Lightning Pose: improved animal pose estimation via semi-supervised learning, Bayesian ensembling and cloud-native open-source tools.

Contemporary pose estimation methods enable precise measurements of behavior via supervised deep learning with hand-labeled video frames. Although effective in many cases, the supervised approach requires extensive labeling and often produces outputs that are unreliable for downstream analyses. Here, we introduce 'Lightning Pose', an efficient pose estimation package with three algorithmic contributions. First, in addition to training on a few labeled video frames, we use many unlabeled videos and penalize the network whenever its predictions violate motion continuity, multiple-view geometry and posture plausibility (semi-supervised learning). Second, we introduce a network architecture that resolves occlusions by predicting pose on any given frame using surrounding unlabeled frames. Third, we refine the pose predictions post hoc by combining ensembling and Kalman smoothing. Together, these components render pose trajectories more accurate and scientifically usable. We released a cloud application that allows users to label data, train networks and process new videos directly from the browser.

Late-Stage C(sp2)-C(sp3) Diversification via Nickel Oxidative Addition Complexes.

Herein, we describe nickel oxidative addition complexes (Ni-OACs) of drug-like molecules as a platform to rapidly generate lead candidates with enhanced C(sp3) fraction. The potential of Ni-OACs to access new chemical space has been assessed not only in C(sp2)-C(sp3) couplings but also in additional bond formations without recourse to specialized ligands and with improved generality when compared to Ni-catalyzed reactions. The development of an automated diversification process further illustrates the robustness of Ni-OACs, thus offering a new gateway to expedite the design-make-test-analyze (DMTA) cycle in drug discovery.

Efficacy of different 8 h time-restricted eating schedules on visceral adipose tissue and cardiometabolic health: A study protocol.

BACKGROUND AND AIMS: To investigate the efficacy and feasibility of three different 8 h time-restricted eating (TRE) schedules (i.e., early, late, and self-selected) compared to each other and to a usual-care (UC) intervention on visceral adipose tissue (VAT) and cardiometabolic health in men and women. METHODS AND RESULTS: Anticipated 208 adults (50% women) aged 30-60 years, with overweight/obesity (25 ≤ BMI<40 kg/m2) and with mild metabolic impairments will be recruited for this parallel-group, multicenter randomized controlled trial. Participants will be randomly allocated (1:1:1:1) to one of four groups for 12 weeks: UC, early TRE, late TRE or self-selected TRE. The UC group will maintain their habitual eating window and receive, as well as the TRE groups, healthy lifestyle education for weight management. The early TRE group will start eating not later than 10:00, and the late TRE group not before 13:00. The self-selected TRE group will select an 8 h eating window before the intervention and maintain it over the intervention. The primary outcome is changes in VAT, whereas secondary outcomes include body composition and cardiometabolic risk factors. CONCLUSION: This study will determine whether the timing of the eating window during TRE impacts its efficacy on VAT, body composition and cardiometabolic risk factors and provide insights about its feasibility.

A network analysis of Hurricane Maria-related traumatic stress and substance use among Puerto Rican youth.

Youth exposed to natural disasters are at risk of developing trauma-related symptoms as well as engaging in substance use. Although previous research has established associations between disaster-related stressors and substance use in youth, less has focused on how symptoms of posttraumatic stress disorder (PTSD) may underpin this association. The current study used network analysis to identify specific PTSD symptoms associated with substance use following a natural disaster. Participants were 91,732 youths (Grades 3-12) from across Puerto Rico who completed a needs assessment 5-9 months after Hurricane Maria made landfall in September 2017. We examined associations between PTSD symptoms and substance use, identified clusters of symptoms and bridges between them, and explored age- and binary gender-related differences in associations between specific PTSD symptoms and substance use. Analyses identified two symptom communities: (a) arousal and reactivity, negative alterations in cognition and mood, and substance use, and (b) avoidance and intrusion. Broader findings suggested that substance use was most strongly associated with PTSD-related irritability and angry outbursts among youths. Surrounding nodes explained only 4.1% of the variance in substance use, but this was higher among youths who reported not having a supportive adult, R2 = 8.5; friend, R2 = 7.9; or teacher/counselor, R2 = 7.7, in their life. The bridge symptoms of sleep disruption and physiological reactivity were identified as potentially critical intervention targets for disrupting PTSD symptom networks after a natural disaster. Implications for triaged mental health care following natural disasters and directions for future research are discussed.

