Miracle-dz/UniFAR-FTUs huggingface dataset:
The Hepatic Central Vein: Structure, Fibrosis, and Role in Liver Biology

The hepatic central vein is a primary source of Wnt2, Wnt9b, and R‐spondin3. These angiocrines activate ß‐catenin signaling to regulate hepatic metabolic zonation and perivenous gene expression in mice. Little is known about the central vein ultrastructure. Here, we describe the morphological–functional correlates of the central vein and its draining and branching patterns. Central vein fibrosis occurs in liver disease and is often accompanied by perivenous perisinusoidal fibrosis, which may affect perivenous gene expression. We review the biological properties of perivenous hepatocytes and glutamine synthetase that serve as a biomarker of perivenous hepatocytes. Glutamine synthetase and P4502E1 are indicators of ß‐catenin activity in centrilobular liver injury and regeneration. The Wnt/ß‐catenin pathway is the master regulator of hepatic metabolic zonation and perivenous gene expression and is modulated by the R‐spondin‐LGR4/5‐ZNRF3/RNF43 module. We examined the structures of the molecules of these pathways and their involvements in liver biology. Central vein‐derived Wnts and R‐spondin3 participate in the cellular–molecular circuitry of the Wnt/ß‐catenin and R‐spondin‐LGR4/5‐ZNRF3/RNF43 module. The transport and secretion of lipidated Wnts in Wnt‐producing cells require Wntless protein. Secreted Wnts are carried on exosomes in the extracellular matrix to responder cells. The modes of release of Wnts and R‐spondin3 from central veins and their transit in the venular wall toward perivenous hepatocytes are unknown. We hypothesize that central vein fibrosis may impact perivenous gene expression. The proposal that the central vein constitutes an anatomical niche of perivenous stem cells that subserve homeostatic hepatic renewal still needs studies using additional mouse models for validation. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1747–1767, 2020. © 2019 American Association for Anatomy
Delay-Differential-Equation Modeling of Mode-Locked Vertical-External-Cavity Surface-Emitting Lasers in Different Cavity Configurations

A simple, versatile model for the dynamics of electrically and optically pumped vertical-external-cavity surface-emitting lasers, which are mode locked by a semiconductor saturable-absorber mirror, is presented. The difference between the laser operation in the linear and folded cavity, as well as the potential for a colliding pulse operation, are studied.
Patient‐reported outcomes and inflammatory biomarkers in patients with locally advanced/metastatic urothelial carcinoma treated with durvalumab in phase 1/2 dose‐escalation study 1108

Durvalumab has shown meaningful clinical activity in patients with metastatic urothelial carcinoma (mUC) in Study 1108 (NCT01693562). An important focus in treatment is health‐related quality of life (HRQOL). Here, patient‐reported outcomes (PROs) from Study 1108 and their relationship with inflammatory biomarkers are explored.
Dual Function of Magnesium in Bone Biomineralization

Magnesium (Mg2+), as a main component of bone, is widely applied to promote bone growth and regeneration. However, Mg2+ can chemically inhibit the crystallization of amorphous calcium phosphate into hydroxyapatite (HA). The underlying mechanisms by which Mg2+ improves bone biomineralization remain elusive. Here, it is demonstrated that Mg2+ plays dual roles in bone biomineralization from a developmental perspective. During embryonic development, the Mg2+ concentration is enriched in the early stage from embryonic day 13.5 (E13.5) to E15.5, but gradually decreases to a stable state in the late phase, after E15.5. Appropriate concentrations of Mg2+ can promote the mineralization of bone marrow mesenchymal stem cells, while excessive Mg2+ impairs their osteogenesis. The earlier the Mg2+ is added, the stronger the observed inhibition of mineralization. In particular, less Mg2+ is present in fully mineralized collagen than in poorly mineralized collagen. Furthermore, a high concentration of Mg2+ changes the crystalline morphology of HA and inhibits collagen calcification. Functionally, a high‐Mg2+ diet inhibits bone biomineralization in mouse offspring. Taken together, the results suggest that appropriate regulation of Mg2+ concentration over time is vital for normal biomineralization. This study is significant for the future design of bone substitutes and implants associated with Mg2+ content.
A Hydrothermal-Assisted Ball Milling Approach for Scalable Production of High-Quality Functionalized MoS2 Nanosheets for Polymer Nanocomposites

