Miracle-dz/UniFAR-FTUs huggingface dataset:
Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution

Gene expression at fine scale Mapping gene expression at the single-cell level within tissues remains a technical challenge. Rodriques et al. developed a method called Slide-seq, whereby RNA was spatially resolved from tissue sections by transfer onto a surface covered with DNA-barcoded beads. Applying Slide-seq to regions of a mouse brain revealed spatial gene expression patterns in the Purkinje layer of the cerebellum and axes of variation across Purkinje cell compartments. The authors used this method to dissect the temporal evolution of cell type–specific responses in a mouse model of traumatic brain injury. Science, this issue p. 1463 An RNA sequencing technique is developed that can measure genome-wide gene expression in complex tissues at 10-micrometer resolution. Spatial positions of cells in tissues strongly influence function, yet a high-throughput, genome-wide readout of gene expression with cellular resolution is lacking. We developed Slide-seq, a method for transferring RNA from tissue sections onto a surface covered in DNA-barcoded beads with known positions, allowing the locations of the RNA to be inferred by sequencing. Using Slide-seq, we localized cell types identified by single-cell RNA sequencing datasets within the cerebellum and hippocampus, characterized spatial gene expression patterns in the Purkinje layer of mouse cerebellum, and defined the temporal evolution of cell type–specific responses in a mouse model of traumatic brain injury. These studies highlight how Slide-seq provides a scalable method for obtaining spatially resolved gene expression data at resolutions comparable to the sizes of individual cells.
Immunotherapy of Melanoma: Facts and Hopes

Melanoma is among the most sensitive of malignancies to immune modulation. Although multiple trials conducted over decades with vaccines, cytokines, and cell therapies demonstrated meaningful responses in a small subset of patients with metastatic disease, a true increase in overall survival (OS) within a randomized phase III trial was not observed until the development of anti–CTLA-4 (ipilimumab). Further improvements in OS for metastatic disease were observed with the anti–PD-1–based therapies (nivolumab, pembrolizumab) as single agents or combined with ipilimumab. A lower bound for expected 5-year survival for metastatic melanoma is currently approximately 35% and could be as high as 50% for the nivolumab/ipilimumab combination among patients who would meet criteria for clinical trials. Moreover, a substantial fraction of long-term survivors will likely remain progression-free without continued treatment. The hope and major challenge for the future is to understand the immunobiology of tumors with primary or acquired resistance to anti–PD-1 or anti–PD-1/anti–CTLA-4 and to develop effective immune therapies tailored to individual patient subsets not achieving long-term clinical benefit. Additional goals include optimal integration of immune therapy with nonimmune therapies, the development and validation of predictive biomarkers in the metastatic setting, improved prognostic and predictive biomarkers for the adjuvant setting, understanding mechanisms of and decreasing toxicity, and optimizing the duration of therapy.
Medical perspectives regarding goals-of-care consultations in Emergency Departments

ABSTRACT Goals-of-care discussions aim to establish patient values for shared medical decision-making. These discussions are relevant towards end-of-life as patients may receive non-beneficial treatments if they have never discussed preferences for care. End-of-life care is provided in Emergency Departments (EDs) but little is known regarding ED-led goals-of-care discussions. We aimed to explore practitioner perspectives on goals-of-care discussions for adult ED patients nearing end-of-life. We report the qualitative component of a mixed methods study regarding a ‘Goals-of-Care’ form in an Australian ED. Eighteen out of 34 doctors who completed the form were interviewed. We characterised ED-led goals-of-care consultations for the first time. Emergency doctors perceive goals-of-care discussions to be relevant to their practice and occurring frequently. They aim to ensure appropriate care is provided prior to review by the admitting team, focusing on limitations of treatment and clarity in the care process. ED doctors felt they could recognise end-of-life and that ED visits often prompt consideration of end-of-life care planning. They wanted long-term practitioners to initiate discussions prior to patient deterioration. There were numerous interpretations of palliative care concepts. Standardisation of language, education, collaboration and further research is required to ensure Emergency practitioners are equipped to facilitate these challenging conversations.
Reactivation of microRNA-506 inhibits gastric carcinoma cell metastasis through ZEB2