Implications of Undocumented Status for Latinx Families During the COVID-19 Pandemic: A Call to Action.

BACKGROUND: A disproportionate number of COVID-19 cases and deaths have been reported among Latinxs in the U.S. Among those most affected by the pandemic are marginalized families, including those that are undocumented and mixed-status, in which some, but not all members are undocumented. Undocumented and mixed-status families face multiple and chronic daily stressors that compromised their health and wellbeing. Salient stressors faced by undocumented Latinx families include poverty, social disadvantage, discrimination, dangerous living and working conditions, and limited access to healthcare. These stressors are frequently compounded with trauma, fear of detention, deportation, and family separation. PURPOSE: Informed by the literature and insights from our community-based work to address the health needs of undocumented and mixed status Latinx families during the pandemic, this paper uses a social determinants of health lens to present a narrative summary that highlights four primary psychosocial stressors faced by these families and their implications for mental health. DISCUSSION: These include stressors pertaining to (a) anti-immigrant rhetoric and actions; (b) family stressors and disruptions in family dynamics; (c) economic changes and financial losses; and (c) limited access to healthcare. Implications of the aforesaid stressors on the mental health of undocumented families and youth are also discussed. In addition, recommendations are provided for the provision of mental health services, best practices, and resources from a strengths-based approach.

Factor structure, internal consistency, and construct validity of the Caregiver strain questionnaire in Latinx families.

Caregiver strain or stress directly related to caring for a youth with emotional and/or behavioral problems may be an important and understudied cultural factor associated with mental health disparities among Latinx families. Caregiver strain is a highly relevant construct for research questions focused on the identification of youth's mental health needs, family-level impacts of youth mental health problems, and utilization of youth mental health services. Unfortunately, there is a dearth of research on measures of caregiver strain and the psychometric properties of existing measures in Latinx samples. This study examined the structural and construct validity of the English version of the Caregiver Strain Questionnaire (CGSQ) with a sample of United States-based Latinx caregivers of youths ages 6-18 (N = 598). Confirmatory factor analysis showed that the original three-factor model of caregiver strain was evidenced in this sample. Internal consistency analyses and a poor factor loading led to the elimination of one item. The factor structure held after item removal. Significant associations between each dimension of caregiver strain with youth internalizing/externalizing symptom severity and utilization of youth mental health services provided evidence of construct validity (i.e., psychological counseling, telepsychology, parenting classes). Results provide important evidence of the psychometric properties of the English CGSQ in a Latinx sample and support its use in future research aimed at unpacking mental health disparities among Latinx youth and families. Researchers should translate and validate the CGSQ in Spanish to increase the utility of this measure for research with Latinx families.

Comparative Evaluation of Boron Sorption Dynamics on Zeolites in Irrigation Waters: An Isothermal Modeling Approach.

Efficient boron removal from irrigation waters is crucial for sustainable agriculture, as elevated levels of boron can be toxic to many plants, limiting growth and crop productivity. In this context, the present study investigated the sorption equilibrium of boron using zeolites in two types of aqueous matrices: a synthetic solution containing only boron and natural irrigation waters. Through the application of various isothermal sorption models (Langmuir, Freundlich, Sips, Toth, Jovanovic, Temkin, Dubinin-Radushkevich, and Redlich-Peterson), the efficacy of zeolite for boron removal under controlled and real conditions was evaluated. The results indicated a notable difference in sorption behavior between the two matrices, reflecting the complexity and heterogeneity of interactions in the boron-zeolite system. In the synthetic solution, the Freundlich model provided the best fit (R2 = 0.9917), suggesting heterogeneous and multilayer sorption, while the Sips model showed high efficacy in describing the sorption in both matrices, evidencing its capability to capture the complex nature of the interaction between boron and zeolite under different environmental conditions. However, in natural irrigation waters, the Jovanovic model demonstrated the most accurate fit (R2 = 0.999), highlighting the importance of physical interactions in boron sorption. These findings underscore the significant influence of the water matrix on the efficacy of zeolite as a boron removal agent, emphasizing the need to consider the specific composition of irrigation water in the design of removal treatments. Additionally, the results stress the importance of selecting the appropriate isothermal model to predict boron sorption behavior, which is crucial for developing effective and sustainable treatment strategies. This study provides a basis for optimizing boron removal in various agricultural and industrial applications, contributing to the design of more efficient and specific water treatment processes.

