Cystic fibrosis has seen a multitude of therapeutic advances targeting its downstream effects. This has led to a steady increase in survival over the past few decades. The recent development of disease-modifying drugs targeting the underlying CFTR mutation has revolutionized treatment for CF. Despite these advances, individuals with CF who are racial and ethnic minorities, from low socioeconomic status, or female sex have worse clinical outcomes. The inequitable access to CFTR modulators from cost and/or genetic eligibility has the potential to further worsen the existing health disparities seen within the CF community.

Non-invasive sensory stimulation in the range of the brain’s gamma rhythm (30-100 Hz) is emerging as a new potential therapeutic strategy for the treatment of Alzheimer’s disease (AD). Here we investigated the effect of repeated combined exposure to 40 Hz synchronized sound and light stimuli on hippocampal long-term potentiation (LTP) in vivo in three rat models of early AD. We employed a very complete model of AD amyloidosis, amyloid precursor protein (APP)-overexpressing transgenic McGill-R-Thy1-APP rats at an early pre-plaque stage, systemic treatment of transgenic APP rats with corticosterone modelling certain environmental AD risk factors and, importantly, intracerebral injection of highly disease-relevant AD patient-derived synaptotoxic beta-amyloid and tau in wild-type animals. We found that daily sessions of 40 Hz sensory stimulation fully abrogated the inhibition of LTP in all three models. Moreover, there was a negative correlation between the magnitude of LTP and the level of active caspase-1 in the hippocampus of transgenic APP animals which suggests that the beneficial effect of 40 Hz stimulation was dependent on modulation of pro-inflammatory mechanisms. Our findings support ongoing clinical trials of gamma-patterned sensory stimulation in early AD.

Safety of Biologicals In Severe Asthma Patients Having COVID-19Running title: COVID-19, biologicals and severe asthma

As implantable medical electronics (IMEs) developed for healthcare monitoring and biomedical therapy are extensively explored and deployed clinically, the demand for non-invasive implantable biomedical electronics is rapidly surging. Current rigid and bulky implantable microelectronic power sources are prone to immune rejection and incision, or cannot provide enough energy for long-term use, which greatly limits the development of implantable medical devices. Herein, a comprehensive review of the historical development of IMEs and the applicable miniaturised power sources along with advantages and limitations is given. Despite recent advances in microfabrication techniques, biocompatible materials have facilitated the development of IMEs system toward non-invasive, ultra-flexible, bioresorbable, wireless and multifunctional, progress in the development of minimally invasive power sources in implantable systems has remained limited. Here we summarise three promising minimally invasive power sources, including energy storage devices (biodegradable primary batteries, rechargeable batteries and supercapacitors), human body energy harvesters (nanogenerators and biofuel cells) and wireless power transfer (far-field radiofrequency radiation, near-field wireless power, ultrasonic and photovoltaic power). The energy storage and harvesting mechanism, configurational design, output power and applications in vivo are discussed. It is expected to give a comprehensive understanding of the IMEs for painless health monitoring and biomedical therapy with long-term stable function

By employing thiazole and 4-chlorothiazole as the A′ units, two A-D-A′-D-A type nonfused-ring electron acceptors (NFREAs) Tz-H and Tz-Cl were designed and synthesized. Replacing thiazole in Tz-H with 4-chlorothiazole can not only remarkably shorten the synthetic route through C-H direct arylation but also enhance molecular planarity with the simultaneous incorporation of S···N and S···Cl non-covalently conformational locks (NoCLs). The photovoltaic devices based on PM6:Tz-Cl exhibited a power conversion efficiency as high as 11.10%, much higher than that of PM6:Tz-H (6.41%), mainly due to more efficient exciton dissociation, better and more balanced carrier mobility, less charge recombination, and more favorable morphology. These findings demonstrate the great potential of NoCLs in achieving low-cost and high-performance NFREAs.

The utilization of cyclobutanones as the synthon in transition metal catalysis has been made great success. Because C(carbonyl)−C bond of cyclobutanones can be cleaved through strain release. Despite those advancements, the main catalysts in literature are Rh catalysts or Ni catalysts and the reaction with C–H bond is still underdeveloped. Herein, we realized the first palladium-catalyzed skeletal reorganisation of cyclobutanones invoving successive cleavage of C(carbonyl)−C bonds and C−H bond cleavage, which con-stitutes an rapid access to diverse indanones.

