Miracle-dz/UniFAR-FTUs huggingface dataset:
Intra-patient evolution of tumor microenvironment in the pathogenesis of treatment-naïve metastatic melanoma patients

During the last decade, major improvements in metastatic melanoma treatment have led to the widespread use of immune checkpoint inhibitors (ICIs) and targeted therapies [1,2]. Although anti–PD-1–based immunotherapy has improved treatment outcomes of patients with metastatic melanoma, all patients do not benefit from it. The tumor microenvironment (TME) is a constantly evolving composition of blood vessels, immune cells, signalling molecules, fibroblasts, stromal cells, and extracellular matrix surrounding the tumor. The TME differs between tumor types, and between patients within the same tumor type and even within similar tumor genotypes. The TME plays a relevant role in immune surveillance and resistance to immunotherapy [3–5]. Melanoma tumor heterogeneity is present between the patients (interpatient heterogeneity), within a tumor (intratumoral heterogeneity) and among tumors within a patient at various sites of the body concurrently or sequentially during the course of the disease (intertumoral or intra-patient heterogeneity) [6,7]. However, the BRAF mutation, which is one of the key driver mutations in melanoma, is thought to be stable and to occur early in the course of melanoma development [8]. BRAF mutation is a predictive marker since only BRAFmutated tumors respond to BRAF inhibitor therapy and mutational status thus affecting treatment selection critically [9–11]. Furthermore, patients with BRAF-mutant metastatic melanoma treated with ipilimumab and nivolumab seem to have a survival benefit compared to patients with wild-type tumors [1], and that treatment-naïve BRAF-mutant melanoma has a distinct immune profile compared with BRAF-wild type melanoma in the TME [12]. TME and immune surveillance seem to play an important role in melanoma pathogenesis. Tumor heterogeneity may affect treatment response and hasten the development of acquired resistance. Specific immune gene expression signatures and individual genes associated with the response to immunotherapy [13–16]. An area less studied is the immune signature gene heterogeneity among samples within a patient. Regulatory T-cell (Treg)-mediated T-cell suppression is an important mechanism for the tumor cells to escape the host’s activated immune system. A central mechanism contributing to impaired T-cell function against tumors or pathogens is T-cell exhaustion. Infection-induced exhaustion is usually reversible, whereas tumor-induced dysfunction of T-cells is only reversible at early malignant stages and irreversible at later stages [17]. In this pilot study we aimed to characterize immunological profiles by gene-expression analysis and to explore if any mutational heterogeneity could be detected between sequential intrapatient primary and metastatic melanoma tumors.
Downlink Resource Sharing in Multichannel Device-to-Device Communication

We consider downlink resource sharing between multiple cellular users (CUs) and device-to-device (D2D) links, where each D2D link reuses multiple CU channels and each CU channel is shared by multiple D2D links. The design goal is to provide quality-of-service protection for CUs and meanwhile enhance the spectral efficiency of D2D links, which leads to a difficult resource sharing problem. We propose a novel efficient approach to address the downlink multichannel D2D resource sharing problem. Numerical results show that the proposed approach exhibits superiority over existing D2D schemes.
Caenorhabditis elegans models for striated muscle disorders caused by missense variants of human LMNA

Striated muscle laminopathies caused by missense mutations in the nuclear lamin gene LMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict which LMNA variants are pathogenic and to understand their physiological effects lag behind variant discovery. We created Caenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic human LMNA variants and variants of unknown significance at conserved residues within the lmn-1 gene. Severe missense variants reduced fertility and/or motility in C. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele, lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we established C. elegans avatars for striated muscle laminopathies and identified LMNA variants that offer insight into lamin mechanisms during normal development.
Intensive care nurse managers’ experiences during the first wave of the Covid-19 pandemic: Implications for future epidemiological crises

Background Nurse managers play an important role in coordinating the multidisciplinary teamwork, which is specifically important in emergency and crises situations like the COVID-19 pandemic. The aim of this qualitative study is twofold: (1) to explore the experiences of the Intensive care units (ICU) nurse managers regarding their work during the first wave of the COVID-19 pandemic, and (2) to analyse what implications might be provided based on experiences of nurse managers for future possible epidemiological crises. Methods In-depth phone interviews were conducted to explore the experiences of ward managers–nurses (n = 15) working in different hospitals across Poland. Interviews were taped and transcribed verbatim, and then qualitatively analysed. Results Three main categories were identified: (1) Challenge of working with the unknown, (2) Nurse managers’ expectations, and (3) Methods of coping and received support. The COVID-19 pandemic strongly affected the work of ICU nurse managers and uncovered the malfunctioning of the healthcare system. Conclusion It is important to improve the knowledge and competence of hospital management personnel through exercises and in-service training on how to handle emergencies in order to improve the management of healthcare facilities, increase the safety of patients and employees, and the quality of healthcare.
Fabrication and integration of a low‐cost 3D printing‐based glucose biosensor for bioprinted liver‐on‐a‐chip