Structure-Based Design of Bicyclic Helical Peptides That Target the Oncogene ß-Catenin.

The inhibition of intracellular protein-protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. The transcriptional co-activator protein and oncogene ß-catenin is a prime example of such a challenging target. Despite extensive targeting efforts, available high-affinity binders comprise only large molecular weight inhibitors. This hampers the further development of therapeutically useful compounds. Herein, we report the design of a considerably smaller peptidomimetic scaffold derived from the α-helical ß-catenin-binding motif of Axin. Sequence maturation and bicyclization provided a stitched peptide with an unprecedented crosslink architecture. The binding mode and site were confirmed by a crystal structure. Further derivatization yielded a ß-catenin inhibitor with single-digit micromolar activity in a cell-based assay. This study sheds light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity.

Sleep fails to depotentiate amygdala-reactivity to negative emotional stimuli in youth with elevated symptoms of anxiety.

Sleep-related problems often precede escalating anxiety in early adolescence. Pushing beyond broad sleep-mental health associations and toward mechanistic theories of their interplay can inform etiological models of psychopathology. Recent studies suggest that sleep depotentiates neural (e.g., amygdala) reactivity during reexposure to negative emotional stimuli in adults. Persistent amygdala reactivity to negative experiences and poor sleep characterize anxiety, particularly at the transition to adolescence. We propose that sleep depotentiates amygdala reactivity in youth but fails to do so among youth with anxiety. Participants (n = 34; 18 males; age, mean [M] = 11.35, standard deviation [SD] = 2.00) recruited from the community and specialty anxiety clinics viewed valenced images (positive, negative, and neutral) across two fMRI sessions (Study, Test), separated by a 10-12-hour retention period of sleep or wake (randomized). Mixed linear models regressed basolateral amygdala (BLA) activation and BLA-medial prefrontal cortex (mPFC) functional connectivity to negative images on Time, Condition, and Anxiety Severity. There were greater reductions in BLA activations to negative target images from Study to Test in the Sleep Condition, which was blunted with higher anxiety (b = -0.065, z = -2.355, p = 0.019). No such sleep- or anxiety-related effects were observed for BLA-mPFC functional connectivity (ps > 0.05). Sleep supports depotentiation of amygdala reactivity to negative stimuli in youth, but this effect is blunted at higher levels of anxiety. Disruptions in sleep-related affective habituation may be a critical, modifiable driver of anxiety.

Constrained peptides mimic a viral suppressor of RNA silencing.

The design of high-affinity, RNA-binding ligands has proven very challenging. This is due to the unique structural properties of RNA, often characterized by polar surfaces and high flexibility. In addition, the frequent lack of well-defined binding pockets complicates the development of small molecule binders. This has triggered the search for alternative scaffolds of intermediate size. Among these, peptide-derived molecules represent appealing entities as they can mimic structural features also present in RNA-binding proteins. However, the application of peptidic RNA-targeting ligands is hampered by a lack of design principles and their inherently low bio-stability. Here, the structure-based design of constrained α-helical peptides derived from the viral suppressor of RNA silencing, TAV2b, is described. We observe that the introduction of two inter-side chain crosslinks provides peptides with increased α-helicity and protease stability. One of these modified peptides (B3) shows high affinity for double-stranded RNA structures including a palindromic siRNA as well as microRNA-21 and its precursor pre-miR-21. Notably, B3 binding to pre-miR-21 inhibits Dicer processing in a biochemical assay. As a further characteristic this peptide also exhibits cellular entry. Our findings show that constrained peptides can efficiently mimic RNA-binding proteins rendering them potentially useful for the design of bioactive RNA-targeting ligands.