Ephemeral gully erosion is a primary mode of soil erosion that is highly visible, affecting soil productivity and restricting land use. Watershed is the basic unit of soil erosion control; existing research has focused on several typical ephemeral gullies or slopes, which do not fully display changes in ephemeral gullies at a watershed scale. This study analyzed the spatial-temporal evolution and development rate of ephemeral gully erosion at the watershed scale on the Loess Plateau from 2009 to 2021 using remote sensing images (0.5 m resolution), unmanned aerial vehicles (UAV), and field investigations. The results revealed that: (1) most ephemeral gullies occurred in southwestern parts of the watershed, with many hills and large slope gradients; (2) average growth rates of each ephemeral gully frequency, length, density, dissection degree, and width were 2.87 km 2 y –1, 1.66 m y –1, 0.12 km km –2 y –1, 0.0125% y –1, and 0.04 m y –1 , respectively; (3) ephemeral gully erosion volume ( V) and length ( L) had a good power function relationship: V = 0 . 0842 L 1 . 1932   ( R 2 = 0 . 80 ) . The root mean square error (RMSE) and coefficient of determination (R 2) between the measured and predicted ephemeral gully volumes suggest that the V–L relationship has a good predictive ability for ephemeral gully volume. Thus, the V–L model was used to evaluate the development rate of ephemeral gully erosion volume in small watersheds from 2009 to 2021, revealing an average value of 743.20 m 3 y –1. This study proposed a feasible model for assessing ephemeral gully volume and volume changes at a watershed scale using high-resolution remote sensing images, providing a reference for understanding the development of ephemeral gully erosion in small watersheds over time.

Spatial isolation is a key driver of population-level variability in traits and genotypes worldwide. Geographical distance between populations typically increases isolation, but organisms face additional environmental barriers when dispersing between suitable habitat patches. Despite the predicted universal nature of the causes of isolation, global comparisons of isolation effects across taxa and geographic systems are few. We assessed the strength of isolation due to geographic and macroclimatic distance for paired marine island and paired mainland populations within the same species. Our meta-analysis included published measurements of phenotypic traits and neutral genetic diversity from 1832 populations of 112 plant and animal species at a global scale. As expected, phenotypic differentiation was higher between marine islands than between populations on the mainland, but spatial patterns of neutral genetic diversity did not vary between the two systems. Geographic distance had comparatively weak effects on the spatial patterns of phenotypes and neutral genetic diversity, but only phenotypic trait variability showed signal of system-dependence. These results suggest that spatial patterns of phenotypic variation are determined by system-dependent eco-evolutionary pressures, while the spatial variability of neutral genetic diversity might be universal. Our approach demonstrates that global biodiversity models that include island biology studies may progress our understanding of the interacting effects of spatial habitat structure, geographic- and environmental distances on biological processes underlying spatial population variability. We formulate future research directions for empirical tests and global syntheses in the field.

Nowadays, Z-source inverter has received several attentions compared to the other power converters owing to its simplicity and reliability. In this paper, a refine control methodology of capacitor voltage control is presented based on third-order small signal analysis. The proposed control is applied to the improved switched inductor Z-Source inverter (ISL ZSI). Proportional, integral and derivative controller (PID) is adopted due to its capability to operate with large operation levels , reliable operation, and cheaper in implementation. In addition, the function of this control can be achieved even with incomplete system data or parameters variations. ISL-ZSI has been presented because of its advantages such as the high gain of DC voltage, low voltage stress for both the Z-network and the inverter bridge switches and ensure good soft starting. in addition, the inrush current has been removed based on its configuration. The proposed control is validated by both experimental and simulation results under input voltage change, load change, and steady state operations using DSP F28335 and MATLAB SIMULINK Real-Time Workspace (RTW).

A method using questionnaire data for estimating the level of under reporting during an outbreak is presented. It is based on rewriting the conditional probabilities for getting tested, being infected, and having symptoms. It shows very good agreement with seroprevalence studies of blood donors. On the one hand, this shows the strength of questionnaires when testing the general population during an outbreak as a means to find the true prevalence. On the other, applying it to covid-19 demonstrates that the asymptomatic cases likely make up around 50% of the infected.

A 31-year-old man with fever, dyspnea, abdominal pain, and jaundice has been admitted to the hospital in the southeast of Iran. Due to the presence of a pathognomonic skin lesion (Tache noire), the patient was diagnosed with Mediterranean spotted fever (MSF) and was treated with doxycycline.

A 66-year-old breast ductal carcinoma patient developed obstructive jaundice, presenting with epigastric discomfort and dark-colored urine. Contrast-enhanced computed tomography and endoscopic retrograde cholangiopancreatography revealed bile duct stenosis. Brushing cytology and tissue biopsy confirmed bile duct metastasis, and a self-expandable metallic stent was placed/replaced endoscopically, extending the patient’s life.