MicroRNAs (miRNAs) are frequently dysregulated in a variety of human cancers, including gastric carcinoma. To improve our understanding of the role of miRNAs in gastric carcinoma and potential identify novel biomarkers or therapeutic agents, we performed microarray analysis to identify differentially expressed miRNAs in gastric carcinoma, compared with paired non-cancerous gastric tissues. We identified significantly differentially expressed miRNAs in gastric carcinoma tissues, including miR-506. We validated the microarray results by quantitative reverse transcription polymerase chain reaction in 26 specimens and confirmed significant downregulation of miR-506 in gastric carcinoma. Bioinformatics analysis predicted ZEB2 (zinc finger E-box-binding homeobox 2) as a potential target of miR-506. MiR-506 levels and ZEB2 levels were inversely correlated in gastric carcinoma, and low miR-506 levels in gastric carcinoma were associated with poor prognosis. Overexpression of miR-506 in gastric carcinoma cells significantly inhibited cell migration and invasion, while depletion of miR-506 in gastric carcinoma cells significantly increased cell migration and invasion. Transplantation of miR-506-overexpressing gastric carcinoma cells developed significantly smaller tumor, compared to the control. Thus, our results suggest that miR-506 may function as a tumor suppressor and targets and inhibits ZEB2 in gastric carcinoma.
Stage‐ and thermal‐specific genetic architecture for preadult viability in natural populations of Drosophila melanogaster

Studying the processes affecting variation for preadult viability is essential to understand the evolutionary trajectories followed by natural populations. This task requires focusing on the complex nature of the phenotype–genotype relationship by taking into account usually neglected aspects of the phenotype and recognizing the modularity between different ontogenetic stages. Here, we describe phenotypic variability for viability during the larval and pupal stages in lines derived from three natural populations of Drosophila melanogaster, as well as the variability for phenotypic plasticity and canalization at two different rearing temperatures. The results indicate that the three populations present significant phenotypic differences for preadult viability. Furthermore, distinct aspects of the phenotype (means, plasticity, canalization, plasticity of canalization) are affected by different genetic bases underlying changes in viability in a stage‐ and environment‐specific manner. These findings explain the generalized maintenance of genetic variability for this fitness trait.
Improving Adherence to Colorectal Cancer Screening: A Randomized Intervention to Compare Screener vs. Survivor Narratives

Interventions are needed to increase colorectal cancer screening (CRCS) uptake. Narratives may have advantages over didactic information. We tested different narratives for increasing CRCS intentions and behaviors, and examined their mechanisms of influence. We randomized 477 unscreened adults 50–75 years old to one of three groups: CRCS information only (1) or CRCS information plus a photo and text narrative of a CRC survivor (2) or CRC screener who did not have cancer (3). Photos were tailored on participants’ sex, age group, and race/ethnicity. Participants completed online surveys before and after intervention exposure, and 1-, 6-, and 12-months follow-up. Thirty percent of participants completed CRCS. Narrative conditions (vs. information only) were negatively associated with intention, but also positively influenced intentions through greater emotional engagement. Survivor (vs. screener) narratives were positively associated with CRCS, and had mixed effects on intention – positively through emotional engagement and negatively through self-referencing engagement to self-efficacy. Survivor narratives elicited more negative affect, which had positive and negative influences on intention. Continued research using path models to understand the mechanisms of narrative effects will inform theory development and message design. Additional measurement evaluation is needed to adequately capture and then compare the effects of different components of narrative engagement.
Clinical Characteristic and Pathogen Spectrum of Neonatal Sepsis in Guangzhou City from June 2011 to June 2017

Background Preterm and low birth weight (birth weight <2500 g) neonates are vulnerable to sepsis, and the causative pathogens vary in different regions and times. The objective of this study was to identify common organisms leading to neonatal sepsis and identify the characteristic of patients infected with different bacteria, which may help in the selection of antibiotics for empirical treatment. Material/Methods We retrospectively collected the clinical and microbiological data of neonates with culture-proven sepsis in our clinical setting from June 2011 to June 2017. The demography, composition, and distribution of the pathogens and the clinical characteristic of the cases infected with different bacteria were analyzed. Results Of a total of 1048 bacteria that were isolated from patient samples, detailed clinical and microbiological data of 297 cases were available. Escherichia coli, Klebsiella pneumoniae, and coagulase-negative Staphylococcus (co-NS) were the top 3 isolated pathogens. Streptococcus agalactiae predominantly led to early-onset sepsis, while K. pneumoniae and Staphylococcus aureus mainly led to late-onset sepsis. K. pneumoniae was mainly acquired in the hospital. Leukopenia was more commonly seen than leukocytosis in our study, and patients infected with K. pneumoniae and Candida spp encountered more thrombocytopenia. Conclusions The results of our study revealed the composition of the pathogens of neonatal sepsis in our region and the clinical characteristic of sepsis caused by different bacteria; these data may help in the selection of antibiotics for empirical treatment of neonates with high risk of sepsis.
Syphilitic hepatitis and neurosyphilis: an observational study of Danish HIV-infected individuals during a 13-year period

