Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanisms of regulation and diversification of deubiquitylating enzyme function

ABSTRACT Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes. This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: ‘Exploitation of the host cell ubiquitin machinery by microbial effector proteins’ by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985–1996). ‘Cell scientist to watch – Mads Gyrd-Hansen’ (J. Cell Sci. 130, 1981–1983). Summary: This Commentary discusses poorly appreciated paradigms of how DUBs are activated, regulated and targeted to their appropriate substrates to achieve precise spatio-temporal control of ubiquitin signals within a specific biological pathway.
The Kv1-associated molecules TAG-1 and Caspr2 are selectively targeted to the axon initial segment in hippocampal neurons

ABSTRACT Caspr2 and TAG-1 (also known as CNTNAP2 and CNTN2, respectively) are cell adhesion molecules (CAMs) associated with the voltage-gated potassium channels Kv1.1 and Kv1.2 (also known as KCNA1 and KCNA2, respectively) at regions controlling axonal excitability, namely, the axon initial segment (AIS) and juxtaparanodes of myelinated axons. The distribution of Kv1 at juxtaparanodes requires axo-glial contacts mediated by Caspr2 and TAG-1. In the present study, we found that TAG-1 strongly colocalizes with Kv1.2 at the AIS of cultured hippocampal neurons, whereas Caspr2 is uniformly expressed along the axolemma. Live-cell imaging revealed that Caspr2 and TAG-1 are sorted together in axonal transport vesicles. Therefore, their differential distribution may result from diffusion and trapping mechanisms induced by selective partnerships. By using deletion constructs, we identified two molecular determinants of Caspr2 that regulate its axonal positioning. First, the LNG2-EGF1 modules in the ectodomain of Caspr2, which are involved in its axonal distribution. Deletion of these modules promotes AIS localization and association with TAG-1. Second, the cytoplasmic PDZ-binding site of Caspr2, which could elicit AIS enrichment and recruitment of the membrane-associated guanylate kinase (MAGuK) protein MPP2. Hence, the selective distribution of Caspr2 and TAG-1 may be regulated, allowing them to modulate the strategic function of the Kv1 complex along axons. Summary: The selective distribution of the cell adhesion molecules Caspr2 and TAG-1 might be responsible for positioning of Kv1 channels at the axon initial segment versus along the axon in hippocampal neurons.
Bleeding Disorders in Congenital Syndromes

Pediatricians provide a medical home for children with congenital syndromes who often need complex multidisciplinary care. There are some syndromes associated with thrombocytopenia, inherited platelet disorders, factor deficiencies, connective tissue disorders, and vascular abnormalities, which pose a real risk of bleeding in affected children associated with trauma or surgeries. The risk of bleeding is not often an obvious feature of the syndrome and not well documented in the literature. This makes it especially hard for pediatricians who may care for a handful of children with these rare congenital syndromes in their lifetime. This review provides an overview of the etiology of bleeding in the different congenital syndromes along with a concise review of the hematologic and nonhematologic clinical manifestations. It also highlights the need and timing of diagnostic evaluation to uncover the bleeding risk in these syndromes emphasizing a primary care approach.
A Study on Relapsed b-Cell Lymphoma in Elderly Patient of Bangladeshi Population with Rituximab, Gemcitabin and Oxaliplatin: an Effective Salvage Regimen

High-dose therapy (HDT) with stem-cell support is the reference treatment for relapsed lymphoma, but is not appropriate for all patients. In Bangladesh High-dose therapy with stem cell support is not yet available. Conventional salvage chemotherapies have been used with limited efficacy and significant toxicity. Rituximab, gemcitabin and oxaliplatin are active as single agents in relapsed or refractory lymphoma, and have demonstrated synergistic effects in vitro and in vivo. Twenty two patients with relapsed or refractory or b-cell lymphoma received up to Six cycle of R-GemOx (rituximab 375mg/m2 on day 1, gemcitabine 1000mg/m2 and oxaliplatin 100mg/m2 on day 2). The majority (60%) had diffuse large b-cell lymphoma. After four cycle of R-GemOx, the overall response rate was 90% (45% complete response (CR)/unconfirmed CR (CRu). High CR/CRu rates were observed in all histological subtypes. In patients who had previously received rituximab, the CR/CRu rate after six cycles was 70%. The 2 year event-free and overall survival rates (median follow-up of 24 months) were 55%, respectively, among responders, the probability of being disease free for 2 years was 70%. Treatment was generally well tolerated. R-GemOx shows promising activity with acceptable toxicity in patients with relapsed/refractory b-cell lymphoma. DOI: http://dx.doi. org/10.3329/akmmcj.v5i1. 18838 Anwer Khan Modern Medical College Journal Vol. 5, No. 1: January 2014, Pages 29-34
ANCA Associated Glomerulonephritis- An In-Depth Review

