم بطريقة قصدية من التربويين وخبراء التعليم من فلسطين وسوريا، وتم سؤالهم عن دور الألعاب التعليمية في تعويض الفاقد التعليمي وزيادة دافعية الطلبة نحو التعلم في الأزمات. النتائج: أظهرت النتائج دور الألعاب التعليمية في زيادة دافعية الطلبة نحو التعلم، وتسريع عملية التعلم، واختصار الوقت والجهد، وتحقيق أكثر من هدف تعليمي باستخدام لعبة واحدة. أما التحديات التي تواجه توظيف الألعاب التعليمية فقد تمثلت في تحديات اقتصادية: كتدني رواتب المعلمين، وضعف البنية التحتية في المدارس. وتحديات تكنولوجية: كضعف مهارة المعلمين في التعامل مع الأجهزة الذكية والألعاب التعليمية الرقمية. وتحديات مرتبطة بمدى جهوزية المدارس، وتوفر المواد والوسائل اللازمة لتوظيف الألعاب التعليمية، ومعرفة المعلمين بأنواع الألعاب التعليمية، وكيفية تصميمها، وتكييفها مع المواد الدراسية المختلفة. بالإضافة إلى تحديات أخرى نفسية واجتماعية. الخلاصة: وخلصت الدراسة إلى أن الألعاب التعليمية تلعب دور مهما في تعويض الفاقد التعليمي وزيادة دافعية الطلبة نحو التعلم في الأزمات. وأوصت الدراسة بضرورة تبني الألعاب التعليمية في العملية التعليمية.

A 57-year-old man with end-stage heart failure presented with incessant ventricular tachycardia in the setting of cardiogenic shock, requiring support with a percutaneous left ventricular assist device. He underwent ablation of the ventricular tachycardia. Hours later the console alarm was evident, and the patient experienced worsening shock and elevated central venous pressure, leading to a diagnosis of cardiac tamponade. (Level of Difficulty: Advanced.)

Animal navigation has been an invaluable source of inspiration for designing different engineering solutions ranging from optimization strategies to control solutions for complex systems. Recent results indicate that zebrafish larvae could exploit local inhomogeneities from the background flow to orient and navigate against a flowing current, a behavior known as rheotaxis. It has been hypothesized that rheotaxis can be explained through a simple yet effective mechanism consisting of the computation of a line integral around the fish body. However, the exact nature of the information generated by these computations has yet to be established. Motivated by these observations, we studied how zebrafish larvae can estimate gradients of continuous scalar functions using local information only. Interestingly, we found that line integrals, representing flow measurements around the fish body, can provide accurate gradient estimates. This result establishes a connection between the rheotaxis mechanism based on line integrals and optimization methods relying on zero-order information (local measurements). We then formulated a zero-order optimization strategy and studied its convergence for planar objective functions. By applying the descent lemma and leveraging the L-smoothness property of the objective function, we derived necessary conditions ensuring the strategy’s convergence to a stationary point. The effectiveness of the zero-order approach was illustrated via numerical examples and the application to target localization problems in mobile robots.