Miracle-dz/UniFAR-FTUs huggingface dataset:
MmTX1 and MmTX2 from coral snake venom potently modulate GABAA receptor activity

Significance In this study, we report the identification of the first potent GABAA receptor-targeting toxins, to our knowledge, in snake venom, which provides a conceptual example for discovering novel ligands to study this receptor family, both functionally and structurally. Moreover, successful synthetic and recombinant production of these toxins [micrurotoxin1 (MmTX1) and MmTX2] will be valuable to further enhance their subtype selectivity or potency. In a broader context, both toxins may provide tools to evoke seizures in assays geared toward testing antiepileptic drugs or as lead molecules for designing therapeutics that modulate GABAA receptor activity. GABAA receptors shape synaptic transmission by modulating Cl− conductance across the cell membrane. Remarkably, animal toxins that specifically target GABAA receptors have not been identified. Here, we report the discovery of micrurotoxin1 (MmTX1) and MmTX2, two toxins present in Costa Rican coral snake venom that tightly bind to GABAA receptors at subnanomolar concentrations. Studies with recombinant and synthetic toxin variants on hippocampal neurons and cells expressing common receptor compositions suggest that MmTX1 and MmTX2 allosterically increase GABAA receptor susceptibility to agonist, thereby potentiating receptor opening as well as desensitization, possibly by interacting with the α+/β− interface. Moreover, hippocampal neuron excitability measurements reveal toxin-induced transitory network inhibition, followed by an increase in spontaneous activity. In concert, toxin injections into mouse brain result in reduced basal activity between intense seizures. Altogether, we characterized two animal toxins that enhance GABAA receptor sensitivity to agonist, thereby establishing a previously unidentified class of tools to study this receptor family.
Reversible Diels–Alder Reaction To Control Wrinkle Patterns: From Dynamic Chemistry to Dynamic Patterns

A facile and robust strategy to produce a reversible wrinkle pattern is presented by controlling a dynamic D-A reaction between furan and maleimide. The smart surface with highly reversible morphology and tunable adhesion, wettability, self-healing, and transparency is realized by the thermoreversible generation and erasure of the wrinkle pattern, which might find broad applications in functional intelligent materials with properties that can be tuned on-demand without altering the material's intrinsic properties.
OSTEOPOROZ SAĞLIK İNANÇ ÖLÇEĞİ, OSTEOPOROZ ÖZ-ETKİLİLİK/YETERLİK ÖLÇEĞİ VE OSTEOPOROZ BİLGİ TESTİ’NİN GEÇERLİLİK VE GÜVENİRLİĞİ

The Reliability and Validity of The Osteoporosis Health Belief Scale, Osteoporosis Self-Efficacy Scale and Osteoporosis Knowledge Test This study was carried out in accordance with methodologicall, and with the aim of determining the reliability and validity of adaptation osteoporosis knowledge test, osteoporosis self-efficacy scale and osteoporosis health belief scale test to the Turkish society. The study included total 125 women in premenoposal period, and living in the region of Evren Pasa Health House's between the dates Nowember 2001-October 2002. The whole study population were included in the study without applying any sampling method in the formation of sampling group. A form including socio- demographic features, and Osteoporosis Health Belief Scale, Osteoporosis Self-Efficacy Scale and Osteoporosis Knowledge Test were used in the collection of the data. The data were assessed with Cronbach alfa, Pearson correlation technique and factor analysis. Stage of study, Cronbach alfa reliability coefficiency of osteoporosis health belief scale was found as 0.79, and it was found out that the scale consisted of seven factors. Cronbach alfa reliability coefficiency of osteoporosis self- efficacy scale was found as 0.94, and it was found out that the scale consisted of two factors. Kuder- Richardson reliability coefficiency of osteopo- rosis knowledge test (KR-20) was found as 0.79. In the result of these analysis, it was detected that the scales of Turkish form had high validity and reliability. Keyword: The osteoporosis health belief scale, The osteoporosis self-efficacy scale, The osteoporosis knowledge test, reliability, validity.
Metal–Organic‐Framework‐Derived Mesoporous Carbon Nanospheres Containing Porphyrin‐Like Metal Centers for Conformal Phototherapy

Mesoporous carbon nanospheres containing porphyrin-like metal centers (denoted as "PMCS") are successfully synthesized by the pyrolysis of an imidazolate framework using a mesoporous-silica protection strategy. The PMCS allow infrared and photoacoustic imaging and synergetic photothermal therapy/photodynamic therapy derived from the porphyrin-like moieties, offering the possibility of real-time monitoring of therapeutic processes and image-guided precise conformal phototherapy. PMCS thus represent a novel multifunctional theranostic platform for improved treatment efficiencies.
Glycosylation profiles determine extravasation and disease-targeting properties of armed antibodies