The most known analogue of graphene, molybdenum disulfide (MoS2) nanosheet, has recently captured great interest because it can present properties beyond graphene in several high technological applications. Nonetheless, the lack of a feasible, sustainable, and scalable approach, in which synthesizing and functionalization of 2H-MoS2 nanosheets occur simultaneously, is still a challenge. Herein, a hydrothermal treatment has been utilised to reduce the effect of breaking mechanisms on the lateral size of produced nanosheets during the ball milling process. It was demonstrated that the hydrothermal pre-treatment led to the initial intercalation of an organic molecule such as 4,4′-diaminodiphenyl sulfone (DDS) within the stacked MoS2 sheets. Such a phenomenon can promote the horizontal shear forces and cause sliding and peeling mechanisms to be the dominated ones during low energy ball milling. Such combined methods can result in the production of 2H functionalized MoS2 nanosheets. The resultant few layers showed an average lateral dimension of more than 640 nm with the thickness as low as ~6 nm and a surface area as high as ~121.8 m2/g. These features of the synthesised MoS2 nanosheets, alongside their functional groups, can result in fully harnessing the reinforcing potential of MoS2 nanosheets for improvement of mechanical properties in different types of polymeric matrices.
New Frontiers in Diagnosis and Therapy of Circulating Tumor Markers in Cerebrospinal Fluid In Vitro and In Vivo

One of the greatest challenges in neuro-oncology is diagnosis and therapy (theranostics) of leptomeningeal metastasis (LM), brain metastasis (BM) and brain tumors (BT), which are associated with poor prognosis in patients. Retrospective analyses suggest that cerebrospinal fluid (CSF) is one of the promising diagnostic targets because CSF passes through central nervous system, harvests tumor-related markers from brain tissue and, then, delivers them into peripheral parts of the human body where CSF can be sampled using minimally invasive and routine clinical procedure. However, limited sensitivity of the established clinical diagnostic cytology in vitro and MRI in vivo together with minimal therapeutic options do not provide patient care at early, potentially treatable, stages of LM, BM and BT. Novel technologies are in demand. This review outlines the advantages, limitations and clinical utility of emerging liquid biopsy in vitro and photoacoustic flow cytometry (PAFC) in vivo for assessment of CSF markers including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNA (miRNA), proteins, exosomes and emboli. The integration of in vitro and in vivo methods, PAFC-guided theranostics of single CTCs and targeted drug delivery are discussed as future perspectives.
Serum Anti-Müllerian Hormone in the Diagnosis of Polycystic Ovary Syndrome in Association with Clinical Symptoms

Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine diseases affecting women of reproductive age. The pathogeny of PCOS is still not completely understood, but one contributing factor that has been proposed is anti-Müllerian hormone (AMH). There is currently no clear correlation between levels of AMH and incidence of PCOS in Saudi Arabian patients. The goal of this study was to determine the threshold of AMH and correlate it with PCOS clinical features to facilitate a proper diagnosis for PCOS. In this case-control study, we recruited 79 PCOS women and 69 normal ovulatory women; PCOS patients were diagnosed according to the Rotterdam criterion. On days 2–4 of the menstrual cycle, transvaginal/abdominal ultrasound was performed and serum levels of AMH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured for all participants. The receiver operating characteristic curve (ROC) was used to determine the AMH diagnostic cut-off at 3.19 ng/mL, with 72% sensitivity and 70% specificity; AMH > 3.19 ng/mL was significantly correlated with PCOS. High AMH levels were correlated with age at menarche, polycystic ovarian morphology (PCOM), and oligo/amenorrhea. Serum AMH is a promising diagnostic marker of ovarian dysfunction in PCOS patients especially in cases in which the evaluation of PCOM was complicated.
Effectiveness of Intraoperative Laser Acupuncture Combined with Antiemetic Drugs for Prevention of Postoperative Nausea and Vomiting.

