Exceptional electronic transport and quantum oscillations in thin bismuth crystals grown inside van der Waals materials.

Confining materials to two-dimensional forms changes the behaviour of the electrons and enables the creation of new devices. However, most materials are challenging to produce as uniform, thin crystals. Here we present a synthesis approach where thin crystals are grown in a nanoscale mould defined by atomically flat van der Waals (vdW) materials. By heating and compressing bismuth in a vdW mould made of hexagonal boron nitride, we grow ultraflat bismuth crystals less than 10 nm thick. Due to quantum confinement, the bismuth bulk states are gapped, isolating intrinsic Rashba surface states for transport studies. The vdW-moulded bismuth shows exceptional electronic transport, enabling the observation of Shubnikov-de Haas quantum oscillations originating from the (111) surface state Landau levels. By measuring the gate-dependent magnetoresistance, we observe multi-carrier quantum oscillations and Landau level splitting, with features originating from both the top and bottom surfaces. Our vdW mould growth technique establishes a platform for electronic studies and control of bismuth's Rashba surface states and topological boundary modes1-3. Beyond bismuth, the vdW-moulding approach provides a low-cost way to synthesize ultrathin crystals and directly integrate them into a vdW heterostructure.

Mind-Body Interventions for Youth with Chronic Medical Conditions: A Scoping Review of the Literature.

Background and purpose: Little is known about the applicability, utilization, and effectiveness of mind-body interventions (MBIs) for conditions that are not predominantly pain, neoplastic, or psychiatric, particularly in pediatric patients. This scoping review describes research pertaining to such interventions in youth with nonpain, noncancer, and nonpsychiatric predominant chronic medical conditions. Methods: Searches of EBSCO CINAHL, Elsevier Scopus, Ovid for MEDLINE, and Ovid PsycInfo were conducted to investigate MBIs in youth under 18 years of age with nonpain, noncancer, and nonpsychiatric predominant chronic medical conditions. Articles published between 2010 and 2020 were included. Abstracts were screened by three authors for inclusion, and disagreements were resolved by a designated author. Selected full-text articles were divided among all authors for review of study quality, intervention feasibility and acceptability, and effectiveness. Results: The search yielded 1010 titles with 15 meeting the final inclusion criteria, studying a total of 641 youth. Participants ranged in age from 6 to 19 years (included studies had data on participants <18 years reported separately); 61.5% were female (n = 394) and 38.5% were male (n = 247). The two most common conditions studied were asthma and irritable bowel syndrome, with yoga being the most popular intervention. Overall, MBIs showed promising preliminary evidence for improving symptoms and quality of life in youth with chronic medical conditions. Conclusion: MBIs have been successfully delivered and show promise in symptom palliation and quality of life improvement for youth with a variety of chronic medical conditions. More data from high-quality randomized controlled trials are needed to further characterize the effectiveness of specific modalities for specific conditions.

Insufflation via a peritoneal dialysis catheter is a safe way to achieve pneumoperitoneum: a case report.

A 66-year-old female with a preoperative high index hostile abdomen was incidentally found to have a right T1a 16 mm renal cell carcinoma mass. She safely underwent robot assisted partial nephrectomy after her peritoneal dialysis catheter was alternatively used for insufflation. This adjustment in technique reduced risk related morbidity and possible conversion to open laparotomy.

Multifaceted roles and regulation of nucleotide-binding oligomerization domain containing proteins.

Nucleotide-binding oligomerization domain-containing proteins, NOD1 and NOD2, are cytosolic receptors that recognize dipeptides and tripeptides derived from the bacterial cell wall component peptidoglycan (PGN). During the past two decades, studies have revealed several roles for NODs beyond detecting PGN fragments, including activation of an innate immune anti-viral response, NOD-mediated autophagy, and ER stress induced inflammation. Recent studies have also clarified the dynamic regulation of NODs at cellular membranes to generate specific and balanced immune responses. This review will describe how NOD1 and NOD2 detect microbes and cellular stress and detail the molecular mechanisms that regulate activation and signaling while highlighting new evidence and the impact on inflammatory disease pathogenesis.

Ruptured Appendicitis Within an Intussusception on Point-of-Care Ultrasound.