Inflammation of vasculature involving small to medium vessels associated with antineutrophil cytoplasmic antibodies or ANCA are collectively referred to as ANCA vasculitidis. In majority of such disorders there are few or no immune deposits and hence the term- “pauci immune vasculitis”. The three main conditions included in this group include microscopic polyangiitis, Granulomatosis with polyangiitis (GPA) - formerly known as Wegener’s granulomatosis, and Eosinophilic Granulomatosis with Polyangiitis (EGPA)-formerly known as Churg-Strauss Syndrome. There have been several advances in the last two decades in the classification, understanding of the pathogenesis and management of these conditions. To provide an update on the classification, pathology and pathogenesis and therapeutic advances for management of ANCA vasculitis is the focus of this in depth review.
Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

ABSTRACT Kindlins play an important role in supporting integrin activation by cooperating with talin; however, the mechanistic details remain unclear. Here, we show that kindlins interacted directly with paxillin and that this interaction could support integrin αIIbβ3 activation. An exposed loop in the N-terminal F0 subdomain of kindlins was involved in mediating the interaction. Disruption of kindlin binding to paxillin by structure-based mutations significantly impaired the function of kindlins in supporting integrin αIIbβ3 activation. Both kindlin and talin were required for paxillin to enhance integrin activation. Interestingly, a direct interaction between paxillin and the talin head domain was also detectable. Mechanistically, paxillin, together with kindlin, was able to promote the binding of the talin head domain to integrin, suggesting that paxillin complexes with kindlin and talin to strengthen integrin activation. Specifically, we observed that crosstalk between kindlin-3 and the paxillin family in mouse platelets was involved in supporting integrin αIIbβ3 activation and in vivo platelet thrombus formation. Taken together, our findings uncover a novel mechanism by which kindlin supports integrin αIIbβ3 activation, which might be beneficial for developing safer anti-thrombotic therapies. Summary: Kindlin supports integrin αIIbβ3 activation by forming a complex with paxillin and talin and thus enhancing talin binding to integrin.
The effects of prolonged exposure to cold on hypoxic pulmonary hypertension in rats

Pulmonary artery hypertension is a common occurrence in mammals exposed to high altitude, yet little is known about the response of cold-acclimated animals. To study this problem pulmonary arterial pressure (Ppa), systemic blood pressure (Psa) and the ratio of Ppa/Psa in cold-acclimated rats (CA, 8 weeks, 6 °C, n = 11) during exposure to low oxygen (10% O2) were measured by direct catheter methods and compared with those of controls raised at 22 °C (C, n = 10). There was no difference between CA and C in values of Ppa at a normal oxygen level (20.9% O2). When rats were exposed to 10% O2 Ppa increased significantly in C, while the increase in CA was not significant. The weights of the total ventricle (TV), right ventricle (RV) and left ventricle (LV) in the CA animals were increased significantly above the C values. The ratio of RV weight (RVW) to LV weight (LVW), however, was higher in C than in CA. During exposure to low oxygen, Psa did not change between the two groups. The ratio of Ppa/Psa was increased significantly in both groups when exposed to hypoxia. There were no significant differences in hematological measurements, including hematocrit (Ht), blood viscosity (CP) and red blood cells (RBC) between the CA and the C. It was concluded that the animals exposed to cold over a long period had no right ventricular hypertrophy (RVH) and the response to hypoxia in Ppa was lower in CA than that in C. The depression in hypoxic pulmonary vasoconstriction in CA may be caused by the decrease of RVW/LVW.
Multiple E2 ubiquitin-conjugating enzymes regulate human cytomegalovirus US2-mediated immunoreceptor downregulation