Cuento de nunca acabar [never-ending story]: Compounding trauma and mental health among undocumented Latinx immigrants.

Research examining the effects of traumatic events on undocumented Latinx immigrants often focuses on assessing posttraumatic stress disorder or general psychological distress, which may obscure the field's understanding of how trauma exposure impacts other common mental health disorders (e.g., anxiety, depression). This study sought to assess the cumulative, individual, and timing effects of immigration-related traumatic events on anxiety and depressive symptoms among undocumented Latinx immigrants. Participants were 253 undocumented Latinx immigrants recruited using respondent-driven sampling who reported their history of immigration-related trauma exposure and symptoms of depression and anxiety. Results suggest that cumulative immigration-related trauma was significantly associated with increases in anxiety and depressive symptoms, τ = .26. Significant positive correlations were found for cumulative trauma at each point in the immigration process (i.e., before immigration, while in transit to the United States, and while living in the United States) such that increases in the number of events were associated with higher anxiety and depressive symptom levels, τ = .11-.29. Trauma frequency differed throughout the immigration process such that some events more commonly occurred before immigration or during transit to the United States, whereas others occurred while an individual resided in the United States. Random forest algorithms uncovered differences in the relative importance of individual traumatic events in explaining the variance of depressive, R2 = .13, and anxiety symptoms, R2 = .14. The findings highlight the importance of providing trauma-informed care when treating anxiety and depression among undocumented Latinx immigrants and considering multidimensional epidemiological approaches in assessing immigration-related trauma.

Juntos hacemos la diferencia [together we make the difference]: A network analysis of Latinx caregivers' use of youth support services.

Latinx families face unique barriers to accessing traditional youth mental health services and may instead rely on a wide range of supports to meet youth emotional or behavioral concerns. Previous studies have typically focused on patterns of utilization for discrete services, classified by setting, specialization, or level of care (e.g., specialty outpatient, inpatient, informal supports), yet little is known about how youth support services might be accessed in tandem. This analysis used data from the Pathways to Latinx Mental Health study - a national sample of Latinx caregivers (N = 598) from across the United States collected at the start of the coronavirus pandemic (i.e., May-June 2020) - to describe the broad network of available supports that are used by Latinx caregivers. Using exploratory network analysis, we found that the use of youth psychological counseling, telepsychology, and online support groups was highly influential on support service utilization in the broader network. Specifically, Latinx caregivers who used one or more of these services for their child were more likely to report utilizing other related sources of support. We also identified five support clusters within the larger network that were interconnected through specific sources of support (i.e., outpatient counseling, crisis, religious, informal, and non-specialty). Findings offer a foundational look at the complex system of youth supports available to Latinx caregivers, highlighting areas for future study, opportunities to advance the implementation of evidence-based interventions, and channels through which to disseminate information about available services.

A diagnostic challenge: chronic cutaneous ulcers as an isolated clinical finding in metastatic Crohn's disease.

Metastasic Crohn disease (MCD) is the most uncommon cutaneous manifestation of Crohn disease. The actual incidence is not clear. There are fewer than 200 cases described in the literature. We report a case of 21 years-old girl that came to our emergency care with large exudative ulcers in the inguinal folds, the vulva, the perianal region and the popliteal fossae. Histopathological examination of the ulcers revealed a non-caseating granulomatous inflammation with abundant multinucleated giant cells and intense lymphocytic infiltrate. Colonoscopy, contrast study of the small bowel and video capsule endoscopy were carried out without evidence of digestive disease. High potency topical steroids (betamethasone 0,5mg/gr twice daily) and 300mg intravenous Infliximab were initiated as the initial line therapy and the ulcers began to heal. We report this case to highlight the presence of cutaneous ulcers without intestinal disease in a young non-pediatric woman as the unique manifestation of the disease.