Introduction: Postoperative nausea and vomiting (PONV) are frequent in patients undergoing laparoscopic cholecystectomy. The aim of this study is to evaluate the effectiveness of intraoperative laser acupuncture stimulation of Pericardium 6 (PC6) and Large Intestine 4 (LI4) acupoints combined with antiemetic drug prophylaxis on PONV. Methods: A total of 88 patients, scheduled for laparoscopic cholecystectomy, were assigned into 2 groups. Group I received bilateral laser acupuncture on PC6 and LI4 acupoints after induction of anesthesia and also received antiemetic drug (metoclopramide) prophylaxis. Patients in Group II received only antiemetic drug prophylaxis. Nausea and vomiting frequencies and need for rescue antiemetic drug (ondansetron) were recorded after extubation, at 30th minute at recovery room and at 6th hour at ward. Results: The incidence of nausea and rescue antiemetic drug need was higher at postoperative 6th hour in Group II. Vomiting was not different in groups at any time. Conclusion: Intraoperative laser acupuncture stimulation of PC6 and LI4 acupoints combined with antiemetic drug prophylaxis decreases nausea and rescue antiemetic drug need in late postoperative period in patients undergoing laparoscopic cholecystectomy.
Investigating the Role of the Eurasian Badger (Meles meles) in the Nationwide Distribution of the Western European Hedgehog (Erinaceus europaeus) in England

Simple Summary The hedgehog is a species known to many in society. What is perhaps less known, is that the hedgehog has been declining across large parts of Europe, including the United Kingdom. Effective hedgehog conservation requires a sound understanding of the causes of the decline. A potential cause is the badger, whose population has been recovering in recent years. The badger is an intraguild predator of the hedgehog, meaning that not only do the two species share the same food, like snails and earthworms, but badgers also predate on hedgehogs. Our study investigates how the presence of hedgehogs is related to the presence of badgers, along with other landscape features. Using information from two nationwide citizen science surveys, we first determine where both species can be found and then identify which factors best explain hedgehog presence. We found that the badger was indeed important, and hedgehogs were less likely to be found in areas where badgers were likely to be found. Interestingly, hedgehogs were also likely to be found in arable land, a habitat not directly thought to be favourable for hedgehogs. Badgers may, therefore, be an important consideration when designing hedgehog conservation plans, and further research of these impacts is needed. Abstract Biodiversity is declining globally, which calls for effective conservation measures. It is, therefore, important to investigate the drivers behind species presence at large spatial scales. The Western European hedgehog (Erinaceus europaeus) is one of the species facing declines in parts of its range. Yet, drivers of Western European hedgehog distribution at large spatial scales remain largely unknown. At local scales, the Eurasian badger (Meles meles), an intraguild predator of the Western European hedgehog, can affect both the abundance and the distribution of the latter. However, the Western European hedgehog and the Eurasian badger have shown to be able to co-exist at a landscape scale. We investigated whether the Eurasian badger may play a role in the likelihood of the presence of the Western European hedgehog throughout England by using two nationwide citizen science surveys. Although habitat-related factors explained more variation in the likelihood of Western European hedgehog presence, our results suggest that Eurasian badger presence negatively impacts the likelihood of Western European hedgehog presence. Intraguild predation may, therefore, be influencing the nationwide distribution of hedgehogs in England, and further research is needed about how changes in badger densities and intensifying agricultural practices that remove shelters like hedgerows may influence hedgehog presence.
Host Range of Bacteriophages Against a World-Wide Collection of Erwinia amylovora Determined Using a Quantitative PCR Assay