Significance Therapeutic antibodies represent the largest and fastest growing class of biopharmaceuticals. There is a trend in moving from intact antibodies toward “armed” antibody products, in which the antibody moiety serves as pharmacodelivery vehicle. The impact of glycosylation on the targeting performance of armed antibodies is still largely unknown. Our article sheds light on the surprising finding that relatively small variations in glycostructures and sialic acid content can have dramatic effects on therapeutic agent performance. A better understanding of the impact of glycosylation on pharmaceutical activity is likely to be relevant not only for future antibody development activities, but also for changes in current manufacturing processes and for the development of biosimilar products. The ability of antibodies to extravasate out of blood vessels is critical for therapeutic activity, because molecular targets for most diseases are located outside of the endothelial lining. By performing detailed biodistribution studies with a novel IL9-armed cancer-specific antibody, we identified a clear correlation between N-linked glycan structures and tumor-targeting efficiencies. Site-specific glycan analysis provided a detailed view of the glycan microheterogeneity present on the IL9 portion of the recombinant protein. Nonsialylated glycan structures have a negative impact on disease-homing activity, highlighting the importance of glycosylation control and characterization during process development.
Structural and energetic determinants of adhesive binding specificity in type I cadherins

Significance Type I cadherins comprise a family of cell–cell adhesion proteins that dimerize in a highly specific fashion. There are small differences in dimerization affinities among family members that are evolutionarily conserved and that have profound effects on cell-patterning behavior. There are few examples where the molecular origins of small affinity differences between closely related proteins have been explored in depth. We have brought an unusually broad range of technologies to bear on the problem in a unique integrated approach. Our results reveal how a subtle combination of physical interactions combine to tune binding affinities and, in the course of our analysis, we discover a new conformational entropy-based mechanism that can also be exploited by other multidomain proteins. Type I cadherin cell-adhesion proteins are similar in sequence and structure and yet are different enough to mediate highly specific cell–cell recognition phenomena. It has previously been shown that small differences in the homophilic and heterophilic binding affinities of different type I family members can account for the differential cell-sorting behavior. Here we use a combination of X-ray crystallography, analytical ultracentrifugation, surface plasmon resonance and double electron-electron resonance (DEER) electron paramagnetic resonance spectroscopy to identify the molecular determinants of type I cadherin dimerization affinities. Small changes in sequence are found to produce subtle structural and dynamical changes that impact relative affinities, in part via electrostatic and hydrophobic interactions, and in part through entropic effects because of increased conformational heterogeneity in the bound states as revealed by DEER distance mapping in the dimers. These findings highlight the remarkable ability of evolution to exploit a wide range of molecular properties to produce closely related members of the same protein family that have affinity differences finely tuned to mediate their biological roles.
A complete Holocene record of trematode–bivalve infection and implications for the response of parasitism to climate change

Significance There is growing concern about how parasites will respond to climate change. Previous studies were based on data from short time scales (10−1 to 103 y), but here we present, to our knowledge, the first analysis of the response of parasites to global change on a longer time scale (104 y), utilizing the subfossil record. A 9,600-y record of clams and flatworm parasites from the Pearl River Delta exhibits a significant spike in parasite prevalence during the initial phase of sea-level rise. This increase is not related to changes in salinity or intermediate host availability. Temperature and productivity cannot be quantified and tested as driving factors. These results suggest stark implications for macrobenthos, fisheries, and human health in the context of climate change. Increasing global temperature and sea-level rise have led to concern about expansions in the distribution and prevalence of complex-lifecycle parasites (CLPs). Indeed, numerous environmental variables can influence the infectivity and reproductive output of many pathogens. Digenean trematodes are CLPs with intermediate invertebrate and definitive vertebrate hosts. Global warming and sea level rise may affect these hosts to varying degrees, and the effect of increasing temperature on parasite prevalence has proven to be nonlinear and difficult to predict. Projecting the response of parasites to anthropogenic climate change is vital for human health, and a longer term perspective (104 y) offered by the subfossil record is necessary to complement the experimental and historical approaches of shorter temporal duration (10−1 to 103 y). We demonstrate, using a high-resolution 9,600-y record of trematode parasite traces in bivalve hosts from the Holocene Pearl River Delta, that prevalence was significantly higher during the earliest stages of sea level rise, significantly lower during the maximum transgression, and statistically indistinguishable in the other stages of sea-level rise and delta progradation. This stratigraphic paleobiological pattern represents the only long-term high-resolution record of pathogen response to global change, is consistent with fossil and recent data from other marine basins, and is instructive regarding the future of disease. We predict an increase in trematode prevalence concurrent with anthropogenic warming and marine transgression, with negative implications for estuarine macrobenthos, marine fisheries, and human health.
The SWI/SNF chromatin remodeling complex regulates germinal center formation by repressing Blimp-1 expression

