Miracle-dz/UniFAR-FTUs huggingface dataset:
CTLA-4 Gene Polymorphism at Position 49 in Exon 1 Reduces the Inhibitory Function of CTLA-4 and Contributes to the Pathogenesis of Graves’ Disease1

Activation of T cells requires at least two signals transduced by the Ag-specific TCR and a costimulatory ligand such as CD28. CTLA-4, expressed on activated T cells, binds to B7 present on APCs and functions as a negative regulator of T cell activation. Our laboratory previously reported the association of Graves’ disease (GD) with a specific CTLA-4 gene polymorphism. In theory, reduced expression or function of CTLA-4 might augment autoimmunity. In the present study, we categorized autoimmune thyroid disease patients and normal controls (NC) by genotyping a CTLA-4 exon 1 polymorphism and investigated the function of CTLA-4 in all subjects. PBMCs and DNA were prepared from GD (n = 45), Hashimoto’s thyroiditis (HT) (n = 18), and NC (n = 43). There were more GD patients with the G/G or A/G alleles (82.2% vs 65.1% in NC), and significantly fewer patients with the A/A allele (17.8% vs 34.9% in NC). In the presence of soluble blocking anti-human CTLA-4 mAb, T cell proliferation following incubation with allogeneic EBV-transformed B cells was augmented in a dose-dependent manner. Augmentation induced by CTLA-4 mAb was similar in GD and NC (GD, HT, NC = 156%, 164%, 175%, respectively). We related CTLA-4 polymorphism to mAb augmentation of T cell proliferation in each subgroup (GD, HT, NC). Although PBMC from individuals with the G/G alleles showed 132% augmentation, those with the A/A alleles showed 193% augmentation (p = 0.019). CTLA-4 polymorphism affects the inhibitory function of CTLA-4. The G allele is associated with reduced control of T cell proliferation and thus contributes to the pathogenesis of GD and presumably of other autoimmune diseases.
Normal and Proton Pump Inhibitor–Mediated Gastrin Levels in Infants 1 to 11 Months Old

Background: Scant data exist on the normal range of serum gastrin in infants. In phase I and III trials of rabeprazole in gastroesophageal reflux disease, we studied serum gastrin levels in infants 1 to 11 months old, and assessed normal ranges and the effect of acid-suppressive drugs. Methods: Overall, 349 treatment-naïve or treatment-experienced (previously exposed to proton pump inhibitors and/or H2-receptor antagonists) infants with gastroesophageal reflux disease were screened for baseline serum gastrin. Repeat gastrin was monitored at early termination or end of study, allowing assessment of 1 to 8 week daily rabeprazole (5- or 10-mg) treatment on gastrin levels. Results: Median (5%–95% range) baseline gastrin was 118 ng/L (39–315) in the treatment-naïve group (n = 251), driven mostly by high levels (121.5 [48–326] ng/L) in the 1- to <4-month-old subgroup. Treatment-experienced infants (n = 98) had elevated baseline gastrin levels (152 [48–487] ng/L; P = 0.0011) with no clear difference between previously proton pump inhibitor–exposed and H2-receptor antagonist–exposed groups. At the end of study, mean (standard deviation) levels were unchanged from baseline in infants withdrawn from rabeprazole to placebo (124 [94] ng/L), but elevated from baseline in those continuing treatment with 5-mg (245 [151] ng/L) and 10-mg (332 [222] ng/L) rabeprazole during the study. Conclusions: Gastrin levels in treatment-naïve infants were elevated through 8 months of age. Between 8 and 12 months of age, they declined so that the median level was within the upper limit of the normal adult range (<100 ng/L). Previous exposure to acid-suppressive medications and short-term exposure to rabeprazole significantly increased gastrin levels in infants younger than 1 year.
Molecular Mechanisms of Liver Injury and Hepatocarcinogenesis: Focusing on the Role of Stress-Activated MAPK

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH2-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway.
Multi‐scale patterns of forest structure and species composition in relation to climate in northeast China

Though a number of studies have focused on the factors that shape the structure and dynamics of temperate forests, little is known about whether these factors vary with spatial scale. In this study we investigated compositional and structural patterns of forests across three spatial scales (plot, local assemblages and regions) in northeast China and asked whether climatic variables shape these patterns. Using a systematic sampling design, we measured diameter at breast height (DBH) and height of trees, and recorded the abundances, percent of cover and heights of shrubs and herbs in 141 plots from 10 nature reserves. We found that summer temperature accounted for most of the variation in species composition, both within and among forest types. DBH, tree height and total basal area all increased significantly with summer temperature while stem density decreased. The DBH frequency distribution depended strongly on temperature (especially winter temperature) and varied among spatial scales, and it tended to be more left-skewed as temperature increased. Taking together, our results suggest that a warming climate could lead to an increase in tree growth and the changes in size structure of temperate forests in northeast China. In particular, the proportion of large trees will in all likelihood increase while that of smaller trees will decrease. Shifts in forest structure in a warmed world will undoubtedly influence forest management practices, ecosystem dynamics, and species conservation.
Local Diagnostic Reference Levels for Adult Computed Tomography Urography Exams