In the last two decades, significant progress has been made in the development of more physiologically relevant organ‐on‐a‐chip (OOC) systems that can mimic tissue microenvironments. Despite the advantages of these microphysiological systems, such as portability, ability to mimic physiological flow conditions, and reduction of the number of reagents required for preparation and detection, they lack real‐time analyte detection with high accuracy. To address this limitation, biosensor technologies have been integrated with OOC systems to facilitate simultaneous analysis of different analytes with a single device. However, the integration of biosensors with OOC systems is challenging because of the competing demands of low‐cost, simple fabrication processes and speed. In this study, we fabricate a glucose‐sensing device and integrate it with a liver‐on‐a‐chip (LOC) platform. A carbon black‐polylactic acid‐based three‐electrode system was printed using fused deposit molding 3D printing technology to simplify the fabrication process. The sensitivity of the fabricated glucose biosensing device was enhanced by coating the electrodes with multi‐walled carbon nanotubes. A biosensing integration study performed using a perfusion‐based LOC demonstrated the stability, biocompatibility, and sensitivity of the proposed glucose sensing device. Furthermore, drug‐toxicity studies conducted using the LOC platform demonstrated the ability of the device to detect a broad range of glucose concentrations and its enhanced sensitivity.
Evaluation of MR anatomically-guided PET reconstruction using a convolutional neural network in PSMA patients

Background. Recently, approaches have utilized the superior anatomical information provided by magnetic resonance imaging (MRI) to guide the reconstruction of positron emission tomography (PET). One of those approaches is the Bowsher’s prior, which has been accelerated lately with a convolutional neural network (CNN) to reconstruct MR-guided PET in the imaging domain in routine clinical imaging. Two differently trained Bowsher-CNN methods (B-CNN0 and B-CNN) have been trained and tested on brain PET/MR images with non-PSMA tracers, but so far, have not been evaluated in other anatomical regions yet. Methods. A NEMA phantom with five of its six spheres filled with the same, calibrated concentration of 18F-DCFPyL-PSMA, and thirty-two patients (mean age 64 ± 7 years) with biopsy-confirmed PCa were used in this study. Reconstruction with either of the two available Bowsher-CNN methods were performed on the conventional MR-based attenuation correction (MRAC) and T1-MR images in the imaging domain. Detectable volume of the spheres and tumors, relative contrast recovery (CR), and background variation (BV) were measured for the MRAC and the Bowsher-CNN images, and qualitative assessment was conducted by ranking the image sharpness and quality by two experienced readers. Results. For the phantom study, the B-CNN produced 12.7% better CR compared to conventional reconstruction. The small sphere volume (<1.8 ml) detectability improved from MRAC to B-CNN by nearly 13%, while measured activity was higher than the ground-truth by 8%. The signal-to-noise ratio, CR, and BV were significantly improved (p < 0.05) in B-CNN images of the tumor. The qualitative analysis determined that tumor sharpness was excellent in 76% of the PET images reconstructed with the B-CNN method, compared to conventional reconstruction. Conclusions. Applying the MR-guided B-CNN in clinical prostate PET/MR imaging improves some quantitative, as well as qualitative imaging measures. The measured improvements in the phantom are also clearly translated into clinical application.
Occupational therapy practice guidelines for children and adolescents with challenges in sensory processing and sensory integration

Occupational therapy is steeped in the sciences that provide knowledge and understanding of human development and function and the variables that influence these aspects of human life. The registration, processing, and integration of sensory information can both support and inhibit the ability for children and adolescents to function in their environment. Up to 15% of school-age children are believed to have sensory challenges, and at least 40% of individuals with developmental disabilities and 80% of those with autism are affected. Using an evidence-based perspective and key concepts from the Occupational Therapy Practice Framework: Domain and Process , this new AOTA Practice Guideline provides an overview and insight into occupational therapy evaluation and intervention for youth that experience sensory information difficulties. Designed primarily for clinical practitioners, this important practice guideline from AOTA Press is a vital reference for occupational therapy students and educators and provides a clear definition on the role of occupational therapy services for policymakers and other health care professionals who work with children and adolescents that face these challenges.
Angelica sinensis polysaccharide improves mitochondrial metabolism of osteoarthritis chondrocytes through PPARγ/SOD2/ROS pathways