Significance Germinal center (GC) response is central for generation of memory B cells and plasma cells that produce high-affinity antibodies, which are crucial for protective immunity against various foreign antigens. Even though key genetic factors for the GC formation are known, it is largely unknown how this process is controlled by epigenetic factors. Here we have demonstrated that the activity of SWI/SNF chromatin remodeling complex is required for the development of both GC B cells and follicular helper T cells. The SWI/SNF complex modulates Bcl-6–mediated Blimp-1 repression, and thus plays as a key mediator in the GC response. Our results provide fundamental insights into the epigenetic regulation in the GC reaction. Germinal center (GC) reaction is crucial in adaptive immune responses. The formation of GC is coordinated by the expression of specific genes including Blimp-1 and Bcl-6. Although gene expression is critically influenced by the status of chromatin structure, little is known about the role of chromatin remodeling factors for regulation of GC formation. Here, we show that the SWI/SNF chromatin remodeling complex is required for GC reactions. Mice lacking Srg3/mBaf155, a core component of the SWI/SNF complex, showed impaired differentiation of GC B and follicular helper T cells in response to T cell-dependent antigen challenge. The SWI/SNF complex regulates chromatin structure at the Blimp-1 locus and represses its expression by interacting cooperatively with Bcl-6 and corepressors. The defect in GC reactions in mice lacking Srg3 was due to the derepression of Blimp-1 as supported by genetic studies with Blimp-1–ablated mice. Hence, our study identifies the SWI/SNF complex as a key mediator in GC reactions by modulating Bcl-6–dependent Blimp-1 repression.
On the factors that promote the diversity of herbivorous insects and plants in tropical forests

Significance A central mission in ecology has been to explain differences in biodiversity across the world and across groups of organisms. This knowledge is not only fundamental as a scientific objective but also for practical issues of major concern to humankind. Plants and phytophagous insects comprise the highest macroscopic diversity on Earth, making it particularly important to know the mechanisms that allow their species to coexist. This study suggests that without insect specialization the maintenance of tropical plant diversity might not be possible. Also, without high divergence of defenses among plants, insect tropical diversity may not persist either. Some of the most fascinating and challenging questions in ecology are why biodiversity is highest in tropical forests and whether the factors involved are unique to these habitats. I did a worldwide test of the hypotheses that plant community divergence in antiherbivore traits results in higher insect herbivore diversity, and that predominant attack by specialized herbivores promotes plant richness. I found strong correlative support for both ideas. Butterfly diversity was greatest in regions where the community average species-pairwise dissimilarity in antiherbivore traits among plant species was highest. There was also a strong positive relationship between specialized (insect) vs. generalized (mammal) herbivores and plant richness. Regions where herbivory impact by mammals was higher than that of insects tended to have lower plant diversities. In contrast, regions in which insects are the main consumers, particularly in the Central and South American tropics, had the highest plant richness. Latitude did not explain any residual variance in insect or plant richness. The strong connections found between insect specialization, plant defense divergence, and plant and insect diversities suggest that increasing our understanding of the ecology of biological communities can aid in considerations of how to preserve biodiversity in the future.
Adaptation of trabecular bone to very high mechanical loads

Summary It is well known that bone adapts to increased mechanical loading by the apposition of newly formed bone. The correlation between load-induced bone stress and strain with bone formation has often been investigated in cortical bone, however, little is known about this relationship in trabecular bone. In particular, nothing is known about trabecular bone adaptation in response to very high mechanical loading close to its fatigue load. Here, we investigated trabecular bone formation in a sheep osteotomy model of the femoral condyle in a region of interest close to the osteotomy, where local stresses in the range of the fatigue strength of trabecular bone occurred. After eight weeks, the trabecular bone volume and the mineral apposition rate increased two-fold and threefold, respectively, at this highly loaded location, compared to the corresponding region of interest in intact femoral condyles under physiological loading. This study demonstrated, for the first time, the remarkable capability of trabecular bone to adapt to stress and strain close to its failure load.
Neural crest cell-derived VEGF promotes embryonic jaw extension