A Computed Tomography Urography (CTU) scan is a medical imaging test that examines the urinary tract, including the bladder, kidneys, and ureters. It helps diagnose various urinary tract diseases with precision. However, patients undergoing CTU imaging receive a relatively high dose of radiation, which can be a concern. In our research paper, we analyzed the Computed Tomography Dose Index (CTDIvol) and Dose-Length Product (DLP) for 203 adult patients who underwent CTU at one of the most important regional centers in Bosnia and Herzegovina that sees a large number of patients. Our study included the distribution of age and sex, the number of phases within one examination, and different clinical indications. We compared our findings with the results available in the scientific literature, particularly the recently published results from 20 European countries. Furthermore, we established the local diagnostic reference levels (LDRLs) that can help set the national diagnostic reference levels (NDRLs). We believe our research is a significant step towards optimizing the protocols used in different hospitals in our country.
Knowledge modeling at the millennium : The design and evolution of Protégé-2000

It has been 13 years since the first version of Protégé was run. The original tool was a small application, aimed mainly at building knowledge-acquisition tools for a few very specialized programs (it grew out of the ONCOCIN project and the subsequent attempts to build expert systems for protocol-based therapy planning). The most recent version, Protégé-2000, incorporates the Open Knowledge Base Connectivity (OKBC) knowledge model, is written to run across a wide variety of platforms, supports customized user-interface extensions, and has been used by over 300 individuals and research groups, most of whom are only peripherally interested in medical informatics. Researchers not directly involved in the project might well wonder how Protégé evolved, what are the reasons for the repeated reimplementations, and how to tell the various versions apart. In this paper, we give an overview of the evolution of Protégé, examining the methodological assumptions underlying the original Protégé system and discussing the ways in which the methodology has changed over time. We conclude with an overview of the latest version of Protégé, Protégé-2000. 1. MOTIVATION AND A TIMELINE The Protégé applications (hereafter ‘Protégé’) are a set of tools that have been evolving for over a decade, from a simple program which helped construct specialized knowledge-bases to a set of general purpose knowledge-base creation and maintenance tools. While Protégé began as a small application designed for a medical domain (protocol-based therapy planning), it has grown and evolved to become a much more general-purpose set of tools for building knowledge-based systems. The original goal of Protégé was to reduce the knowledge-acquisition bottleneck (Hayes-Roth et al, 1983) by minimizing the role of the knowledge-engineer in constructing knowledge-bases. In order to do this, Musen (1988, 1989b) posited that knowledge-acquisition proceeds in welldefined stages and that knowledge acquired in one stage could be used to generate and customize knowledge-acquisition tools for subsequent stages. In (Musen, 1988), Protégé was defined as an application that takes advantage of this structured information to simplify the knowledgeacquisition process. The original Protégé was described this way (Musen, 1988): Protégé is neither an expert system itself nor a program that builds expert systems directly. Instead, Protégé is a tool that helps users build other tools that are custom-tailored to assist with knowledgeacquisition for expert systems in specific application areas. The original Protégé demonstrated the viability of this approach, and of the use of task-specific knowledge to generate and customize knowledge-acquisition tools. But as with many first-
Brain Imaging, Connectionism, and Cognitive Neuropsychology

I’m still an ultra-cognitive-neuropsychologist after all these years, and so my comments on Trevor Harley’s most interesting book review will be from that perspective. Ultra-cognitive-neuropsychologists take cognitive neuropsychology to be a branch of cognitive psychology. The aim of cognitive psychology is to learn more about the mental information-processing systems that people use to carry out various cognitive activities. Some cognitive psychologists do that by studying the performance of people whose cognitive processing systems are normal. Others do it by studying people in whom some cognitive processing system is abnormal: Such investigators are cognitive neuropsychologists. Cognitive neuropsychologists are not studying the brain. Investigating the brain processes upon which carrying out cognitive activities depends is a different discipline with a different name: It is called cognitive neuroscience. Some cognitive neuropsychologists are also cognitive neuroscientists because they do both kinds of work (Tim Shallice, Chris Frith, or Martha Farah, for example); some are just plain cognitive neuropsychologists (John Marshall, Alfonso Caramazza, or Max Coltheart, for example).
Exploring the Role of Platelets in Virus-Induced Inflammatory Demyelinating Disease and Myocarditis

