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Structure-based drug design is highly dependent on the availability of structures of the protein of interest in complex with lead compounds. Ideally, this information can be used to guide the chemical optimization of a compound into a pharmaceutical drug candidate. A limitation of the main structural method used today – conventional X-ray crystallography – is that it only provides structural information about the protein complex in its frozen state. Serial crystallography is a relatively new approach that offers the possibility to study protein structures at room temperature (RT). Here, we explore the use of serial crystallography to determine the structures of the pharmaceutical target, soluble epoxide hydrolase. We introduce a new method to screen for optimal microcrystallization conditions suitable for use in serial crystallography and present a number of RT ligand-bound structures of our target protein. From a comparison between the RT structural data and previously published cryo-temperature structures, we describe an example of a temperature-dependent difference in the ligand-binding mode and observe that flexible loops are better resolved at RT. Finally, we discuss the current limitations and potential future advances of serial crystallography for use within pharmaceutical drug discovery.

Abstract The complex neuromuscular network that controls body movements is the target of severe diseases that result in paralysis and death. Here, we report the development of a robust and efficient self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells that can be maintained long-term in simple adherent conditions. The timely application of specific patterning signals instructs the simultaneous development and differentiation of position-specific brachial spinal neurons, skeletal muscles, and terminal Schwann cells. High-content imaging reveals self-organized bundles of aligned muscle fibers surrounded by innervating motor neurons that form functional neuromuscular junctions. Optogenetic activation and pharmacological interventions show that the spinal neurons actively instruct the synchronous skeletal muscle contraction. The generation of a soNMJ model from spinal muscular atrophy patient-specific iPSCs reveals that the number of NMJs and muscle contraction is severely affected, resembling the patient’s pathology. In the future, the soNMJ model could be used for high-throughput studies in disease modeling and drug development. Thus, this model will allow us to address unmet needs in the neuromuscular disease field.

Background: One of the goals of the Multi-site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM) study was to evaluate whether clinicians experienced in diagnosing and caring for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) recognized the same clinical entity. Methods: We enrolled participants from seven specialty clinics in the United States. We used baseline data (n = 465) on standardized questions measuring general clinical characteristics, functional impairment, post-exertional malaise, fatigue, sleep, neurocognitive/autonomic symptoms, pain, and other symptoms to evaluate whether patient characteristics differed by clinic. Results: We found few statistically significant and no clinically significant differences between clinics in their patients’ standardized measures of ME/CFS symptoms and function. Strikingly, patients in each clinic sample and overall showed a wide distribution in all scores and measures. Conclusions: Illness heterogeneity may be an inherent feature of ME/CFS. Presenting research data in scatter plots or histograms will help clarify the challenge. Relying on case–control study designs without subgrouping or stratification of ME/CFS illness characteristics may limit the reproducibility of research findings and could obscure underlying mechanisms.

Abstract Objective The US risdiplam expanded access program (EAP; NCT04256265) was opened to provide individuals with Type 1 or 2 spinal muscular atrophy (SMA) who had no satisfactory treatment options access to risdiplam prior to commercial availability. The program was designed to collect safety data during risdiplam treatment. Methods Patients were enrolled from 23 non‐preselected sites across 17 states and treated with risdiplam orally once daily. Eligible patients had a 5q autosomal recessive Type 1 or 2 SMA diagnosis, were aged ≥2 months at enrollment, and were ineligible for available and approved SMA treatments or could not continue treatment due to a medical condition, lack/loss of efficacy, or the COVID‐19 pandemic. Results Overall, 155 patients with Type 1 (n = 73; 47.1%) or 2 SMA (n = 82; 52.9%) were enrolled and 149 patients (96.1%) completed the EAP (defined as obtaining access to commercial risdiplam, if desired). The median treatment duration was 4.8 months (range, 0.3–9.2 months). The median patient age was 11 years (range, 0–50 years), and most patients (n = 121; 78%) were previously treated with a disease‐modifying therapy. The most frequently reported adverse events were diarrhea (n = 10; 6.5%), pyrexia (n = 7; 4.5%), and upper respiratory tract infection (n = 5; 3.2%). The most frequently reported serious adverse event was pneumonia (n = 3; 1.9%). No deaths were reported. Interpretation In the EAP, the safety profile of risdiplam was similar to what was reported in pivotal risdiplam clinical trials. These safety data provide further support for the use of risdiplam in the treatment of adult and pediatric patients with SMA.

Hurricanes and extreme stormwater events can transport fecal contaminants and a wide range of bacterial pathogens to receiving rivers and streams, threatening public health. This study investigated the impact of flooding on bacterial diversity and the occurrence of fecal and potential bacterial pathogens in Texas Rivers over a short (3 weeks and 3 months) and long time (12 months) after Hurricane Harvey. Water samples were collected from 8 sampling sites of Guadalupe and San Antonio Rivers during three sampling events and bacterial community structure was evaluated using next-generation sequencing (NGS). Results showed that Proteobacteria, Actinobacteria, Bacteroidetes, and Cyanobacteria were the predominant phyla in the water samples. Hierarchal cluster analysis and principal coordinate analysis indicated that bacterial community structure was significantly different in the water samples collected from flooded and non-flooded sites. At genus level, eight fecal-associated and twelve potentially pathogenic bacterial genera were detected in water samples, mainly from flooded sites collected during short-term sampling events. Overall, results suggest that NGS-based microbial water quality monitoring of environmental samples after flooding events could provide critical information about the wide range of pathogens, which can be further assessed by specific methods to identify the risk of exposure.

Desde o início, o ministério petrino do Papa Francisco tem sido cheio de surpresas e ele tem sido um homem de contradições. Ele tem dado esperança a muitos, cristãos, outros crentes e humanistas seculares, especialmente com sua abordagem pastoral da misericórdia, mas também tem encontrado oposição feroz, mesmo entre o escalão superior da hierarquia, alguns dos quais atacaram publicamente sua ortodoxia e pediu sua renúncia. Em seus ensinamentos sobre evangelização, casamento e sexualidade, ecologia e amizade social, Francisco abriu novos caminhos e desafiou a Igreja a tornar visível o rosto misericordioso de Deus para o mundo. Sobre o diálogo inter-religioso, o papa, como era de se esperar, reiterou amplamente os ensinamentos do Vaticano II e até agora não emitiu uma exortação apostólica ou encíclica sobre o assunto. Consistente com sua perspectiva pastoral, ele enfatizou os aspectos sociopolíticos e culturais do diálogo inter-religioso e evitou amplamente questões doutrinárias ainda controversas. Por outro lado, sua amizade com muitos líderes não-cristãos e seus vários obiter dicta ampliaram o horizonte inter-religioso e abriram a porta para novas explorações na teologia da religião e o escopo do encontro inter-religioso. Seu reconhecimento explícito das religiões não-cristãs como “canais” do Espírito Santo sugere seu papel como meios de salvação não apenas para seus adeptos, mas também de certo modo para os cristãos. Além disso, os quatro princípios da metafísica franciscana sugerem maneiras novas e eficazes de conduzir o diálogo inter-religioso.

This paper proposes an innovative methodology for finding how many lifting techniques people with chronic low back pain (CLBP) can demonstrate with camera data collected from 115 participants. The system employs a feature extraction algorithm to calculate the knee, trunk and hip range of motion in the sagittal plane, Ward’s method, a combination of K-means and Ensemble clustering method for classification algorithm, and Bayesian neural network to validate the result of Ward’s method and the combination of K-means and Ensemble clustering method. The classification results and effect size show that Ward clustering is the optimal method where precision and recall percentages of all clusters are above 90, and the overall accuracy of the Bayesian Neural Network is 97.9%. The statistical analysis reported a significant difference in the range of motion of the knee, hip and trunk between each cluster, F (9, 1136) = 195.67, p < 0.0001. The results of this study suggest that there are four different lifting techniques in people with CLBP. Additionally, the results show that even though the clusters demonstrated similar pain levels, one of the clusters, which uses the least amount of trunk and the most knee movement, demonstrates the lowest pain self-efficacy.