ABSTRACT Misfolded endoplasmic reticulum (ER) proteins are dislocated towards the cytosol and degraded by the ubiquitin–proteasome system in a process called ER-associated protein degradation (ERAD). During infection with human cytomegalovirus (HCMV), the viral US2 protein targets HLA class I molecules (HLA-I) for degradation via ERAD to avoid elimination by the immune system. US2-mediated degradation of HLA-I serves as a paradigm of ERAD and has facilitated the identification of TRC8 (also known as RNF139) as an E3 ubiquitin ligase. No specific E2 enzymes had previously been described for cooperation with TRC8. In this study, we used a lentiviral CRISPR/Cas9 library targeting all known human E2 enzymes to assess their involvement in US2-mediated HLA-I downregulation. We identified multiple E2 enzymes involved in this process, of which UBE2G2 was crucial for the degradation of various immunoreceptors. UBE2J2, on the other hand, counteracted US2-induced ERAD by downregulating TRC8 expression. These findings indicate the complexity of cellular quality control mechanisms, which are elegantly exploited by HCMV to elude the immune system. Summary: Multiple ubiquitin E2 enzymes involved in cytomegalovirus US2-mediated ERAD of immunoreceptors are identified. UBE2G2 is required for ERAD, whereas UBE2J2 counteracts it by downregulating the crucial TRC8 ubiquitin ligase.
Development of a Pediatric Adverse Events Terminology

In 2009, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Pediatric Terminology Harmonization Initiative to establish a core library of terms to facilitate the acquisition and sharing of knowledge between pediatric clinical research, practice, and safety reporting. A coalition of partners established a Pediatric Terminology Adverse Event Working Group in 2013 to develop a specific terminology relevant to international pediatric adverse event (AE) reporting. Pediatric specialists with backgrounds in clinical care, research, safety reporting, or informatics, supported by biomedical terminology experts from the National Cancer Institute’s Enterprise Vocabulary Services participated. The multinational group developed a working definition of AEs and reviewed concepts (terms, synonyms, and definitions) from 16 pediatric clinical domains. The resulting AE terminology contains >1000 pediatric diseases, disorders, or clinical findings. The terms were tested for proof of concept use in 2 different settings: hospital readmissions and the NICU. The advantages of the AE terminology include ease of adoption due to integration with well-established and internationally accepted biomedical terminologies, a uniquely temporal focus on pediatric health and disease from conception through adolescence, and terms that could be used in both well- and underresourced environments. The AE terminology is available for use without restriction through the National Cancer Institute’s Enterprise Vocabulary Services and is fully compatible with, and represented in, the Medical Dictionary for Regulatory Activities. The terminology is intended to mature with use, user feedback, and optimization.
Flow patterns of larval fish: undulatory swimming in the intermediate flow regime

SUMMARY Fish larvae, like many adult fish, swim by undulating their body. However, their body size and swimming speeds put them in the intermediate flow regime, where viscous and inertial forces both play an important role in the interaction between fish and water. To study the influence of the relatively high viscous forces compared with adult fish, we mapped the flow around swimming zebrafish (Danio rerio) larvae using two-dimensional digital particle image velocimetry (2D-DPIV) in the horizontal and transverse plane of the fish. Fish larvae initiate a swimming bout by bending their body into a C shape. During this initial tail-beat cycle, larvae shed two vortex pairs in the horizontal plane of their wake, one during the preparatory and one during the subsequent propulsive stroke. When they swim `cyclically' (mean swimming speed does not change significantly between tail beats), fish larvae generate a wide drag wake along their head and anterior body. The flow along the posterior body is dominated by the undulating body movements that cause jet flows into the concave bends of the body wave. Patches of elevated vorticity form around the jets, and travel posteriorly along with the body wave, until they are ultimately shed at the tail near the moment of stroke reversal. Behind the larva, two vortex pairs are formed per tail-beat cycle (the tail beating once left-to-right and then right-to-left) in the horizontal plane of the larval wake. By combining transverse and horizontal cross sections of the wake, we inferred that the wake behind a cyclically swimming zebrafish larva contains two diverging rows of vortex rings to the left and right of the mean path of motion, resembling the wake of steadily swimming adult eels. When the fish larva slows down at the end of a swimming bout, it gradually reduces its tail-beat frequency and amplitude, while the separated boundary layer and drag wake of the anterior body extend posteriorly to envelope the entire larva. This drag wake is considerably wider than the larval body. The effects of the intermediate flow regime manifest as a thick boundary layer and in the quick dying-off of the larval wake within less than half a second.
Elasticity, unexpected contractility and the identification of actin and myosin in lobster arteries