Theiler’s murine encephalomyelitis virus (TMEV) infection has been used as a mouse model for two virus-induced organ-specific immune-mediated diseases. TMEV-induced demyelinating disease (TMEV-IDD) in the central nervous system (CNS) is a chronic inflammatory disease with viral persistence and an animal model of multiple sclerosis (MS) in humans. TMEV infection can also cause acute myocarditis with viral replication and immune cell infiltration in the heart, leading to cardiac fibrosis. Since platelets have been reported to modulate immune responses, we aimed to determine the role of platelets in TMEV infection. In transcriptome analyses of platelets, distinct sets of immune-related genes, including major histocompatibility complex (MHC) class I, were up- or downregulated in TMEV-infected mice at different time points. We depleted platelets from TMEV-infected mice by injecting them with platelet-specific antibodies. The platelet-depleted mice had significantly fewer viral antigen-positive cells in the CNS. Platelet depletion reduced the severities of TMEV-IDD and myocarditis, although the pathology scores did not reach statistical significance. Immunologically, the platelet-depleted mice had an increase in interferon (IFN)-γ production with a higher anti-TMEV IgG2a/IgG1 ratio. Thus, platelets may play roles in TMEV infection, such as gene expression, viral clearance, and anti-viral antibody isotype responses.
Efficient Node Admission and Certificateless Secure Communication in Short-Lived MANETs

Decentralized node admission is an essential and fundamental security service in mobile ad hoc networks (MANETs). It is needed to securely cope with dynamic membership and topology as well as to bootstrap other important security primitives (such as key management) and services (such as secure routing) without the assistance of any centralized trusted authority. An ideal admission technique must involve minimal interaction among MANET nodes, since connectivity can be unstable. Also, since MANETs are often composed of weak or resource-limited devices, admission must be efficient in terms of computation and communication. Most previously proposed admission protocols are prohibitively expensive and require heavy interaction among MANET nodes. In this paper, we focus on a common type of MANET that is formed on a temporary basis, and present a secure, efficient, and a fully noninteractive admission technique geared for this type of a network. Our admission protocol is based on secret sharing techniques using bivariate polynomials. We also present a new scheme that allows any pair of MANET nodes to efficiently establish an on-the-fly secure communication channel.
Impact of Gate/Spacer-Channel Underlap, Gate Oxide EOT, and Scaling on the Device Characteristics of a DG-RFET

A reconfigurable field-effect transistor (RFET) with the ability to provide both n- and p-type characteristics with a single transistor is among the class of those emerging devices which show great promise to become the building block of future nanoelectronics. A comprehensive investigation using extensive 3-D device simulations on the effects of varying the gate–channel and spacer-channel underlap on the device characteristics of such a DG-RFET is reported for the first time in this paper. It is demonstrated that by appropriate designing of the gate- and spacer-channel underlap, the on-current and on–off current ratio of the device can be significantly improved. Moreover, it is also found that increasing the gate dielectric constant for a fixed equivalent oxide thickness improves its delay performance. Finally, we have also reported results related to the scaling properties of such a device.
The Long-Term Esthetic and Radiographic Outcome of Implants Placed in the Anterior Maxilla after Ridge Preservation, Combining Bovine Xenograft with Collagen Matrix

The objective of the study was to evaluate the long-term esthetic and radiographic results of implants placed in the anterior maxilla after ridge preservation, combining bovine xenograft with collagen matrix. Fifteen patients who required a single tooth extraction because of fracture, root resorption, or extended caries were included in the study. After extraction, all sites were grafted using Deproteinized Bovine Bone Mineral (DBBM) with collagen and covered by a resorbable collagen matrix (CM). Five months after socket grafting, implants were successfully installed. The implant diameter range was between 3.8 and 4.2 mm. All patients were monitored for over 7 years, both clinically and radiographically. Three independent observers evaluated the long-term esthetic outcome, employing the Pink Esthetic Score (PES) technique. Over a period exceeding seven years, a 100% survival rate was observed for all 15 implants, with minimal marginal bone loss. The mean PES was 11.40 (±1.44) at the first assessment and 11.38 (±1.63) at the second assessment. The difference was not statistically significant (p = 0.978), and the scores of PES measurements indicated excellent esthetic results even after seven years. Based on these preliminary results, it seems that placing collagen bovine bone in a fresh extraction socket, covered with a collagen matrix, can preserve the alveolar ridge and provide long-term stable esthetic results.
Barriers Associated with Adherence to Cervical Cancer Screening Among Women Living with HIV in Nkhatabay District, Malawi: A Mixed-Methods Study