Objective Syphilis is an STI that potentially affects any organ. Syphilitic hepatitis and neurosyphilis have been reported in both HIV-uninfected and HIV-infected individuals. The aim of this study was to investigate syphilitic hepatitis and neurosyphilis among HIV-infected individuals during a 13-year period. Methods This retrospective study included all HIV-infected individuals ≥18 years diagnosed with syphilis between 1 May 2004 and 31 December 2016 in Copenhagen, Denmark. We used the unique 10-digit personal identification number assigned to all individuals in Denmark to link data from two nationwide registers to identify the patients. Patient files were revised to obtain clinical and laboratory data. Results A total of 509 episodes of syphilis were diagnosed in 427 HIV-infected individuals attending three hospitals in Copenhagen, Denmark. The majority of the patients were men (99.5%), and the majority of men were men who have sex with men (96%). Twenty-seven patients (6%) met the criteria for neurosyphilis, and the neurological symptoms included ocular and auditory abnormalities, headache, paraesthesia, vertigo, facial paresis, motor weakness and unexplained pain in the legs. The patients with neurosyphilis were diagnosed in the secondary stage (84%) and in the early latent (8%) or late latent (8%) stage. Among the patients tested for liver affection, 41% met the criteria for syphilitic hepatitis. The patients with syphilitic hepatitis were diagnosed in the secondary stage (82%), primary stage (10%), and in the early latent (5%) or late latent (3%) stage. Conclusions The study emphasises that patients with syphilis, also those seen at STI clinics, should undergo a thorough clinical examination and questioning to reveal neurological symptoms. Identification of patients with neurosyphilis is crucial since these patients undergo a different treatment. The study also emphasises that syphilis should be considered as a diagnosis in sexually active patients with liver .
Recognition of alpha-mannan by dectin 2 is essential for onset of Kawasaki disease-like murine vasculitis induced by Candida albicans cell-wall polysaccharide

Abstract Objectives: Using a murine model of systemic Kawasaki disease (KD)–like vasculitis induced by Candida albicans cell–wall–derived mannan · β–glucan · protein complexes, the objective was to elucidate the relationships of β–glucan receptor dectin–1 (D1) and α–mannan receptor dectin–2 (D2) to the onset of that vasculitis. Methods: The incidence and histological severity of vasculitis were compared among mice lacking the genes for D1 or D2 (i.e. D1−/− and D2−/−) and wild–type (WT) mice. Results: The incidences of vasculitis in the three animal groups were 100% (18/18) in the WT group, 100% (18/18) in the D1−/− group, and 0% (0/18) in the D2−/− group. In the WT and D1−/− mice, severe inflammatory cell infiltration, consisting mainly of neutrophils and macrophages, was seen in the aortic root and the coronary arteries. On the other hand, in the D2−/− mice, not even mild vascular lesions such as endoarteritis were seen. Conclusion: Recognition of α–mannan by D2 played an important role in the onset of vasculitis in the studied murine model.
The entorhinal cognitive map is attracted to goals

Reward and the map in the brain Recent findings suggest a more complex role of grid cells in the brain than simply coding for space. The grid map in the entorhinal cortex, which is responsible for encoding spatial information, is not as rigid as originally thought and can be distorted by environmental modifications (see the Perspective by Quian Quiroga). Butler et al. compared grid cell coding during a free-foraging task and a spatial memory task in rats. They discovered that entorhinal spatial maps restructure to incorporate the location of a learned reward. Boccara et al. tested the influence of behaviorally relevant information on the cognitive map that emerges from grid cell firing in the rat medial entorhinal cortex. They found that grid cells participate in neural coding of the goal locality, not the whole environment. Science, this issue p. 1447, p. 1443; see also p. 1388 Goal learning in rats leads to a local distortion of grid cell rate maps, suggesting a complex code beyond simply encoding space. Grid cells with their rigid hexagonal firing fields are thought to provide an invariant metric to the hippocampal cognitive map, yet environmental geometrical features have recently been shown to distort the grid structure. Given that the hippocampal role goes beyond space, we tested the influence of nonspatial information on the grid organization. We trained rats to daily learn three new reward locations on a cheeseboard maze while recording from the medial entorhinal cortex and the hippocampal CA1 region. Many grid fields moved toward goal location, leading to long-lasting deformations of the entorhinal map. Therefore, distortions in the grid structure contribute to goal representation during both learning and recall, which demonstrates that grid cells participate in mnemonic coding and do not merely provide a simple metric of space.
Evaluation of a Multidisciplinary Pain, Agitation, and Delirium Guideline in Mechanically Ventilated Critically Ill Adults