Predictors of Functional Outcome After Thrombectomy in Patients With Prestroke Disability in Clinical Practice.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) in ischemic stroke patients with poor prestroke conditions remains controversial. We aimed to analyze the frequency of previously disabled patients treated with MT in clinical practice, the safety and clinical response to MT of patients with preexisting disability, and the disabled patient characteristics associated with a better response to MT. METHODS: We studied all consecutive patients with anterior circulation occlusion treated with MT from January 2017 to December 2019 included in the Codi Ictus Catalunya registry-a government-mandated, prospective, hospital-based data set. Prestroke disability was defined as modified Rankin Scale score 2 or 3. Functional outcome at 90 days was centrally assessed by a blinded evaluator of the Catalan Stroke Program. Favorable outcome (to return at least to prestroke modified Rankin Scale at 90 days) and safety and secondary outcomes were compared with patients without previous disability. Logistic regression analysis was used to assess the association between prestroke disability and outcomes and to identify a disabled patient profile with favorable outcome after MT. RESULTS: Of 2487 patients included in the study, 409 (17.1%) had prestroke disability (313 modified Rankin Scale score 2 and 96 modified Rankin Scale score 3). After adjustment for covariates, prestroke disability was not associated with a lower chance of achieving favorable outcome at 90 days (24% versus 30%; odds ratio, 0.79 [0.57-1.08]), whereas it was independently associated with a higher risk of symptomatic intracranial hemorrhage (5% versus 3%; odds ratio, 2.04 [1.11-3.72]) and long-term mortality (31% versus 18%; odds ratio, 1.74 [1.27-2.39]) compared with patients without disability. Prestroke disabled patients without diabetes, Alberta Stroke Program Early CT Score >8 and National Institutes of Health Stroke Scale score <17 showed similar safety and outcome results after MT as patients without prestroke disability. CONCLUSIONS: Despite a higher mortality and risk of symptomatic intracranial hemorrhage, prestroke-disabled patients return as often as independent patients to their prestroke level of function, especially those nondiabetic patients with favorable early ischemic signs profile. These data support a potential benefit of MT in patients with previous mild or moderate disability after large anterior vessel occlusion stroke.

Targeting the interaction of ß-catenin and TCF/LEF transcription factors to inhibit oncogenic Wnt signaling.

The Wnt/ß-catenin signaling pathway is crucially involved in embryonic development, stem cell maintenance and tissue renewal. Hyperactivation of this pathway is associated with the development and progression of various types of cancers. The transcriptional coactivator ß-catenin represents a pivotal component of the pathway and its interaction with transcription factors of the TCF/LEF family is central to pathway activation. Inhibition of this crucial protein-protein interaction via direct targeting of ß-catenin is considered a promising strategy for the inactivation of oncogenic Wnt signaling. This review summarizes advances in the development of Wnt antagonists that have been shown to directly bind ß-catenin.

Long-term taurine administration improves motor skills in a tubulinopathy rat model by decreasing oxidative stress and promoting myelination.

The taiep rat undergoes hypomyelination and progressive demyelination caused by an abnormal microtubule accumulation in oligodendrocytes, which elicits neuroinflammation and motor behavior dysfunction. Based on taurine antioxidant and proliferative actions, this work explored whether its sustained administration from the embryonic age to adulthood could prevent neuroinflammation, stimulate cell proliferation, promote myelination, and relieve motor impairment. Taurine (50 mg/L of drinking water = 50 ppm) was given to taiep pregnant rats on gestational day 15 and afterward to the male offspring until eight months of age. We measured the levels of nitric oxide (NO), malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA), CXCL1, CXCR2 receptor, growth factors (BNDF and FGF2), cell proliferation, and myelin content over time. Integral motor behavior was also evaluated. Our results showed that taurine administration significantly decreased NO and MDA + 4-HDA levels, increased cell proliferation, and promoted myelination in an age- and brain region-dependent fashion compared with untreated taiep rats. Taurine effect on chemokines and growth factors was also variable. Taurine improved vestibular reflexes and limb muscular strength in perinatal rats and fine movements and immobility episodes in adult rats. These results show that chronic taurine administration partially alleviates the taiep neuropathology.

The Potential Impact of Neuroimaging and Translational Research on the Clinical Management of Lacunar Stroke.