Background Cervical cancer (CC) incidence among Women Living with HIV (WLHIV) is high compared to the general population of women. As such, the Malawi National CC guideline recommends yearly screening among WLHIV. However, only 15.9% of WLHIV were screened nationally using Visual Inspection with Acetic Acid (VIA) by 2015 and there is no data regarding adherence and barriers to yearly screening. This study assessed adherence levels and associated barriers to yearly Cervical Cancer screening (CCS) among WLHIV. Methods A cross-sectional concurrent mixed-method study was conducted at Nkhatabay District Hospital (NBDH) and Chintheche Rural Hospital (CRH) in Malawi. A sample of 205 WLHIV participated in quantitative strand and in-depth interviews were conducted with 10 health care workers and 10 WLHIV. Quantitative data were analysed using STATA version 16. Pearson’s chi-square test and Multivariate logistic regression analysis were performed. P value was set at 0.05. Qualitative data were analysed deductively following six steps of thematic analysis. Results Only 5.4% (n=11) of the participants had been screened as required. Women aged ≥45 had 4 times the odds of being screened for CC compared to ≤30 (OR 4.18, 95% CI 0.65–26.8). WLHIV on ART > 10 years had more than 5 times the odds of being screened (OR 5.9, 95% CI 1.08–33.19) compared with those on ART <3 years. Use of male service providers (p =< 0.001), fear of the VIA procedure (p = <0.001) and lack of interest (p = <0.015) were significant barriers to adherence. Qualitative findings revealed a lack of knowledge regarding CCS protocol and the use of male providers. Conclusion WLHIV face many challenges in accessing CCS and adherence to yearly CCS is very low. There is urgent need for targeted community awareness, scaling up of HPV tests and incorporation of CCS into routine integrated outreach services.
Engineered Bivalent Ligands to Bias ErbB Receptor-mediated Signaling and Phenotypes*

The ErbB receptor family is dysregulated in many cancers, and its therapeutic manipulation by targeted antibodies and kinase inhibitors has resulted in effective chemotherapies. However, many malignancies remain refractory to current interventions. We describe a new approach that directs ErbB receptor interactions, resulting in biased signaling and phenotypes. Due to known receptor-ligand affinities and the necessity of ErbB receptors to dimerize to signal, bivalent ligands, formed by the synthetic linkage of two neuregulin-1β (NRG) moieties, two epidermal growth factor (EGF) moieties, or an EGF and a NRG moiety, can potentially drive homotypic receptor interactions and diminish formation of HER2-containing heterodimers, which are implicated in many malignancies and are a prevalent outcome of stimulation by native, monovalent EGF, or NRG. We demonstrate the therapeutic potential of this approach by showing that bivalent NRG (NN) can bias signaling in HER3-expressing cancer cells, resulting in some cases in decreased migration, inhibited proliferation, and increased apoptosis, whereas native NRG stimulation increased the malignant potential of the same cells. Hence, this new approach may have therapeutic relevance in ovarian, breast, lung, and other cancers in which HER3 has been implicated.
Outcome at 5–6 years of prematurely born children who received morphine as neonates

AIM To assess outcome at 5–6 years in a cohort of very preterm infants (<34 weeks of gestation) who had been randomly allocated within a controlled clinical trial to receive morphine or non-morphine treatment in the neonatal period. METHODS Assessments were made on 87 children at 5–6 years who had been recruited in the neonatal period to two sequential controlled studies (1989–92). Infants requiring mechanical ventilation had been randomly allocated to receive either morphine (n=62) or other (n=33) solutions starting on the first day of life. Each child was seen by a single experienced observer and assessed at 5–6 years using the WPPSI-R, Movement ABC, and the Child Behaviour Checklist. The performance of children exposed to morphine was compared with that of those in the non-morphine group. Blood samples for thyroid stimulating hormone (TSH) measurement were obtained from children whose parents gave consent. RESULTS There was no significant difference in any of the three test scales between infants in the two groups, but there was a trend towards better performance in all three tests in the morphine group. Assessment of TSH values in a subgroup of the survivors showed no difference in thyroid function between the two groups. CONCLUSION Exposure to morphine in the neonatal period to facilitate mechanical ventilation does not seem to have any adverse effects on intelligence, motor function, or behaviour when these children are assessed at 5–6 years of age.