GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

A Jovian analogue orbiting a white dwarf star.

Studies1,2 have shown that the remnants of destroyed planets and debris-disk planetesimals can survive the volatile evolution of their host stars into white dwarfs3,4, but few intact planetary bodies around white dwarfs have been detected5-8. Simulations predict9-11 that planets in Jupiter-like orbits around stars of ≲8 M☉ (solar mass) avoid being destroyed by the strong tidal forces of their stellar host, but as yet, there has been no observational confirmation of such a survivor. Here we report the non-detection of a main-sequence lens star in the microlensing event MOA-2010-BLG-477Lb12 using near-infrared observations from the Keck Observatory. We determine that this system contains a 0.53 ± 0.11 M☉ white-dwarf host orbited by a 1.4 ± 0.3 Jupiter-mass planet with a separation on the plane of the sky of 2.8 ± 0.5 astronomical units, which implies a semi-major axis larger than this. This system is evidence that planets around white dwarfs can survive the giant and asymptotic giant phases of their host's evolution, and supports the prediction that more than half of white dwarfs have Jovian planetary companions13. Located at approximately 2.0 kiloparsecs towards the centre of our Galaxy, it is likely to represent an analogue to the end stages of the Sun and Jupiter in our own Solar System.

De novo design of modular protein hydrogels with programmable intra- and extracellular viscoelasticity.

Relating the macroscopic properties of protein-based materials to their underlying component microstructure is an outstanding challenge. Here, we exploit computational design to specify the size, flexibility, and valency of de novo protein building blocks, as well as the interaction dynamics between them, to investigate how molecular parameters govern the macroscopic viscoelasticity of the resultant protein hydrogels. We construct gel systems from pairs of symmetric protein homo-oligomers, each comprising 2, 5, 24, or 120 individual protein components, that are crosslinked either physically or covalently into idealized step-growth biopolymer networks. Through rheological assessment, we find that the covalent linkage of multifunctional precursors yields hydrogels whose viscoelasticity depends on the crosslink length between the constituent building blocks. In contrast, reversibly crosslinking the homo-oligomeric components with a computationally designed heterodimer results in viscoelastic biomaterials exhibiting fluid-like properties under rest and low shear, but solid-like behavior at higher frequencies. Exploiting the unique genetic encodability of these materials, we demonstrate the assembly of protein networks within living mammalian cells and show via fluorescence recovery after photobleaching (FRAP) that mechanical properties can be tuned intracellularly in a manner similar to formulations formed extracellularly. We anticipate that the ability to modularly construct and systematically program the viscoelastic properties of designer protein-based materials could have broad utility in biomedicine, with applications in tissue engineering, therapeutic delivery, and synthetic biology.

Literature-based predictions of Mendelian disease therapies.

In the effort to treat Mendelian disorders, correcting the underlying molecular imbalance may be more effective than symptomatic treatment. Identifying treatments that might accomplish this goal requires extensive and up-to-date knowledge of molecular pathways-including drug-gene and gene-gene relationships. To address this challenge, we present "parsing modifiers via article annotations" (PARMESAN), a computational tool that searches PubMed and PubMed Central for information to assemble these relationships into a central knowledge base. PARMESAN then predicts putatively novel drug-gene relationships, assigning an evidence-based score to each prediction. We compare PARMESAN's drug-gene predictions to all of the drug-gene relationships displayed by the Drug-Gene Interaction Database (DGIdb) and show that higher-scoring relationship predictions are more likely to match the directionality (up- versus down-regulation) indicated by this database. PARMESAN had more than 200,000 drug predictions scoring above 8 (as one example cutoff), for more than 3,700 genes. Among these predicted relationships, 210 were registered in DGIdb and 201 (96%) had matching directionality. This publicly available tool provides an automated way to prioritize drug screens to target the most-promising drugs to test, thereby saving time and resources in the development of therapeutics for genetic disorders.

Bioluminescence Resonance Energy Transfer (BRET)-Mediated Protein Release from Self-Illuminating Photoresponsive Biomaterials.