In this paper, the authors present a new method to synthesize an adaptive sliding controller for Twin Rotor MIMO System (TRMS) based on Synergetic Control Theory (SCT). This system represents a prototype of a helicopter with two degrees of freedom and is widely used in automatic control laboratories. The complexity of the control problem is due to the nonlinear cross-coupling between the main and tail rotors. Uncertainty in system parameters further increases the complexity of the control problem. In Synergetic Control Theory, manifolds are designed for each channel. The control law is found based on sequential manifolds and the Analytical Design of Aggregated Regulators (ADAR) method. The adaptive law when the parameters are uncertain is given based on the analysis of system stability thanks to the Lyapunov function of the first manifold. Finally, the effectiveness of the proposed controller is demonstrated by numerical simulation results and comparison with conventional Sliding Mode Control (SMC). [ABSTRACT FROM AUTHOR]

Surveillance and outbreak reporting systems in Vietnam required improvements to function effectively as early warning and response systems. Accordingly, the Ministry of Health of Vietnam, in collaboration with the US Centers for Disease Control and Prevention, launched a pilot project in 2016 focusing on community and hospital event–based surveillance. The pilot was implemented in 4 of Vietnam’s 63 provinces. The pilot demonstrated that event-based surveillance resulted in early detection and reporting of outbreaks, improved collaboration between the healthcare facilities and preventive sectors of the ministry, and increased community participation in surveillance and reporting.

The article begins with a brief defi nition of „World Christianity” and elaborates three theses for conceiving the relationship between missiology and theology, the understanding and practice of Christian missions, and the teaching of missiology. I argue that outside missiology there is no theology. I also reject the separation between church history and missiology, the division between the historic churches of the West and the „mission lands” of the rest, and a narrow focus of the goal of Christian missions on conversion and church-planting. Finally, I recommend a shift from „church history” to „history of Christianity.”

Ovarian cancer, the most deadly gynecological malignancy in U.S. women, metastasizes uniquely, spreading through the peritoneal cavity and often generating widespread metastatic sites before diagnosis. The vast majority of ovarian cancer cases occur in women over 40 and the median age at diagnosis is 63. Additionally, elderly women receive poorer prognoses when diagnosed with ovarian cancer. Despite age being a significant risk factor for the development of this cancer, there are little published data which address the impact of aging on ovarian cancer metastasis. Here we report that the aged host is more susceptible to metastatic success using two murine syngeneic allograft models of ovarian cancer metastasis. This age-related increase in metastatic tumor burden corresponds with an increase in tumor infiltrating lymphocytes (TILs) in tumor-bearing mice and alteration of B cell-related pathways in gonadal adipose tissue. Based on this work, further studies elucidating the status of B cell TILs in mouse models of metastasis and human tumors in the context of aging are warranted.

Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival of motor neuron (SMN) protein. SMN is part of a multiprotein complex that facilitates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN has also been found to associate with mRNA-binding proteins, but the nature of this association was unknown. Here, we have employed a combination of biochemical and advanced imaging methods to demonstrate that SMN promotes the molecular interaction between IMP1 protein and the 3′ UTR zipcode region of β-actin mRNA, leading to assembly of messenger ribonucleoprotein (mRNP) complexes that associate with the cytoskeleton to facilitate trafficking. We have identified defects in mRNP assembly in cells and tissues from SMA disease models and patients that depend on the SMN Tudor domain and explain the observed deficiency in mRNA localization and local translation, providing insight into SMA pathogenesis as a ribonucleoprotein (RNP)-assembly disorder.