Significance Craniofacial development is a complex morphogenic event that relies on highly orchestrated interactions between multiple cell types. Since the first description of Meckel’s cartilage in the lower jaw more than 180 years ago, we have come to realize that expansion of this specialized structure underpins correct mandible development. Here we demonstrate that an intricate association between neural crest cells and blood vessels plays an important role in promoting chondrocyte proliferation and expansion of Meckel’s cartilage as a prerequisite of correct mandibular morphogenesis. These findings provide direct insight into the origins and potential treatments of highly prevalent disorders affecting the mandible. Jaw morphogenesis depends on the growth of Meckel’s cartilage during embryogenesis. However, the cell types and signals that promote chondrocyte proliferation for Meckel’s cartilage growth are poorly defined. Here we show that neural crest cells (NCCs) and their derivatives provide an essential source of the vascular endothelial growth factor (VEGF) to enhance jaw vascularization and stabilize the major mandibular artery. We further show in two independent mouse models that blood vessels promote Meckel’s cartilage extension. Coculture experiments of arterial tissue with NCCs or chondrocytes demonstrated that NCC-derived VEGF promotes blood vessel growth and that blood vessels secrete factors to instruct chondrocyte proliferation. Computed tomography and X-ray scans of patients with hemifacial microsomia also showed that jaw hypoplasia correlates with mandibular artery dysgenesis. We conclude that cranial NCCs and their derivatives provide an essential source of VEGF to support blood vessel growth in the developing jaw, which in turn is essential for normal chondrocyte proliferation, and therefore jaw extension.
Organization and dynamics of the nonhomologous end-joining machinery during DNA double-strand break repair

Significance Nonhomologous end-joining (NHEJ) is the main pathway for repair of DNA double-strand breaks (DSBs), the most cytotoxic form of DNA damage resulting from ionizing radiation, chemotherapeutics, and normal cellular processes. The mechanisms that control NHEJ play key roles in development, in immunity, and in response to cancer therapy; however, the current state of knowledge regarding the physical nature of the NHEJ repair process is limited. Here we used super-resolution microscopy to define the organization of NHEJ complexes in cells, showing that long filaments form at either side of the break. Single-molecule FRET revealed dynamic behavior in which breaks can pair in an adjacent, non–end-to-end configuration. Nonhomologous end-joining (NHEJ) is a major repair pathway for DNA double-strand breaks (DSBs), involving synapsis and ligation of the broken strands. We describe the use of in vivo and in vitro single-molecule methods to define the organization and interaction of NHEJ repair proteins at DSB ends. Super-resolution fluorescence microscopy allowed the precise visualization of XRCC4, XLF, and DNA ligase IV filaments adjacent to DSBs, which bridge the broken chromosome and direct rejoining. We show, by single-molecule FRET analysis of the Ku/XRCC4/XLF/DNA ligase IV NHEJ ligation complex, that end-to-end synapsis involves a dynamic positioning of the two ends relative to one another. Our observations form the basis of a new model for NHEJ that describes the mechanism whereby filament-forming proteins bridge DNA DSBs in vivo. In this scheme, the filaments at either end of the DSB interact dynamically to achieve optimal configuration and end-to-end positioning and ligation.
Predator lipids induce paralytic shellfish toxins in bloom-forming algae

Significance We report the chemical basis for a critical question in ocean science: how do single-celled algae, which are responsible for almost half of Earth's photosynthesis, sense their environment to respond appropriately to the lethal threat of predation? The increasing frequency of toxic algal blooms, with worldwide consequences to human health, fisheries, and marine ecosystem functioning, has garnered much attention in recent years, but it has remained unclear how algal toxicity is regulated. With the current paper, we show that substantial (20×) induction of toxicity occurs when one species of algae is exposed to a family of previously unknown chemical cues from predatory zooplankton (copepods). The copepodamides represent the first discovery, to our knowledge, of chemical cues mediating interactions between marine zooplankton and their prey. Interactions among microscopic planktonic organisms underpin the functioning of open ocean ecosystems. With few exceptions, these organisms lack advanced eyes and thus rely largely on chemical sensing to perceive their surroundings. However, few of the signaling molecules involved in interactions among marine plankton have been identified. We report a group of eight small molecules released by copepods, the most abundant zooplankton in the sea, which play a central role in food webs and biogeochemical cycles. The compounds, named copepodamides, are polar lipids connecting taurine via an amide to isoprenoid fatty acid conjugate of varying composition. The bloom-forming dinoflagellate Alexandrium minutum responds to pico- to nanomolar concentrations of copepodamides with up to a 20-fold increase in production of paralytic shellfish toxins. Different copepod species exude distinct copepodamide blends that contribute to the species-specific defensive responses observed in phytoplankton. The signaling system described here has far reaching implications for marine ecosystems by redirecting grazing pressure and facilitating the formation of large scale harmful algal blooms.