Osteoarthritis (OA) is a common degenerative joint disease, which is characterized by wear of articular cartilage and narrow joint space, resulting in joint movement disorder. At present, accurate molecular mechanisms and effective interventions are still being explored. Here, we propose that angelica sinensis polysaccharide (ASP) alleviates OA progression by activating peroxisome proliferator‐activated receptor gamma (PPARγ). Therapeutic effect of ASP improving mitochondrial metabolism of OA chondrocytes was evaluated in vitro and in vivo, respectively. During cell experiments, the concentration and time response of tert butyl hydroperoxide (TBHP) and ASP were determined by cell viability. Apoptosis was detected by flow cytometry. Mitochondrial metabolism was detected by reactive oxygen species (ROS), mitochondrial membrane potential (MMP), release of cytochrome C, adenosine triphosphate (ATP) production, and superoxide dismutase 2 (SOD2) activity. Expressions of Aggrecan, collagen type II (Col2a1), PPARγ, and SOD2 were detected by qRT‐PCR and western blot. In animal experiments, we detected cell apoptosis and target protein expression separately through terminal deoxynucleotidyl transferase dUTP nick end‐labeling (TUNEL) staining and immunohistochemistry. Pretreatment of ASP significantly activated PPARγ and SOD2 in rat chondrocytes incubated with TBHP, cleared ROS, improved mitochondrial metabolism, increased chondrocytes viability, and alleviated chondrocytes apoptosis. In vivo, the administration of ASP could effectively ameliorate cartilage degeneration in OA rats, promote extracellular matrix synthesis, and decelerate the progress of OA. Our research identifies the role of ASP in mitochondrial metabolism of OA chondrocytes through PPARγ/SOD2/ROS pathways, which provides a new idea for the treatment of OA.
Newly identified Middle–Late Permian mafic–ultramafic intrusions in the southeastern margin of the Central Asian Orogenic Belt: Petrogenesis and its implications

Hao, L. B. , Sun, L. J., Zhao, Y. Y. and Lu, J. L. (2013) SHRIMP zircon U–Pb dating of Chajian mafic–ultramafic rocks in Hongqiling mine field, Jilin Province, and its implications. Earth Sci. J. China Univ. Geosci. 38, 233–240 (in Chinese with English abstract). Hao, L. B. , Wu, C. , Sun, L. J., Zhao, Y. Y. , Lu, J. L. and Li, J. (2014a) Characteristics of Re–Os isotope from Hongqiling Cu–Ni sulfide deposit in Jilin and its significance. J. Jilin
Identification of hybrid amyloid strains assembled from amyloid-β and human islet amyloid polypeptide

Cross-fibrillation of amyloid-β (Aβ) peptides and human islet amyloid polypeptides (hIAPP) has revealed a close correlation between Alzheimer’s disease and type 2 diabetes (T2D). Importantly, different amyloid strains are likely to lead to the clinical pathological heterogeneity of degenerative diseases due to toxicity. However, given the complicated cross-interactions between different amyloid peptides, it is still challenging to identify the polymorphism of the hybrid amyloid strains and reveal mechanistic insights into aggregation, but highly anticipated due to their significance. In this study, we investigated the cross-fibrillation of Aβ peptides and different hIAPP species (monomers, oligomers, and fibrils) using combined experimental and simulation approaches. Cross-seeding and propagation of different amyloid peptides monitored by experimental techniques proved that the three species of hIAPP aggregates have successively enhanced Aβ fibrillation, especially for hIAPP fibrils. Moreover, the polymorphism of these morphologically similar hybrid amyloid strains could be distinguished by testing their mechanical properties using quantitative nanomechanical mapping, where the assemblies of Aβ-hIAPP fibrils exhibited the high Young’s modulus. Furthermore, the enhanced internal molecular interactions and β-sheet structural transformation were proved by exploring the conformational ensembles of Aβ-hIAPP heterodimer and Aβ-hIAPP decamer using molecular dynamic simulations. Our findings pave the way for identifying different hybrid amyloid strains by quantitative nanomechanical mapping and molecular dynamic simulations, which is important not only for the precise classification of neurodegenerative disease subtypes but also for future molecular diagnosis and therapeutic treatment of multiple interrelated degenerative diseases.
Advances in field-effect biosensors towards point-of-use

The future of medical diagnostics calls for portable biosensors at the point of care, aiming to improve healthcare by reducing costs, improving access, and increasing quality—what is called the ‘triple aim’. Developing point-of-care sensors that provide high sensitivity, detect multiple analytes, and provide real time measurements can expand access to medical diagnostics for all. Field-effect transistor (FET)-based biosensors have several advantages, including ultrahigh sensitivity, label-free and amplification-free detection, reduced cost and complexity, portability, and large-scale multiplexing. They can also be integrated into wearable or implantable devices and provide continuous, real-time monitoring of analytes in vivo, enabling early detection of biomarkers for disease diagnosis and management. This review analyzes advances in the sensitivity, parallelization, and reusability of FET biosensors, benchmarks the limit of detection of the state of the art, and discusses the challenges and opportunities of FET biosensors for future healthcare applications.
Biological diversification linked to environmental stabilization following the Sturtian Snowball glaciation