Background: A multidisciplinary team updated an institution-specific pain, agitation, and delirium (PAD) guideline based on the recommendations from the Society of Critical Care Medicine (SCCM) PAD guidelines. This institution-specific guideline emphasized protocolized sedation with increased as needed boluses, and nonbenzodiazepine infusions, daily sedation interruption, and pairing of spontaneous awakening (SAT) and breathing trials (SBT). Objective: The purpose of this study was to evaluate the impact of implementation of a PAD guideline on clinical outcomes and medication utilization in an academic medical center intensive care unit (ICU). It was hypothesized that implementation of an updated guideline would improve clinical outcomes and decrease usage of benzodiazepine infusions. Methods: Pre-post retrospective chart review of 2417 (1147 pre, 1270 post) critically ill, mechanically ventilated adults in a medical/surgical ICU over a 2-year period (1 year pre and post guideline implementation). Results: After guideline implementation, average ventilation days was reduced (3.98 vs 3.43 days, P = .0021), as well as ICU and hospital length of stay (LOS) (4.79 vs 4.34 days, P = .048 and 13.96 vs 12.97 days, P = .045, respectively). Hospital mortality (19 vs 19%, P = .96) and acute physiology and chronic health evaluation (APACHE) IV scores (77.28 vs 78.75, P = .27) were similar. After guideline implementation, the percentage of patients receiving midazolam infusions decreased (422/1147 [37%] vs 363/1270 patients [29%], P = .0001). The percentage of patients receiving continuous infusion propofol (679/1147 [59%] vs 896/1270 [70%], P = .0001) and dexmedetomidine (78/1147 [7%] vs 147/1270 [12%], P = .0001) increased. Conclusions: Implementing a multidisciplinary PAD guideline utilizing protocolized sedation and daily sedation interruption decreased ventilation days and ICU and hospital LOS while decreasing midazolam drip usage.
Understanding the marvels behind liver regeneration

Tissue regeneration is a process by which the remaining cells of an injured organ regrow to offset the missed cells. This field is relatively a new discipline that has been a focus of intense research by clinicians, surgeons, and scientists for decades. It constitutes the cornerstone of tissue engineering, creation of artificial organs, and generation and utilization of therapeutic stem cells to undergo transformation to different types of mature cells. Many medical experts, scientists, biologists, and bioengineers have dedicated their efforts to deeply comprehend the process of liver regeneration, striving for harnessing it to invent new therapies for liver failure. Liver regeneration after partial hepatectomy in rodents has been extensively studied by researchers for many years. It is divided into three important distinctive phases including (a) Initiation or priming phase which includes an overexpression of specific genes to prepare the liver cells for replication, (b) Proliferation phase in which the liver cells undergo a series of cycles of cell division and expansion and finally, (c) termination phase which acts as brake to stop the regenerative process and prevent the liver tissue overgrowth. These events are well controlled by cytokines, growth factors, and signaling pathways. In this review, we describe the function, embryology, and anatomy of human liver, discuss the molecular basis of liver regeneration, elucidate the hepatocyte and cholangiocyte lineages mediating this process, explain the role of hepatic progenitor cells and elaborate the developmental signaling pathways and regulatory molecules required to procure a complete restoration of hepatic lobule.
SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic–smoking interaction analysis

Smoking cessation prolongs survival and decreases mortality of patients with non‐small‐cell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenome‐wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a two‐stage study design to identify DNA methylation–smoking cessation interactions that affect overall survival for early‐stage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histology‐stratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation–smoking cessation interaction terms. Interactions with false discovery rate‐q ≤ 0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histology‐specific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510SIPA1L3) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)interaction = 1.12; 95% confidence interval (CI): 1.07–1.16; P = 4.30 × 10–7]. Further, the effect of smoking cessation on early‐stage LUAD survival varied across patients with different methylation levels of cg02268510SIPA1L3. Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34–0.82; P = 4.61 × 10–3) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86–1.70; P = 0.266) of cg02268510SIPA1L3. Moreover, there was an antagonistic interaction between elevated methylation of cg02268510SIPA1L3 and smoking cessation (HRinteraction = 2.1835; 95% CI: 1.27–3.74; P = 4.46 × 10−3). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510SIPA1L3. The results have implications for not only smoking cessation after diagnosis, but also possible methylation‐specific drug targeting.
Neural basis of somatosensory target detection independent of uncertainty, relevance, and reports

Research on somatosensory awareness has yielded highly diverse findings with putative neural correlates ranging from activity within somatosensory cortex to activation of widely distributed frontoparietal networks. Divergent results from previous studies may reside in cognitive processes that often coincide with stimulus awareness in experimental settings. To scrutinise the specific relevance of regions implied in the target detection network, we used functional magnetic resonance imaging (n = 27) on a novel somatosensory detection task that explicitly controls for stimulus uncertainty, behavioural relevance, overt reports, and motor responses. Using Bayesian Model Selection, we show that responses reflecting target detection are restricted to secondary somatosensory cortex, whereas activity in insular, cingulate, and motor regions is best explained in terms of stimulus uncertainty and overt reports. Our results emphasise the role of sensory-specific cortex for the emergence of perceptual awareness and dissect the contribution of the frontoparietal network to classical detection tasks.