The catchment approach has been traditionally limited to small, experimental catchments where water fluxes can be determined with high accuracy. However, larger catchments where landscape management occurs have emergent drivers of streamflow at scale, and thus may exhibit novel responses to land cover disturbance. We used statistical models of water yield and annual maximum peak streamflow for multiple forested catchments in the low-relief glaciated region of central North America to investigate how forest disturbance may affect water yield and peak flows in similar landscapes. We utilized linear models, linear mixed effects models, and probabilistic flood-frequency analysis, with Bayesian parameter estimation in two case studies in Minnesota, USA: 1) a wildfire comprising ~30% of a 650km 2 wilderness Upper Kawishiwi catchment, and 2) 11 catchments within the St. Louis River Basin ranging from 56 to 8,880 km 2 with a patchwork disturbance regime wherein ~0.25% to 1% of the catchment is harvested or converted to non-forest land use each year. We also assessed for the most likely hydrological recovery year after forest disturbance, and the relative importance of stationary and nonstationary drivers of streamflow. We found forest disturbance correlated with declines in water yield for low-level disturbance regimes, but that water yield increased in response to the large-scale wildfire. Positive and negative associations of forest disturbance with peak flows were observed, generally with low confidence. Hydrologic recovery time ranged from 5 to 12 years for water yield and peak flows following disturbance. Despite these effects of forest disturbance on streamflow, effects of climate variability and stationary catchment size factors were more prominent drivers of streamflow. Basins larger than ~50 km 2 in low-relief glaciated regions were resilient to forest cover change when it comprised <30% of basin area, but climate change may have a larger effect than could be mitigated by land management.

Disseminated Fungal Disease Caused by Magnusiomyces clavatus in a Pediatric Cancer Patient: First Case Report in North America and Review of the LiteraturePaul G. Mitchell MD 1, Bill H. Chang MD, PhD2, Lorne W. Walker MD, PhD3

Active engagement improves learning and memory, and self- vs. externally generated stimuli are processed differently: perceptual intensity and neural responses are attenuated. Whether the attenuation is linked to memory formation remains to be understood. This study investigates whether active oculomotor control over auditory stimuli – controlling for movement and stimulus predictability – benefits associative learning, and studies the underlying neural mechanisms. Using EEG and eyetracking we explored the impact of control during learning on the processing and memory recall of arbitrary oculomotor-auditory associations. Participants (N=23) learned associations through active exploration or passive observation, using a gaze-controlled interface to generate sounds. Our results show faster learning progress in the active condition. ERPs time-locked to the onset of sound stimuli showed that learning progress was linked to an attenuation of the P3a component. The detection of matching movement-sound pairs triggered a target-matching P3b response. There was no general modulation of ERPs through active learning. However, participants could be divided into different learner types: those who benefited strongly from active control during learning and those who did not. The strength of the N1 attenuation effect for self-generated stimuli was correlated with memory gain in active learning. Our results show that control helps learning and memory and modulates sensory responses. Individual differences during sensory processing predict the strength of the memory benefit. Taken together, these results help to disentangle the effects of agency, unspecific motor-based neuromodulation, and stimulus predictability on ERP components and establish a link between self-generation effects and active learning memory gain.

The use of adeno-associated viruses (AAV) as vectors for gene and cell therapy has risen considerably in recent years. Consequently, the amount of AAV vectors required during the validation and clinical trials has also increased. AAV serotype 6 (AAV6) is well-documented for its efficiency in transducing different cell types and has been successfully used in gene and cell therapy protocols. However, the number of vectors required to effectively deliver the transgene to one single cell has been estimated at 106 viral genomes (VG). Overall, this means that large-scale production of AAV6 is needed. Suspension cell-based platforms are currently limited to low-cell-density productions, hindering the potential of this production process to increase yields. Here, we investigate the improvement of the production of AAV6 at higher cell densities. The production was performed by transient transfection of HEK293SF cells. When the plasmid DNA is provided on a cell basis, the production can be carried out at medium cell density without effects on cell-specific titer or particle functionality, resulting in titers above 1010 VG/mL. Medium supplementation alleviated the cell density effect, in terms of VG/cell, at high-cell-density productions. On the other hand, the cell-specific functional titer was not maintained, and further studies are necessary to understand the observed limitations. The medium-cell-density production method reported here lays the foundation for large-scale process operations, potentially solving the current vector shortage in AAV manufacturing.

Model organisms such as the Gram-positive bacterium Bacillus subtilis have been studied intensively for decades. However, even for such model organisms no function has been identified for about one fourth of all proteins. It has recently been realized that such understudied proteins as well as poorly studied functions set a limitation to our understanding of the requirements for cellular life, and the Understudied Proteins Initiative has been launched. Obviously, poorly studied proteins that are strongly expressed, are likely to be most important to the cell and should therefore have priority in further studies. Since the functional analysis of unknown proteins can be extremely laborious, a minimal knowledge is required prior to targeted functional studies. In this review, we discuss strategies to obtain such a minimal annotation, e.g. from global interaction, expression or localization studies. We present a set of 41 highly expressed and poorly studied proteins of B. subtilis. Several of these proteins are thought or known to bind RNA and/or the ribosome, some may may control the metabolism of B. subtilis, and another subset of particularly small proteins may act as regulatory elements to control the expression of downstream genes. Moreover, we discuss the challenges of poorly studied functions with a focus on RNA-binding proteins, amino acid transport and the control of metabolic homeostasis. The identification of the functions of the selected proteins will strongly advance our knowledge on B. subtilis, but also on other organisms since many of the proteins are conserved in many groups of bacteria.

Title: Developing and testing complex behaviour change interventions to support proactive deprescribingRunning title: Behaviour change and deprescribing