The body fossil and biomarker records hint at an increase in biotic complexity between the two Cryogenian Snowball Earth episodes (ca. 661 million to ≤650 million years ago). Oxygen and nutrient availability can promote biotic complexity, but nutrient (particularly phosphorus) and redox dynamics across this interval remain poorly understood. Here, we present high-resolution paleoredox and phosphorus phase association data from multiple globally distributed drill core records through the non-glacial interval. These data are first correlated regionally by litho- and chemostratigraphy, and then calibrated within a series of global chronostratigraphic frameworks. The combined data show that regional differences in postglacial redox stabilization were partly controlled by the intensity of phosphorus recycling from marine sediments. The apparent increase in biotic complexity followed a global transition to more stable and less reducing conditions in shallow to mid-depth marine environments and occurred within a tolerable climatic window during progressive cooling after post-Snowball super-greenhouse conditions.
Impact of the use of GeneXpert on TB diagnosis and anti-TB treatment outcome at health facilities in Addis Ababa, Ethiopia in the post-millennium development years

Background GeneXpert is an effective and rapid molecular system used for tuberculosis (TB) diagnosis. It is expected to improve the detection rate and treatment outcomes needed to meet the sustainable development goals (SDG) and End TB strategy targets set for 2030. This study aimed to evaluate the impact of GeneXpert on diagnosis and anti-TB treatment outcomes in the post-millennium development goals (MDGs) in the capital city of Ethiopia. Hence, the global priority indicator based on the End TB Strategy for TB treatment success rate was met early in 2018 in Addis Ababa, Ethiopia, which was anticipated to be met by 2025. Methods A retrospective health facilities-based study was conducted in Addis Ababa, Ethiopia. Records of all TB cases diagnosed and treated in selected health facilities from January 1st, 2015 to December 31st, 2018 were reviewed and included in the study. Data analysis of descriptive and inferential statistics was conducted using SPSS version 20. Results The reviewed records have shown that a total of 45,158 presumptive pulmonary TB (PTB) cases had accessed TB diagnosis services. Of which, 28.9% (13072/45158) were tested by AFB microscopy and 71.1% (32086/45158) were tested by GeneXpert. During the study period, the coverage of Xpert MTB/RIF testing increased to 94.9% in 2018 compared to 1.6% in 2015. The number of presumptive PTB cases tested with the GeneXpert system showed a significant increase compared to smear microscopy. The odds of positivity were detected in males compared to females. The odds of detecting TB cases were much higher among study participants aged 15–44 years compared to younger than 15 years. Treatment success rate showed a relative improvement each year between 2015 and 2018 with a mean of 92.6%. Reduced odds of treatment successes were observed in age categories older than 35 years, and in TB/HIV co-infected patients. Increased odds of treatment successes were reported in the years between 2016 and 2018 compared to 2015. Conclusion Scaling up the Xpert MTB/RIF assay as a point-of-care test for presumptive TB cases in resource-limited settings would have a significant impact to meet the SDG and End TB strategy both in TB detection and treatment success rates.
Baseline tumor gene expression signatures correlate with chemoimmunotherapy treatment responsiveness in canine B cell lymphoma

Pet dogs develop spontaneous diffuse large B cell lymphoma (DLBCL), and veterinary clinical trials have been employed to treat canine DLBCL and to inform clinical trials for their human companions. A challenge that remains is selection of treatment to improve outcomes. The dogs in this study were part of a larger clinical trial evaluating the use of combinations of doxorubicin chemotherapy, anti-CD20 monoclonal antibody, and one of three small molecule inhibitors: KPT-9274, TAK-981, or RV1001. We hypothesized that significant differential expression of genes (DEGs) in the tumors at baseline could help predict which dogs would respond better to each treatment based on the molecular pathways targeted by each drug. To this end, we evaluated gene expression in lymph node aspirates from 18 trial dogs using the NanoString nCounter Canine Immuno-oncology (IO) Panel. We defined good responders as those who relapsed after 90 days, and poor responders as those who relapsed prior to 90 days. We analyzed all dogs at baseline and compared poor responders to good responders, and found increased CCND3 correlated with poor prognosis and increased CD36 correlated with good prognosis, as is observed in humans. There was minimal DEG overlap between treatment arms, prompting separate analyses for each treatment cohort. Increased CREBBP and CDKN1A for KPT-9274, increased TLR3 for TAK-981, and increased PI3Kδ, AKT3, and PTEN, and decreased NRAS for RV1001 were associated with better prognoses. Trends for selected candidate biomarker genes were confirmed via qPCR. Our findings emphasize the heterogeneity in DLBCL, similarities and differences between canine and human DLBCL, and ultimately identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs.