Krabbegaarde1459

Postzygotic somatic mutations have been found associated with human disease, including diseases other than cancer. Most information on somatic mutations has come from studying clonally amplified mutant cells, based on a growth advantage or genetic drift. However, almost all somatic mutations are unique for each cell, and the quantitative analysis of these low-abundance mutations in normal tissues remains a major challenge in biology. Here, we introduce single-molecule mutation sequencing (SMM-seq), a novel approach for quantitative identification of point mutations in normal cells and tissues.Convolutional neural networks (CNNs) have gained much attention because they can provide superior complex image recognition through convolution operations. Convolution processes require repeated multiplication and accumulation operations, which are difficult tasks for conventional computing systems. Compute-in-memory (CIM) that uses parallel data processing is an ideal device structure for convolution operations. CIM based on two-terminal synaptic devices with a crossbar structure has been developed, but unwanted leakage current paths and the high-power consumption remain as the challenges. Here, we demonstrate integrated ferroelectric thin-film transistor (FeTFT) synaptic arrays that can provide efficient parallel programming and data processing for CNNs by the selective and accurate control of polarization in the ferroelectric layer. In addition, three-terminal FeTFTs can act as both nonvolatile memory and access device, which tackle issues from two-terminal devices. An integrated FeTFT synaptic array with parallel programming capabilities can perform convolution operations to extract image features with a high-recognition accuracy.There is an increasingly growing demand for nonantibiotic strategies to overcome drug resistance in bacterial biofilm infections. Here, a novel "gas-sensitized hyperthermia" strategy is proposed for appreciable bacteria killing by the smart design of a metal-organic framework (MOF)-sealed Prussian blue-based nanocarrier (MSDG). Once the biofilm microenvironment (BME) is reached, the acidity-activated MOF degradation allows the release of diallyl trisulfide and subsequent glutathione-responsive generation of hydrogen sulfide (H2S) gas. Upon near-infrared irradiation, H2S-sensitized hyperthermia arising from MSDG can efficiently eliminate biofilms through H2S-induced extracellular DNA damage and heat-induced bacterial death. The generated H2S in the biofilm can stimulate the polarization of macrophages toward M2 phenotype for reshaping immune microenvironment. Subsequently, the secretion of abundant regeneration-related cytokines from M2 macrophages accelerates tissue regeneration by reversing the infection-induced pro-inflammatory environment in an implant-related infection model. Collectively, such BME-responsive nano-antibacterials can achieve biofilm-specific H2S-sensitized thermal eradiation and immunomodulatory tissue remodeling, thus realizing the renaissance of precision treatment of refractory implant-related infections.In contrast to prokaryotes wherein GUG and UUG are permissive start codons, initiation frequencies from non-AUG codons are generally low in eukaryotes, with CUG being considered as strongest. Here, we report that combined 5-cytosine methylation (5mC) and pseudouridylation (Ψ) of near-cognate non-AUG start codons convert GUG and UUG initiation strongly favored over CUG initiation in eukaryotic translation under a certain context. This prokaryotic-like preference is attributed to enhanced NUG initiation by Ψ in the second base and reduced CUG initiation by 5mC in the first base. Molecular dynamics simulation analysis of tRNAiMet anticodon base pairing to the modified codons demonstrates that Ψ universally raises the affinity of codonanticodon pairing within the ribosomal preinitiation complex through partially mitigating discrimination against non-AUG codons imposed by eukaryotic initiation factor 1. We propose that translational control by chemical modifications of start codon bases can offer a new layer of proteome diversity regulation and therapeutic mRNA technology.The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter ABCA3 plays a critical role in pulmonary surfactant biogenesis. Mutations in human ABCA3 have been recognized as the most frequent causes of inherited surfactant dysfunction disorders. Despite two decades of research, in vitro biochemical and structural studies of ABCA3 are still lacking. Here, we report the cryo-EM structures of human ABCA3 in two distinct conformations, both at resolution of 3.3 Å. In the absence of ATP, ABCA3 adopts a "lateral-opening" conformation with the lateral surfaces of transmembrane domains (TMDs) exposed to the membrane and features two positively charged cavities within the TMDs as potential substrate binding sites. ATP binding induces pronounced conformational changes, resulting in the collapse of the potential substrate binding cavities. Our results help to rationalize the disease-causing mutations in human ABCA3 and suggest a conserved "lateral access and extrusion" mechanism for both lipid export and import mediated by ABCA transporters.Skeletal muscle (SkM) is a highly dynamic tissue that responds to physiological adaptations or pathological conditions, and SkM mitochondria play a major role in bioenergetics, regulation of intracellular calcium homeostasis, pro-oxidant/antioxidant balance, and apoptosis. Flavonoids are polyphenolic compounds with the ability to modulate molecular pathways implicated in the development of mitochondrial myopathy. Therefore, it is pertinent to explore its potential application in conditions such as aging, disuse, denervation, diabetes, obesity, and cancer. To evaluate preclinical and clinical effects of flavonoids on SkM structure and function. We performed a systematic review of published studies, with no date restrictions applied, using PubMed and Scopus. The following search terms were used "flavonoids" OR "flavanols" OR "flavones" OR "anthocyanidins" OR "flavanones" OR "flavan-3-ols" OR "catechins" OR "epicatechin" OR "(-)-epicatechin" AND "skeletal muscle." The studies included in this review were preclinical studies, clinical trials, controlled clinical trials, and randomized-controlled trials that investigated the influence of flavonoids on SkM health. Three authors, independently, assessed trials for the review. Any disagreement was resolved by consensus. The use of flavonoids could be a potential tool for the prevention of muscle loss. Their effects on metabolism and on mitochondria function suggest their use as muscle regulators.Introduction Second medical opinions (SOs) can strengthen patients' certainty in decision making. In Germany, both personally delivered and telemedical SOs (often based on documents only) are provided. Our aim was to analyze the experiences of people who obtained telemedical SOs. We also investigated different routes of SO delivery (personally/by phone/documents only). Materials and Methods German residents who obtained a telemedical SO via an online portal between January 2016 and February 2019 (n = 1,247) were contacted by post between August and November 2019 up to three times. The results were analyzed descriptively. Results The 368 participants (response rate 30%) were 54% male, 95% statutory health insured, and 61 years old (median; interquartile range 51-72). Approximately 75% were (rather) satisfied with obtaining the SO via the online portal. The most preferred route of SO delivery was a personally delivered SO, which 80% would (rather) consider, followed by 70% (rather) considering SOs based on documents only and 48% (rather) considering SOs by phone. The most often mentioned advantage of telemedical SOs was independence of time and place, while the most important disadvantage was the standardized process resulting in a lack of direct and personal contact between the patient and the physician. Discussion Although our results show that SOs (based on documents only) support patients and that patient satisfaction was high, personally delivered SOs were still preferred. Future research on the use of SOs based on documents only (in which patient population and in what situations) is needed.