ABSTRACT: This case describes a 21-month-old girl who was transferred to our pediatric emergency department with daily fevers for 9 days and concern for intussusception on an ultrasound obtained at the outside hospital. Her examination was notable for diffuse tenderness to palpation with no rebound or guarding. Point-of-care-ultrasound (POCUS) revealed a noncompressible, target-shaped structure in the right midabdomen, which appeared to contain a dilated loop of bowel surrounded by a hypoechoic fluid collection. This was confirmed by radiology-performed ultrasound and computed tomography scan, which showed an ileocolic intussusception containing a dilated echogenic loop of bowel consistent with perforated acute appendicitis and associated abscess with surrounding inflammatory changes. To our knowledge, this is the first reported case of perforated appendicitis within an intussusception identified on POCUS in a pediatric patient. This case demonstrates the utility of POCUS in facilitating the recognition of an atypical diagnosis of a perforated appendicitis contained within an intussusception and helping to guide further evaluation and management.

Modified stepping behaviour during outdoor winter walking increases resistance to forward losses of stability.

Healthy humans are proficient at maintaining stability when faced with diverse walking conditions, however, the control strategies that lead to this proficiency are unclear. Previous laboratory-based research has predominantly concluded that corrective stepping is the main strategy, but whether this finding holds when facing everyday obstacles outside of the laboratory is uncertain. We investigated changes in gait stability behaviour when walking outdoors in the summer and winter, hypothesizing that as ground conditions worsened in the winter, the stepping strategy would be hindered. Stability would then be maintained through compensatory strategies such as with ankle torques and trunk rotation. Data was collected in the summer and winter using inertial measurement units to collect kinematics and instrumented insoles to collect vertical ground reaction forces. Using the goodness of fit for a multivariate regression between the centre of mass state and foot placement we found that, counter to our hypothesis, stepping was not hindered by winter conditions. Instead, the stepping strategy was modified to increase the anterior-posterior margin of stability, increasing the resistance to a forward loss of stability. With stepping being unhindered, we did not observe any additional compensation from the ankle or trunk strategies.

A comprehensive survey of coronaviral main protease active site diversity in 3D: Identifying and analyzing drug discovery targets in search of broad specificity inhibitors for the next coronavirus pandemic.

Although the rapid development of therapeutic responses to combat SARS-CoV-2 represents a great human achievement, it also demonstrates untapped potential for advanced pandemic preparedness. Cross-species efficacy against multiple human coronaviruses by the main protease (MPro) inhibitor nirmatrelvir raises the question of its breadth of inhibition and our preparedness against future coronaviral threats. Herein, we describe sequence and structural analyses of 346 unique MPro enzymes from all coronaviruses represented in the NCBI Virus database. Cognate substrates of these representative proteases were inferred from their polyprotein sequences. We clustered MPro sequences based on sequence identity and AlphaFold2-predicted structures, showing approximate correspondence with known viral subspecies. Predicted structures of five representative MPros bound to their inferred cognate substrates showed high conservation in protease:substrate interaction modes, with some notable differences. Yeast-based proteolysis assays of the five representatives were able to confirm activity of three on inferred cognate substrates, and demonstrated that of the three, only one was effectively inhibited by nirmatrelvir. Our findings suggest that comprehensive preparedness against future potential coronaviral threats will require continued inhibitor development. Our methods may be applied to candidate coronaviral MPro inhibitors to evaluate in advance the breadth of their inhibition and identify target coronaviruses potentially meriting advanced development of alternative countermeasures.

Validation of Inertial Sensors to Evaluate Gait Stability.

The portability of wearable inertial sensors makes them particularly suitable for measuring gait in real-world walking situations. However, it is unclear how well inertial sensors can measure and evaluate gait stability compared to traditional laboratory-based optical motion capture. This study investigated whether an inertial sensor-based motion-capture suit could accurately assess gait stability. Healthy adult participants were asked to walk normally, with eyes closed, with approximately twice their normal step width, and in tandem. Their motion was simultaneously measured by inertial measurement units (IMU) and optical motion capture (Optical). Gait stability was assessed by calculating the margin of stability (MoS), short-term Lyapunov exponents, and step variability, along with basic gait parameters, using each system. We found that IMUs were able to detect the same differences among conditions as Optical for all but one of the measures. Bland-Altman and intraclass correlation (ICC) analysis demonstrated that mediolateral parameters (step width and mediolateral MoS) were measured less accurately by IMUs compared to their anterior-posterior equivalents (step length and anterior-posterior MoS). Our results demonstrate that IMUs can be used to evaluate gait stability through detecting changes in stability-related measures, but that the magnitudes of these measures might not be accurate or reliable, especially in the mediolateral direction.

Telemedicine use among patients with metastatic breast cancer during the COVID-19 pandemic: Differences by race, age, and region.

PURPOSE: Our objective was to describe differences in telemedicine use among women with metastatic breast cancer (mBC) by race, age, and geographic region. METHODS: This was a retrospective cohort study of women with recurrent or de novo mBC treated in US community cancer practices that initiated a new line of therapy between March 2020 and February 2021. Multivariable modified Poisson regression models were used to calculate adjusted rate ratios (RR) and robust 95% confidence intervals (CI) associated with telemedicine visits within 90 days of therapy initiation. RESULTS: Overall, among 3412 women with mBC, 751 (22%) patients had telemedicine visits following therapy initiation, with lower risks observed among older women (<50 years: 24%; 50-64 years: 22%; 65-74 years: 21%; ≥75 years: 20%). Greater telemedicine use was observed among Asian women (35%) compared to White (21%), Black (18%), and Hispanic (21%) women. Fewer telemedicine visits occurred in Southern (12%) and Midwestern (17%) states versus Northeastern (37%) or Western (36%) states. In multivariable models, women ages ≥75 years had significantly lower risks of telemedicine visits (RR = 0.76, 95% CI 0.62-0.95) compared to ages <50 years. Compared to patients in Northeastern states, women in Midwestern (RR = 0.46, 95% CI 0.37-0.57) and Southern (RR = 0.31, 95% CI 0.26-0.37) states had significantly lower risks of telemedicine visits; but not women in Western states (RR = 0.96, 95% CI 0.83-1.12). No statistically significant differences in telemedicine use were found between racial groups in overall multivariable models. CONCLUSIONS: In this study of community cancer practices, older mBC patients and those living in Southern and Midwestern states were less likely to have telemedicine visits. Preferences for communication and delivery of care may have implications for measurement of exposures and endpoints in pharmacoepidemiologic studies of cancer patients.

Hormetic effect of an Ethanolic Graviola Leaf Extract on HGF-1 cells survival.

Plant-extracted compounds have been used for centuries in traditional pharmacopeia. Some of them have proven to be excellent drug alternatives for cancer treatment as they target metabolic pathways that are key to cancer cells such as apoptosis, energy-producing catabolic pathways, and the response to oxidative stress. Since some anticancer drugs have been shown to produce dose dependent biologically opposite effects, it is crucial to determine the range of doses for which the compounds have maximum therapeutic benefits. Annona muricata or Graviola is a tropical tree that is common in the Puerto Rican landscape. Although a plethora of studies conducted in vitro and in vivo studies have indeed reported that extracts prepared from the Graviola root, fruit, bark, and leaves possess antiproliferative activities in a large variety of cancer cells, the efficiency of Graviola extracts to curb the progression of head and neck cancers has been overlooked. Furthermore, the bioactivity of Graviola extracts on sane/non-cancerous cells has largely been ignored. The present work reports the in vitro antiproliferative/anticancer behavior of an ethanolic Graviola leaf extract on squamous cell carcinoma cell lines 9 and 25 vs. a sane/non-cancerous human gingival fibroblast cell line-1. Our results show that the Graviola extract induces cell death in the squamous cell carcinoma cell lines at all concentrations tested and a dose-dependent biphasic concentration-dependent/hormetic effect on the fibroblastic cells. This suggests that, at low doses, the phytochemicals present in the prepared Graviola extract could offer potential therapeutic avenues for curbing the progression of head and neck cancers.

Human biomechanics perspective on robotics for gait assistance: challenges and potential solutions.

Technological advancements in robotic devices have the potential to transform human mobility through gait assistance. However, the integration of physical hardware and software control algorithms with users to assist with impaired gait poses several challenges, such as allowing the user to adopt a variety of gaits and the process for evaluating the efficacy and performance of these assistive devices. Here, I discuss some of the challenges in the development of assistive devices and the use of biomechanical concepts and tools for control and test validation. Several potential solutions are proposed through the case study of one project that aimed to provide gait assistance for individuals with a spinal cord injury. Further challenges and future directions are discussed, with emphasis that diverse perspectives and approaches in gait assistance will accelerate engineering solutions towards regaining mobility.

Learning from and Leveraging Multi-Level Changes in Responses to the COVID 19 Pandemic to Facilitate Breast Cancer Prevention Efforts.

The coronavirus pandemic (COVID-19) has had multilevel effects on non-COVID-19 health and health care, including deferral of routine cancer prevention and screening and delays in surgical and other procedures. Health and health care use has also been affected by pandemic-related loss of employer-based health insurance, food and housing disruptions, and heightened stress, sleep disruptions and social isolation. These disruptions are projected to contribute to excess non-COVID-19 deaths over the coming decades. At the same time municipalities, health systems and individuals are making changes in response to the pandemic, including modifications in the environmental to promote health, implementation of telehealth platforms, and shifts towards greater self-care and using remote platforms to maintain social connections. We used a multi-level biopsychosocial model to examine the available literature on the relationship between COVID-19-related changes and breast cancer prevention to identify current gaps in knowledge and identify potential opportunities for future research. We found that COVID-19 has impacted several aspects of social and economic life, through a variety of mechanisms, including unemployment, changes in health care delivery, changes in eating and activity, and changes in mental health. Some of these changes should be reduced, while others should be explored and enhanced.

Anoctamin 1 antagonism potentiates conventional tocolytic-mediated relaxation of pregnant human uterine smooth muscle.

BACKGROUND: Currently available tocolytic agents are not effective treatment for preterm labor beyond 48 h. A major reason is the development of maternal side effects which preclude the maintenance of an effective steady-state drug concentration. One strategy that can mitigate these side effects is utilizing synergistic drug combinations to reduce the drug concentrations necessary to elicit a clinical effect. We have previously shown that three anoctamin 1 (ANO1) antagonists mediate potent relaxation of precontracted human uterine smooth muscle (USM). In this study, we aimed to determine whether a combination of sub-relaxatory doses of tocolytic drugs in current clinical use [the L-type voltage-gated calcium channel (VGCC) blocker, nifedipine (NIF); and the ß2-adrenergic (ß2AR) agonist, terbutaline (TRB)] will potentiate USM relaxation with two ANO1 antagonists [benzbromarone (BB) and MONNA (MN)]. OBJECTIVE: This study sought to examine the synergistic potency and mechanistic basis of two ANO1 antagonists with currently available tocolytic drugs. Functional endpoints assessed included relaxation of pre-contracting pregnant human USM tissue, inhibition of intracellular calcium release, and reduction of spontaneous transient inward current (STIC) recordings in human uterine smooth muscle cells. METHODS: Human myometrial strips and primary human USM cells were used in organ bath and calcium flux experiments with different combinations of sub-threshold doses of ANO1 antagonists and terbutaline or nifedipine to determine if ANO1 antagonists potentiate tocolytic drugs. RESULTS: The combination of sub-threshold doses of two ANO1 antagonists and current tocolytic drugs demonstrate a significant degree of synergy to relax human pregnant USM compared to the effects achieved when these drugs are administered individually. CONCLUSION: A combination of sub-threshold doses of VGCC blocker and ß2AR agonist with ANO1 antagonists potentiates relaxation of oxytocin-induced contractility and calcium flux in human USM ex vivo. Our findings may serve as a foundation for novel tocolytic drug combinations.

Light-Mediated Inhibition of Colonic Smooth Muscle Constriction and Colonic Motility via Opsin 3.

Opsin photoreceptors outside of the central nervous system have been shown to mediate smooth muscle photorelaxation in several organs. We hypothesized that opsin receptor activation in the colon would have a similar effect and influence colonic motility. We detected Opsin 3 (OPN3) protein expression in the colonic wall and demonstrated that OPN3 was present in enteric neurons in the muscularis propria of the murine colon. Precontracted murine colon segments demonstrated blue light (BL) -mediated relaxation ex vivo. This photorelaxation was wavelength specific and was increased with the administration of the chromophore 9-cis retinal and a G protein receptor kinase 2 (GRK2) inhibitor. Light-mediated relaxation of the colon was not inhibited by L-NAME or tetrodotoxin (TTX). Furthermore, BL exposure in the presence of 9-cis retinal decreased the frequency of colonic migrating motor complexes (CMMC) in spontaneously contracting mouse colons ex vivo. These results demonstrate for the first time a receptor-mediated photorelaxation of colonic smooth muscle and implicate opsins as possible new targets in the treatment of spasmodic gastrointestinal dysmotility.

Opsin 3-Gαs Promotes Airway Smooth Muscle Relaxation Modulated by G Protein Receptor Kinase 2.

Recently, we characterized blue light-mediated relaxation (photorelaxation) of airway smooth muscle (ASM) and implicated the involvement of opsin 3 (OPN3), an atypical opsin. In the present study, we characterized the cellular signaling mechanisms of photorelaxation. We confirmed the functional role of OPN3 in blue light photorelaxation using trachea from OPN3 null mice (maximal relaxation 52 ± 13% compared with wild-type mice 90 ± 4.3%, P < 0.05). We then demonstrated colocalization of OPN3 and Gαs using co-IP and proximity ligation assays in primary human ASM cells, which was further supported by an increase in cAMP in mouse trachea treated with blue light compared with dark controls (23 ± 3.6 vs. 14 ± 2.6 pmol cAMP/ring, P < 0.05). Downstream PKA (protein kinase A) involvement was shown by inhibiting photorelaxation using Rp-cAMPS (P < 0.0001). Moreover, we observed converging mechanisms of desensitization by chronic ß2-agonist exposure in mouse trachea and correlated this finding with colocalization of OPN3 and GRK2 (G protein receptor kinase) in primary human ASM cells. Finally, an overexpression model of OPN1LW (a red light photoreceptor in the same opsin family) in human ASM cells showed an increase in intracellular cAMP levels following red light exposure compared with nontransfected cells (48 ± 13 vs. 13 ± 2.1 pmol cAMP/mg protein, P < 0.01), suggesting a conserved photorelaxation mechanism for wavelengths of light that are more tissue penetrant. Together, these results demonstrate that blue light photorelaxation in ASM is mediated by the OPN3 receptor interacting with Gαs, which increases cAMP levels, activating PKA and modulated by GRK2.

Upper body and ankle strategies compensate for reduced lateral stability at very slow walking speeds.

At the typical walking speeds of healthy humans, step placement seems to be the primary strategy to maintain gait stability, with ankle torques and upper body momentum providing additional compensation. The average walking speeds of populations with an increased risk of falling, however, are much slower and may require differing control strategies. The purpose of this study was to analyse mediolateral gait stability and the contributions of the different control strategies at very slow walking speeds. We analysed an open dataset including kinematics and kinetics from eight healthy subjects walking at speeds from 0.1 to 0.6 m s-1 as well as a self-selected speed. As gait speed slowed, we found that the margin of stability (MoS) decreased linearly. Increased lateral excursions of the extrapolated centre of mass, caused by increased lateral excursions of the trunk, were not compensated for by an equivalent increase in the lateral centre of pressure, leading to decreased MoS. Additionally, both the ankle eversion torque and hip abduction torque at the minimum MoS event increased at the same rate as gait speed slowed. These results suggest that the contributions of both the ankle and the upper body to stability are more crucial than stepping at slow speeds, which have important implications for populations with slow gait and limited motor function.

Correction to: Activation of an Endogenous Opsin 3 Light Receptor Mediates Photo-Relaxation of Pre-Contracting Late Gestation Human Uterine Smooth Muscle Ex Vivo.

This article was updated to correct Joy Y. Vink's name in the author listing.

A near-infrared probe for non-invasively monitoring cerebrospinal fluid flow by 18F-positron emitting tomography and fluorescence.

PURPOSE: Knowing the precise flow of cerebrospinal fluid (CSF) is important in the management of multiple neurological diseases. Technology for non-invasively quantifying CSF flow would allow for precise localization of injury and assist in evaluating the viability of certain devices placed in the central nervous system (CNS). METHODS: We describe a near-infrared fluorescent dye for accurately monitoring CSF flow by positron emission tomography (PET) and fluorescence. IR-783, a commercially available near-infrared dye, was chemically modified and radiolabeled with fluorine-18 to give [18F]-IR783-AMBF3. [18F]-IR783-AMBF3 was intrathecally injected into the rat models with normal and aberrant CSF flow and evaluated by the fluorescence and PET/MRI or PET/CT imaging modes. RESULTS: IR783-AMBF3 was clearly distributed in CSF-containing volumes by PET and fluorescence. We compared IR783-AMBF3 (fluorescent at 778/793 nm, ex/em) to a shorter-wavelength, fluorescein equivalent (fluorescent at 495/511 nm, ex/em). IR783-AMBF3 was superior for its ability to image through blood (hemorrhage) and for imaging CSF-flow, through-skin, in subdural-run lumboperitoneal shunts. IR783-AMBF3 was safe under the tested dosage both in vitro and in vivo. CONCLUSION: The superior imaging properties of IR783-AMBF3 could lead to enhanced accuracy in the treatment of patients and would assist surgeons in non-invasively diagnosing diseases of the CNS.

A lysosome specific, acidic-pH activated, near-infrared Bodipy fluorescent probe for noninvasive, long-term, in vivo tumor imaging.

Long-term, in vivo, fluorescent cell tracking probes are useful for understanding complex cellular processes including tissue regeneration, communication, development, invasion, and cancer metastasis. A near-infrared fluorescent, water-soluble probe is particularly important for studying these biological events and processes. Herein, a lysosome specific, near-infrared Bodipy probe with increased fluorescent intensity in the acidic, lysosome environment is reported. This Bodipy probe is packaged in a nanoparticle using DSPE-PEG2000. The resulting nanoparticle is intravenously delivered to a tumor xenograft, where the fluorescent Bodipy becomes useful for non-invasive, long-term, in vivo fluorescent tumor imaging for periods greater than 36 days. These long-term, in vitro and in vitro tracking data indicate that the described Bodipy nanoparticles hold great potential for monitoring biological processes.

Activation of an Endogenous Opsin 3 Light Receptor Mediates Photo-Relaxation of Pre-Contracting Late Gestation Human Uterine Smooth Muscle Ex Vivo.

Spontaneous preterm birth (sPTB) remains a worldwide healthcare challenge. Preterm labor (PTL) is thought to be the largest reversible cause of sPTB, but current tocolytic therapies are ineffective and associated with systemic side effects from chronic use. Therefore, identifying novel mechanisms that promote human uterine smooth muscle (hUSM) relaxation is essential to improving clinical management of PTL. Here, we aimed to determine if an extraocular opsin receptor (OPN 3,4,5) system is expressed in pregnant hUSM and to characterize how photo-mediated relaxation of pre-contracting hUSM may be facilitated by external application of light. Translational studies were performed with hUSM from healthy late gestation patients (n = 8) and non-pregnant, similarly aged patients undergoing hysterectomy (n = 4). First, RT-PCR screened for mRNA coding for components of the classical extraocular light receptors (OPN 3,4,5). We found a restricted repertoire of opsin receptors (OPN3) expressed in pregnant hUSM tissue. Immunohistochemistry was performed to confirm protein expression. Pre-contracting late gestation hUSM strips were studied in functional organ bath studies to determine if photo-mediated relaxation is intensity or wavelength dependent. Functional organ bath studies revealed acute photo-mediated relaxation occurring in an intensity- and wavelength-dependent manner. Finally, coimmunoprecipitation of OPN3 with Gs following light activation suggests that a component of photo-relaxation occurs via G protein-coupled receptor machinery. This is the first report of light-mediated relaxation of pre-contracted human myometrium. Activation of endogenous light receptors on human myometrium may become a novel, non-invasive tocolytic strategy.