Erwinia amylovora is a globally devastating pathogen of apple, pear, and other Rosaceous plants. The use of lytic bacteriophages for disease management continues to garner attention as a possible supplement or alternative to antibiotics. A quantitative productive host range was established for 10 Erwinia phages using 106 wild type global isolates of E. amylovora, and the closely related Erwinia pyrifoliae, to investigate the potential regional efficacy of these phages within a biopesticide. Each host was individually infected with each of the 10 Erwinia phages and phage production after 8 h incubation was measured using quantitative real time PCR (qPCR) in conjunction with a standardized plasmid. PCR amplicons for all phages used in the study were incorporated into a single plasmid, allowing standardized quantification of the phage genome copy number after the infection process. Nine of the tested phages exhibited a broad host range, replicating their genomes by at least one log in over 88% of tested hosts. Also, every Amygdaloideae infecting E. amylovora host was able to increase at least one phage by three logs. Bacterial hosts isolated in western North America were less susceptible to most phages, as the mean genomic titre produced dropped by nearly two logs, and this phenomenon was strongly correlated to the amount of exopolysaccharide produced by the host. This method of host range analysis is faster and requires less effort than traditional plaque assay techniques, and the resulting quantitative data highlight subtle differences in phage host preference not observable with typical plaque-based host range assays. These quantitative host range data will be useful to determine which phages should be incorporated into a phage-mediated biocontrol formulation to be tested for regional and universal control of E. amylovora.
Associations among Neighborhood Socioeconomic Deprivation, Physical Activity Facilities, and Physical Activity in Youth during the Transition from Childhood to Adolescence

Background: This study aims to examine the longitudinal association of neighborhood socioeconomic deprivation (SED) with physical activity in youth during the transition from elementary to middle school, and to determine if access to physical activity facilities moderates this relationship. Methods: Data were obtained from the Transitions and Activity Changes in Kids (TRACK) study, which was a multilevel, longitudinal study designed to identify the factors that influence changes in physical activity as youth transition from elementary to middle school. The analytic sample for the current study included 660 youth with complete data in grades 5 (baseline) and 7 (follow-up). A repeated measures multilevel framework was employed to examine the relationship between SED and physical activity over time and the potential moderating role of elements of the built environment. Results: Decreases in physical activity varied by the degree of neighborhood SED with youth residing in the most deprived neighborhoods experiencing the greatest declines in physical activity. Access to supportive physical activity facilities did not moderate this relationship. Conclusion: Future research studies are needed to better understand how neighborhood SED influences youth physical activity over time.
Prevalence of isolated nocturnal hypertension according to 2018 European Society of Cardiology and European Society of Hypertension office blood pressure categories.

OBJECTIVES To estimate the prevalence of isolated nocturnal hypertension (INH) and its relationships with office blood pressure (BP) categories defined by 2018 ESC/ESH guidelines. METHODS We conducted a prospective cohort study in consecutive patients referred to perform an ambulatory blood pressure monitoring (ABPM) for diagnosis or therapeutic purposes. Office BP measurements and ABPM was performed in the same visit. The cohort was divided according to office BP in optimal, normal, high-normal and hypertension. The prevalence and adjusted risk for combined daytime and nocturnal hypertension and INH were estimated for each category. RESULTS We evaluated 1344 individuals, 59.3% women (51 ± 14 years old) and 40.7% men (52 ± 15 years old). 61.5% of the individuals had nocturnal hypertension, 12.9% INH and 48.7% combined daytime and nocturnal hypertension. Prevalence of combined daytime and nocturnal hypertension increased through office BP categories (P < 0.001). Conversely, prevalence of INH was lower in individuals with hypertension than in normotensives (7.4 vs. 17.2%, P < 0.001) and similar between nonhypertensive office BP categories, 16.6, 15 and 19.4% for optimal, normal and high-normal BP, respectively (P < 0.399). In individuals with office BP values less than 140/90 mmHg, the prevalence phenotypes of masked hypertension were 8.6, 17.2 and 30.2% for daytime, INH and combined daytime and nocturnal hypertension, respectively. Adjusted risk for combined daytime and nocturnal hypertension increased significantly through office BP categories; conversely, the risk for INH was similar in all nonhypertensive office BP categories. CONCLUSION Nocturnal hypertension was the more prevalent phenotype of masked hypertension and more than one-third of the individuals with nocturnal hypertension had INH. The risk for INH was not related to nonhypertensive office BP categories.
Motor inactivity in hibernating frogs: Linking plasticity that stabilizes neuronal function to behavior in the natural environment