The Danish Breast Cancer Group Internal Mammary Node study demonstrated improved 8-year overall survival (OS) with internal mammary node irradiation (IMNI) in patients with node-positive early breast cancer. Here, we present long-term results from the Danish Breast Cancer Group Internal Mammary Node study cohort.

This nationwide, prospective cohort study allocated patients with node-positive early breast cancer to adjuvant radiotherapy with or without IMNI depending on cancer laterality. Patients with right-sided cancer received IMNI. Patients with left-sided cancer were treated without IMNI because of risk of radiation-induced heart disease. Other treatment was independent of laterality. Recilisib price The primary study end point was OS. Secondary end points were distant recurrence and breast cancer mortality. Analyses were by intention to treat.

During 2003-2007, 3,089 women were allocated to IMNI (right-sided, n = 1,491) or no IMNI (left-sided, n = 1,598). With a median follow-up of 14.8 years, 589 patients with anom breast cancer, thereby improving long-term survival.Our knowledge of monoclonal gammopathies is continuously evolving. Once accepted as a possible precursor condition to multiple myeloma, monoclonal gammopathies as an entity are now associated with many renal, neurologic, and dermatologic disorders of clinical significance. This change has created a challenge for patients and clinicians, as a monoclonal gammopathy may be a harbinger not of multiple myeloma but of other lymphoproliferative disorders such as light-chain amyloidosis and Waldenström macroglobulinemia. Early recognition of monoclonal gammopathies along with a careful workup are essential in determining the next steps in the care of a given patient. Recognition has become all the more important as we understand how to triage the 4% to 9% of patients with monoclonal gammopathies depending on age, with the goal of limiting overdiagnosis and misdiagnosis. In this review, we focus on treatment strategies for patients with monoclonal gammopathies that are not multiple myeloma, including smoldering multiple myeloma, light-chain amyloidosis, and Waldenström macroglobulinemia.Annually, nearly 2 million people are diagnosed with cancer. Cancer is the second leading cause of death in the United States. Strong evidence supports exercise in the prevention of seven different types of cancers. Among cancer survivors, exercise across the cancer care continuum is effective at reducing various treatment-related adverse effects, such as fatigue, anxiety, and depression, and improves quality of life, physical function, sleep, and bone health. Considering the benefits of exercise for people living with and beyond cancer, there are several models to facilitate the implementation of exercise as part of the cancer care plan. These models span clinically supervised settings to supervised and nonsupervised community-based settings. Barriers such as payment and workforce development prevent the implementation of these programs nationwide. Oncology providers and cancer care team members also play an important role in promoting exercise to cancer survivors. In fact, a salient theme for motivating survivors to engage in exercise is support from their medical oncologist.