Lacunar infarcts represent one of the most frequent subtypes of ischemic strokes and may represent the first recognizable manifestation of a progressive disease of the small perforating arteries, capillaries, and venules of the brain, defined as cerebral small vessel disease. The pathophysiological mechanisms leading to a perforating artery occlusion are multiple and still not completely defined, due to spatial resolution issues in neuroimaging, sparsity of pathological studies, and lack of valid experimental models. Recent advances in the endovascular treatment of large vessel occlusion may have diverted attention from the management of patients with small vessel occlusions, often excluded from clinical trials of acute therapy and secondary prevention. However, patients with a lacunar stroke benefit from early diagnosis, reperfusion therapy, and secondary prevention measures. In addition, there are new developments in the knowledge of this entity that suggest potential benefits of thrombolysis in an extended time window in selected patients, as well as novel therapeutic approaches targeting different pathophysiological mechanisms involved in small vessel disease. This review offers a comprehensive update in lacunar stroke pathophysiology and clinical perspective for managing lacunar strokes, in light of the latest insights from imaging and translational studies.

Patterns of Child Mental Health Service Utilization Within a Multiple EBP System of Care.

The current study (1) characterizes patterns of mental health service utilization over 8 years among youth who received psychotherapy in the context of a community implementation of multiple evidence-based practices (EBPs), and (2) examined youth-, provider- and service-level predictors of service use patterns. Latent profile analyses were performed on 5,663,930 administrative claims data furnished by the county department of mental health. Multinomial logistic regression with Vermunt's method was used to examine predictors of care patterns. Based on frequency, course, cost, and type of services, three distinct patterns of care were identified: (1) Standard EBP Care (86.3%), (2) Less EBP Care (8.5%), and (3) Repeated/Chronic Care (5.2%). Youth age, ethnicity, primary language, primary diagnosis and secondary diagnosis, provider language and provider type, and caregiver involvement and service setting were significant predictors of utilization patterns. Although the majority of youth received care aligned with common child EBP protocols, a significant portion of youth (13.7%) received no evidence-based care or repeated, costly episodes of care. Findings highlight opportunities to improve and optimize services, particularly for youth who are adolescents or transition-aged, Asian-American/Pacific Islander, Spanish-speaking, or presenting with comorbidities.

Controlling Antibacterial Activity Exclusively with Visible Light: Introducing a Tetra-ortho-Chloro-Azobenzene Amino Acid.

The introduction of a novel tetra-ortho-chloroazobenzene amino acid (CEBA) has enabled photoswitching of the antimicrobial activity of tyrocidine A analogues by using exclusively visible light, granting spatiotemporal control under benign conditions. Compounds bearing this photoswitchable amino acid become active upon irradiation with red light, but quickly turn-off upon exposure to other visible light wavelengths. Critically, sunlight quickly triggers isomerisation of the red light-activated compounds into their original trans form, offering an ideal platform for self-deactivation upon release into the environment. Linear analogues of tyrocidine A were found to provide the best photocontrol of their antimicrobial activity, leading to compounds active against Acinetobacter baumannii upon isomerisation. Exploration of their N- and C-termini has provided insights into key elements of their structure and has allowed obtaining new antimicrobials displaying excellent strain selectivity and photocontrol.

Stroke etiologies in patients with COVID-19: the SVIN COVID-19 multinational registry.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) is associated with a small but clinically significant risk of stroke, the cause of which is frequently cryptogenic. In a large multinational cohort of consecutive COVID-19 patients with stroke, we evaluated clinical predictors of cryptogenic stroke, short-term functional outcomes and in-hospital mortality among patients according to stroke etiology. METHODS: We explored clinical characteristics and short-term outcomes of consecutively evaluated patients 18 years of age or older with acute ischemic stroke (AIS) and laboratory-confirmed COVID-19 from 31 hospitals in 4 countries (3/1/20-6/16/20). RESULTS: Of the 14.483 laboratory-confirmed patients with COVID-19, 156 (1.1%) were diagnosed with AIS. Sixty-one (39.4%) were female, 84 (67.2%) white, and 88 (61.5%) were between 60 and 79 years of age. The most frequently reported etiology of AIS was cryptogenic (55/129, 42.6%), which was associated with significantly higher white blood cell count, c-reactive protein, and D-dimer levels than non-cryptogenic AIS patients (p