All animals must generate reliable neuronal activity to produce adaptive behaviors in an ever‐changing environment. Neural systems are thought to achieve this goal, in part, through cellular and synaptic plasticity mechanisms that stabilize electrophysiological functions. Despite strong evidence for a role in regulating neuronal properties, these plasticity mechanisms have been difficult to link to natural behaviors in animals. In this review, I discuss how animals that inhabit extreme environments can address this challenge. As an example, I highlight recent work from frogs that stop breathing for several months during hibernation and, in response, use classic mechanisms of stabilizing plasticity to support respiratory motor output shortly after emergence. Furthermore, I describe problems for neuronal stability that may benefit from the study of hibernators: how circuits with variable modes of output control stabilizing mechanisms over long time scales and why some neural systems mount robust compensatory responses and others do not. By continuing to appreciate how diverse animal groups overcome challenges in the natural environment, we will broaden our view of the role that plasticity mechanisms play in stabilizing the nervous system.
A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia

We present a laboratory-based prognostic calculator (designated CRO score) to risk stratify treatment-free survival in early stage (Rai 0) chronic lymphocytic leukemia (CLL) developed using a training-validation model in a series of 1,879 cases from Italy, the United Kingdom and the United States. By means of regression analysis, we identified five prognostic variables with weighting as follows: deletion of the short arm of chromosome 17 and unmutated immunoglobulin heavy chain gene status, 2 points; deletion of the long arm of chromosome 11, trisomy of chromosome 12, and white blood cell count >32.0x103/microliter, 1 point. Low-, intermediate- and high-risk categories were established by recursive partitioning in a training cohort of 478 cases, and then validated in four independent cohorts of 144 / 395 / 540 / 322 cases, as well as in the composite validation cohort. Concordance indices were 0.75 in the training cohort and ranged from 0.63 to 0.74 in the four validation cohorts (0.69 in the composite validation cohort). These findings advocate potential application of our novel prognostic calculator to better stratify early-stage CLL, and aid case selection in risk-adapted treatment for early disease. Furthermore, they support immunocytogenetic analysis in Rai 0 CLL being performed at the time of diagnosis to aid prognosis and treatment, particularly in today’s chemofree era.
The Association between Alcohol Consumption and Serum Metabolites and the Modifying Effect of Smoking

Alcohol consumption is an important lifestyle factor that is associated with several health conditions and a behavioral link with smoking is well established. Metabolic alterations after alcohol consumption have yet to be comprehensively investigated. We studied the association of alcohol consumption with metabolite patterns (MPs) among 2433 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study, and a potential modification by smoking. Alcohol consumption was self-reported through dietary questionnaires and serum metabolites were measured by a targeted approach. The metabolites were summarized as MPs using the treelet transform analysis (TT). We fitted linear models with alcohol consumption continuously and in five categories. We stratified the continuously modelled alcohol consumption by smoking status. All models were adjusted for potential confounders. Among men, alcohol consumption was positively associated with six MPs and negatively associated with one MP. In women, alcohol consumption was inversely associated with one MP. Heavy consumers differed from other consumers with respect to the “Long and short chain acylcarnitines” MP. Our findings suggest that long and short chain acylcarnitines might play an important role in the adverse effects of heavy alcohol consumption on chronic diseases. The relations seem to depend on gender and smoking status.