Phototriggered release of various cargos, including soluble protein factors and small molecules, has the potential to correct aberrant biological events by offering spatiotemporal control over local therapeutic levels. However, the poor penetration depth of light historically limits implementation to subdermal regions, necessitating alternative methods of light delivery to achieve the full potential of photodynamic therapeutic release. Here, we introduce a strategy exploiting bioluminescence resonance energy transfer (BRET)-an energy transfer process between light-emitting Nanoluciferase (NLuc) and a photosensitive acceptor molecule-to drive biomolecule release from hydrogel biomaterials. Through a facile, one-pot, and high-yielding synthesis (60-70%), we synthesized a heterobifunctional ruthenium cross-linker bearing an aldehyde and an azide (CHO-Ru-N3), a compound that we demonstrate undergoes predictable exchange of the azide-bearing ligand under blue-green light irradiation (>550 nm). Following site-specific conjugation to NLuc via sortase-tag enhanced protein ligation (STEPL), the modified protein was covalently attached to a poly(ethylene glycol) (PEG)-based hydrogel via strain-promoted azide-alkyne cycloaddition (SPAAC). Leveraging the high photosensitivity of Ru compounds, we demonstrate rapid and equivalent release of epidermal growth factor (EGF) via either direct illumination or via BRET-based bioluminolysis. As NLuc-originated luminescence can be controlled equivalently throughout the body, we anticipate that this unique protein release strategy will find use for locally triggered drug delivery following systemic administration of a small molecule.

One-Step Purification and N-Terminal Functionalization of Bioactive Proteins via Atypically Split Inteins.

Site-specific installation of non-natural functionality onto proteins has enabled countless applications in biotechnology, chemical biology, and biomaterials science. Though the N-terminus is an attractive derivatization location, prior methodologies targeting this site have suffered from low selectivity, a limited selection of potential chemical modifications, and/or challenges associated with divergent protein purification/modification steps. In this work, we harness the atypically split VidaL intein to simultaneously N-functionalize and purify homogeneous protein populations in a single step. Our method─referred to as VidaL-tagged expression and protein ligation (VEPL)─enables modular and scalable production of N-terminally modified proteins with native bioactivity. Demonstrating its flexibility and ease of use, we employ VEPL to combinatorially install 4 distinct (multi)functional handles (e.g., biotin, alkyne, fluorophores) to the N-terminus of 4 proteins that span three different classes: fluorescent (Enhanced Green Fluorescent Protein, mCherry), enzymatic (ß-lactamase), and growth factor (epidermal growth factor). Moving forward, we anticipate that VEPL's ability to rapidly generate and isolate N-modified proteins will prove useful across the growing fields of applied chemical biology.

Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Comparison of minimally invasive to standard temporal lobectomy approaches to epilepsy surgery: Seizure relief and visual confrontation naming outcomes.

The purpose of this study was to systematically examine three different surgical approaches in treating left medial temporal lobe epilepsy (mTLE) (viz., subtemporal selective amygdalohippocampectomy [subSAH], stereotactic laser amygdalohippocampotomy [SLAH], and anterior temporal lobectomy [ATL]), to determine which procedures are most favorable in terms of visual confrontation naming and seizure relief outcome. This was a retrospective study of 33 adults with intractable mTLE who underwent left temporal lobe surgery at three different epilepsy surgery centers who also underwent pre-, and at least 6-month post-surgical neuropsychological testing. Measures included the Boston Naming Test (BNT) and the Engel Epilepsy Surgery Outcome Scale. Fisher's exact tests revealed a statistically significant decline in naming in ATLs compared to SLAHs, but no other significant group differences. 82% of ATL and 36% of subSAH patients showed a significant naming decline whereas no SLAH patient (0%) had a significant naming decline. Significant postoperative naming improvement was seen in 36% of SLAH patients in contrast to 9% improvement in subSAH patients and 0% improvement in ATLs. Finally, there were no statistically significant differences between surgical approaches with regard to seizure freedom outcome, although there was a trend towards better seizure relief outcome among the ATL patients. Results support a possible benefit of SLAH in preserving visual confrontation naming after left TLE surgery. While result interpretation is limited by the small sample size, findings suggest outcome is likely to differ by surgical approach, and that further research on cognitive and seizure freedom outcomes is needed to inform patients and providers of potential risks and benefits with each.

Photopatterned biomolecule immobilization to guide three-dimensional cell fate in natural protein-based hydrogels.

Hydrogel biomaterials derived from natural biopolymers (e.g., fibrin, collagen, decellularized extracellular matrix) are regularly utilized in three-dimensional (3D) cell culture and tissue engineering. In contrast to those based on synthetic polymers, natural materials permit enhanced cytocompatibility, matrix remodeling, and biological integration. Despite these advantages, natural protein-based gels have lagged behind synthetic alternatives in their tunability; methods to selectively modulate the biochemical properties of these networks in a user-defined and heterogeneous fashion that can drive encapsulated cell function have not yet been established. Here, we report a generalizable strategy utilizing a photomediated oxime ligation to covalently decorate naturally derived hydrogels with bioactive proteins including growth factors. This bioorthogonal photofunctionalization is readily amenable to mask-based and laser-scanning lithographic patterning, enabling full four-dimensional (4D) control over protein immobilization within virtually any natural protein-based biomaterial. Such versatility affords exciting opportunities to probe and direct advanced cell fates inaccessible using purely synthetic approaches in response to anisotropic environmental signaling.

The mindful gaze: trait mindful people under an instructed emotion regulation goal selectively attend to positive stimuli.

Trait mindfulness confers emotional benefits and encourages skillful emotion regulation, in part because it helps people more deliberately attend to internal experiences and external surroundings. Such heightened attentional control might help skillfully deploy one's attention towards certain kinds of stimuli, which may in turn help regulate emotions, but this remains unknown. Testing how trait mindful people deploy attention when regulating their emotions could help uncover the specific mechanisms of mindfulness that confer its emotional benefits. The present study aimed to determine whether high trait mindfulness is associated with sustained attention biases to (i.e. longer gaze at) emotional scenes, when all participants are given the emotion regulation goal of staying in a positive mood. To measure this, we used eye tracking to assess selective attention to positive, neutral, and negative photographs. Higher trait mindfulness was associated with both a stronger attention bias for positive (vs. neutral and vs. negative) images, as well as greater success staying in a positive mood during viewing. Surprisingly, this attention bias towards the positive images did not mediate the relationship between mindfulness and maintenance of positive mood. Future work should compare visual attention to other emotion regulation strategies that may maximise positive affect for mindful people.

Staff Perceptions on the Effectiveness of GRiP-S, a New Approach to Clinical Supervision Incorporating Safewards: An Interpretive Phenomenological Analysis.

This study explored the impact of an innovative approach to clinical supervision for mental health nurses which integrates Safewards, named Group Reflective integrated Practice with Safewards - GRiP-S. Qualitative data was collected through 10 individual semi-structured interviews with nursing staff who had participated within the clinical supervision approach. Interviews provided insights into the nursing staff's perception and experience of the clinical supervision approach. Through interpretive phenomenological analysis six themes emerged (i) illuminating embodied practice of Safewards, (ii) building confidence through empowering connections, (iii) creating a culture of positive change, (iv) identifying internal motivation for and external barriers to supervision engagement, (v) navigating a global pandemic, and (vi) the transformative role of reflection. Findings demonstrated that the GRiP-S approach assisted mental health nurses' adoption of Safewards interventions in practice, while supporting the development of a cohesive staff team. The impact of COVID-19 within the study setting was addressed and nurses identified how the Safewards model assisted in navigating challenges during this time. Findings further supported prior research on the role of the supervisor and supervisee relationship. This study supports the integration of Safewards within reflective clinical supervision for mental health nursing staff to assist in Safewards fidelity and nursing staff personal and professional development.

Post-mastectomy Breast Reconstruction With Gas vs Saline Tissue Expanders: Does the Fill Type Matter?

The most common reconstruction technique following mastectomy is a 2-stage technique that involves tissue expansion followed by definitive implant-based reconstruction (IBR). Tissue expanders (TEs) have classically used saline for initial fill; however, TEs with an initial gas fill (GTE)-including the CO2-based AeroForm (AirXpanders, San Francisco, CA) TE and TEs initially filled with atmospheric air-have been increasingly used in the past decade. We aimed to compare the outcomes in breast reconstruction for tissue expanders initially filled with saline vs gas. PubMed was queried for studies comparing gas- and saline-filled tissue expanders (STEs) used in IBR. A meta-analysis was performed on major postoperative outcomes and the required expansion and definitive reconstruction time. Eleven studies were selected and included in the analysis. No significant differences existed between tissue expansion with GTEs vs STEs for 11 of the 13 postoperative outcomes investigated. Out of the complications investigated, only the risk of infection/cellulitis/abscess formation was significantly lower in the GTE cohort (odds ratio 0.62; 95% CI, 0.47 to 0.82; P = .0009). The time to definitive reconstruction was also significantly lower in the GTE cohort (mean difference [MD], 45.85 days; 95% CI, -57.80 to -33.90; P < .00001). The total time to full expansion approached significance in the GTE cohort (MD, -20.33 days; 95% CI, -41.71 to 1.04; P = .06). A cost analysis considering TE cost and infection risk determined that GTE use saved a predicted $2055.34 in overall healthcare costs. Surgical outcomes for both fill types were predominantly similar; however, GTEs were associated with a significantly decreased risk of postoperative infection compared to saline-filled TEs. GTEs could also reduce healthcare expenditures and require less time until definitive reconstruction after placement.

Complication Profiles of Smooth vs Textured Tissue Expanders in Breast Reconstruction: A Systematic Review and Meta-Analysis.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a type of non-Hodgkin lymphoma first linked with breast implants in 2011. The correlation between BIA-ALCL and textured devices has led to increased use of smooth devices. However, much of the data surrounding smooth and textured devices investigates breast implants specifically and not tissue expanders. OBJECTIVES: We performed a systematic review and a meta-analysis to compare surgical outcomes for smooth tissue expanders (STEs) and textured tissue expanders (TTEs). METHODS: A search was performed on PubMed, including articles from 2016 to 2023 (n = 419). Studies comparing TTEs and STEs and reported complications were included. A random-effects model was utilized for meta-analysis. RESULTS: A total of 5 articles met inclusion criteria, representing 1709 patients in the STE cohort and 1716 patients in the TTE cohort. The mean duration of tissue expansion with STEs was 221.25 days, while TTEs had a mean time of tissue expansion of 220.43 days.Our meta-analysis found no differences in all surgical outcomes except for explantation risk. STE use was associated with increased odds of explantation by over 50% compared to TTE use (odds ratio = 1.53; 95% CI = 1.15 to 2.02; P = .003). CONCLUSIONS: Overall, STEs and TTEs had similar complication profiles. However, STEs had 1.5 times higher odds of explantation. The incidence of BIA-ALCL is low, and only a single case of BIA-ALCL has been reported with TTEs. This indicates that TTEs are safe and may lower the risk of early complications requiring explantation. Further studies are warranted to further define the relationship between tissue expanders and BIA-ALCL.

An Integrated Phenotypic and Genotypic Approach Reveals a High-Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain.

OBJECTIVE: Collier/Olf/EBF (COE) transcription factors have distinct expression patterns in the developing and mature nervous system. To date, a neurological disease association has been conclusively established for only the Early B-cell Factor-3 (EBF3) COE family member through the identification of heterozygous loss-of-function variants in individuals with autism spectrum/neurodevelopmental disorders (NDD). Here, we identify a symptom severity risk association with missense variants primarily disrupting the zinc finger domain (ZNF) in EBF3-related NDD. METHODS: A phenotypic assessment of 41 individuals was combined with a literature meta-analysis for a total of 83 individuals diagnosed with EBF3-related NDD. Quantitative diagnostic phenotypic and symptom severity scales were developed to compare EBF3 variant type and location to identify genotype-phenotype correlations. To stratify the effects of EBF3 variants disrupting either the DNA-binding domain (DBD) or the ZNF, we used in vivo fruit fly UAS-GAL4 expression and in vitro luciferase assays. RESULTS: We show that patient symptom severity correlates with EBF3 missense variants perturbing the ZNF, which is a key protein domain required for stabilizing the interaction between EBF3 and the target DNA sequence. We found that ZNF-associated variants failed to restore viability in the fruit fly and impaired transcriptional activation. However, the recurrent variant EBF3 p.Arg209Trp in the DBD is capable of partially rescuing viability in the fly and preserved transcriptional activation. INTERPRETATION: We describe a symptom severity risk association with ZNF perturbations and EBF3 loss-of-function in the largest reported cohort to date of EBF3-related NDD patients. This analysis should have potential predictive clinical value for newly identified patients with EBF3 gene variants. ANN NEUROL 2022;92:138-153.

Compartmentalization of specialized metabolites across vegetative and reproductive tissues in two sympatric Psychotria species.

PREMISE: The specialized metabolites of plants are recognized as key chemical traits in mediating the ecology and evolution of sundry plant-biotic interactions, from pollination to seed predation. Intra- and interspecific patterns of specialized metabolite diversity have been studied extensively in leaves, but the diverse biotic interactions that contribute to specialized metabolite diversity encompass all plant organs. Focusing on two species of Psychotria shrubs, we investigated and compared patterns of specialized metabolite diversity in leaves and fruit with respect to each organ's diversity of biotic interactions. METHODS: To evaluate associations between biotic interaction diversity and specialized metabolite diversity, we combined UPLC-MS metabolomic analysis of foliar and fruit specialized metabolites with existing surveys of leaf- and fruit-centered biotic interactions. We compared patterns of specialized metabolite richness and variance among vegetative and reproductive tissues, among plants, and between species. RESULTS: In our study system, leaves interact with a far larger number of consumer species than do fruit, while fruit-centric interactions are more ecologically diverse in that they involve antagonistic and mutualistic consumers. This aspect of fruit-centric interactions was reflected in specialized metabolite richness-leaves contained more than fruit, while each organ contained over 200 organ-specific specialized metabolites. Within each species, leaf- and fruit-specialized metabolite composition varied independently of one another across individual plants. Contrasts in specialized metabolite composition were stronger between organs than between species. CONCLUSIONS: As ecologically disparate plant organs with organ-specific specialized metabolite traits, leaves and fruit can each contribute to the tremendous overall diversity of plant specialized metabolites.

Infarct Collagen Topography Regulates Fibroblast Fate via p38-Yes-Associated Protein Transcriptional Enhanced Associate Domain Signals.

RATIONALE: Myocardial infarction causes spatial variation in collagen organization and phenotypic diversity in fibroblasts, which regulate the heart's ECM (extracellular matrix). The relationship between collagen structure and fibroblast phenotype is poorly understood but could provide insights regarding the mechanistic basis for myofibroblast heterogeneity in the injured heart. OBJECTIVE: To investigate the role of collagen organization in cardiac fibroblast fate determination. METHODS AND RESULTS: Biomimetic topographies were nanofabricated to recapitulate differential collagen organization in the infarcted mouse heart. Here, adult cardiac fibroblasts were freshly isolated and cultured on ECM topographical mimetics for 72 hours. Aligned mimetics caused cardiac fibroblasts to elongate while randomly organized topographies induced circular morphology similar to the disparate myofibroblast morphologies measured in vivo. Alignment cues also induced myofibroblast differentiation, as >60% of fibroblasts formed αSMA (α-smooth muscle actin) stress fibers and expressed myofibroblast-specific ECM genes like Postn (periostin). By contrast, random organization caused 38% of cardiac fibroblasts to express αSMA albeit with downregulated myofibroblast-specific ECM genes. Coupling topographical cues with the profibrotic agonist, TGFß (transforming growth factor beta), additively upregulated myofibroblast-specific ECM genes independent of topography, but only fibroblasts on flat and randomly oriented mimetics had increased percentages of fibroblasts with αSMA stress fibers. Increased tension sensation at focal adhesions induced myofibroblast differentiation on aligned mimetics. These signals were transduced by p38-YAP (yes-associated protein)-TEAD (transcriptional enhanced associate domain) interactions, in which both p38 and YAP-TEAD (yes-associated protein transcriptional enhanced associate domain) binding were required for myofibroblast differentiation. By contrast, randomly oriented mimetics did not change focal adhesion tension sensation or enrich for p38-YAP-TEAD interactions, which explains the topography-dependent diversity in fibroblast phenotypes observed here. CONCLUSIONS: Spatial variations in collagen organization regulate cardiac fibroblast phenotype through mechanical activation of p38-YAP-TEAD signaling, which likely contribute to myofibroblast heterogeneity in the infarcted myocardium.

Variations, validations, degradations, and noninvasive determination of pregnancy using fecal steroid metabolites in free-ranging pronghorn.

Pregnancy status is a key parameter used to assess reproductive performance of a species as it represents a starting point for measuring vital rates. Vital rates allow managers to determine trends in populations such as neonate survival and recruitment; two important factors in ungulate population growth rates. Techniques to determine pregnancy have generally involved capture and restraint of the animal to obtain blood samples for determining serum hormone levels. Non-invasive pregnancy assessment, via feces, eliminates any hazards between handler and animal, as well as removes handling-induced physiological biases. Using noninvasive fecal sampling, we conducted hormone validations, investigated pregnancy rates, and determined hormone degradation rates across five subpopulations of pronghorn (Antilocapra americana) in Idaho. Samples were collected during April-May of 2018 and 2019 from adult pronghorn of known sex and age class. Metabolites of testosterone, cortisol, 17ß-estradiol, and progesterone were measured in fecal samples, and concentrations of estradiol and progesterone were examined for pregnancy determination. Average fecal progesterone metabolite (FPM) levels of pregnant females were more than double compared to levels of nonpregnant females. Fecal estrogen metabolite (FEM) levels did not differ during concurrent sampling. The largest difference in FPM levels between pregnant and nonpregnant females began on 28 April. Pregnancy determination sampling showed average FPM levels for all five subpopulations were significantly different than the nonpregnant female validation group. Nonetheless, pregnancy rates for some subpopulations lacked conclusive estimates due to early fecal sampling. Fecal glucocorticoid metabolites (FGM) levels significantly differed between pregnant females and male pronghorn, but did not differ from nonpregnant females. Degradation rates of FPM and FGM differed across days, with values for FPM from Day 1 being significantly different from all subsequent days, and after Day 9 for FGM, demonstrating the requirement of fresh samples to accurately measure hormone concentrations. We concluded that a noninvasive method to diagnosis pregnancy is possible in pronghorn via progesterone metabolites if fresh samples are collected during late gestation.

Bioactive site-specifically modified proteins for 4D patterning of gel biomaterials.

Protein-modified biomaterials can be used to modulate cellular function in three dimensions. However, as the dynamic heterogeneous control over complex cell physiology continues to be sought, strategies that permit a reversible and user-defined tethering of fragile proteins to materials remain in great need. Here we introduce a modular and robust semisynthetic approach to reversibly pattern cell-laden hydrogels with site-specifically modified proteins. Exploiting a versatile sortase-mediated transpeptidation, we generate a diverse library of homogeneous, singly functionalized proteins with bioorthogonal reactive handles for biomaterial modification. We demonstrate the photoreversible immobilization of fluorescent proteins, enzymes and growth factors to gels with excellent spatiotemporal resolution while retaining native protein bioactivity. Localized epidermal growth factor presentation enables dynamic regulation over proliferation, intracellular mitogen-activated protein kinase signalling and subcellularly resolved receptor endocytosis. Our method broadly permits the modification and patterning of a wide range of proteins, which provides newfound avenues to probe and direct advanced cellular fates in four dimensions.

AVADA: toward automated pathogenic variant evidence retrieval directly from the full-text literature.

PURPOSE: Both monogenic pathogenic variant cataloging and clinical patient diagnosis start with variant-level evidence retrieval followed by expert evidence integration in search of diagnostic variants and genes. Here, we try to accelerate pathogenic variant evidence retrieval by an automatic approach. METHODS: Automatic VAriant evidence DAtabase (AVADA) is a novel machine learning tool that uses natural language processing to automatically identify pathogenic genetic variant evidence in full-text primary literature about monogenic disease and convert it to genomic coordinates. RESULTS: AVADA automatically retrieved almost 60% of likely disease-causing variants deposited in the Human Gene Mutation Database (HGMD), a 4.4-fold improvement over the current best open source automated variant extractor. AVADA contains over 60,000 likely disease-causing variants that are in HGMD but not in ClinVar. AVADA also highlights the challenges of automated variant mapping and pathogenicity curation. However, when combined with manual validation, on 245 diagnosed patients, AVADA provides valuable evidence for an additional 18 diagnostic variants, on top of ClinVar's 21, versus only 2 using the best current automated approach. CONCLUSION: AVADA advances automated retrieval of pathogenic monogenic variant evidence from full-text literature. Far from perfect, but much faster than PubMed/Google Scholar search, careful curation of AVADA-retrieved evidence can aid both database curation and patient diagnosis.

Programming Stimuli-Responsive Behavior into Biomaterials.

Stimuli-responsive materials undergo triggered changes when presented with specific environmental cues. These dynamic systems can leverage biological signals found locally within the body as well as exogenous cues administered with spatiotemporal control, providing powerful opportunities in next-generation diagnostics and personalized medicine. Here, we review the synthetic and strategic advances used to impart diverse responsiveness to a wide variety of biomaterials. Categorizing systems on the basis of material type, number of inputs, and response mechanism, we examine past and ongoing efforts toward endowing biomaterials with customizable sensitivity. We draw an analogy to computer science, whereby a stimuli-responsive biomaterial transduces a set of inputs into a functional output as governed by a user-specified logical operator. We discuss Boolean and non-Boolean operations, as well as the various chemical and physical modes of signal transduction. Finally, we examine current limitations and promising directions in the ongoing development of programmable stimuli-responsive biomaterials.