SUMMARY Lobster arteries, which exhibit non-uniform elasticity when stretched, have a trilaminar organization. The inner layer is an elastic connective tissue and the outer layer is a collagenous connective tissue; the middle layer of an artery is an aggregation of cells containing microfilaments. Arterial cells possess actin, myosin and tropomyosin. Except for the dorsal abdominal artery, striated muscle cells are not evident in the walls of any of the vessels. The neurotransmitter glutamic acid and the neurohormone proctolin elicit slow circumferential contractions in all of the arteries leaving the lobster heart. Only the dorsal abdominal artery contracts when stimulated electrically. Longitudinal strips of the arteries do not respond to either drugs or electrical stimulation. Arterial contraction will have profound effects on resistance to blood flow and may be an important component of the control mechanisms regulating blood distribution.
Rapid prediction of optimum population size in genetic programming using a novel genotype -: fitness correlation

The main aim of landscape analysis has been to quantify the 'hardness' of problems. Early steps have been made towards extending this into Genetic Programming. However, few attempts have been made to extend the use of landscape analysis into the prediction of ways to make a problem easy, through the optimal setting of control parameters. This paper introduces a new class of landscape metrics, which we call 'Genotype-Fitness Correlations'. An example of this family of metrics is applied to six real-world regression problems. It is demonstrated that genotype-fitness correlations may be used to estimate optimum population sizes for the six problems. We believe that this application of a landscape metric as guidance in the setting of control parameters is an important step towards the development of an adaptive algorithm that can respond to the perceived landscape in 'real-time', i.e. during the evolutionary search process itself.
Sudden Death After Febrile Seizure Case Report: Cerebral Suppression Precedes Severe Bradycardia

A 20-month-old girl with febrile seizures died suddenly during an EEG. Advanced data analysis suggests that diffuse cerebral suppression preceded a dramatic increase in parasympathetic tone before death. A 20-month-old girl with a complex chromosomal disorder had first presentation of febrile status epilepticus and was admitted to the hospital. Two days after her initial seizure, she died suddenly and unexpectedly during a video EEG monitoring study. An advanced analysis of the physiologic changes in the hours and minutes leading up to death was undertaken. The electrocardiography over the last 19 minutes of life was reviewed, and the R-R intervals were manually measured. Heart rate variability was assessed through calculation of the SD of the R-R intervals and the root mean square of successive differences over successive 100 beat periods. Instantaneous heart rate, SD of the R-R intervals, the root mean square of successive differences, and oxygen saturation were plotted against time over the last 19 minutes of life. Diffuse cerebral suppression on EEG was observed 10 minutes before death, followed minutes later by severe bradycardia and increased heart rate variability. Although the child did not meet criteria for a diagnosis of epilepsy, the sequence of physiologic changes leading up to death suggests a pathophysiology similar to sudden unexplained death in epilepsy. A comparable pattern of diffuse cerebral suppression preceding parasympathetic overactivity has been suggested in some rare cases of adults who have experienced sudden unexplained death in epilepsy during video EEG monitoring.
Role of the PGC-1 family in the metabolic adaptation of goldfish to diet and temperature

SUMMARY In mammals, the peroxisome proliferator-activated receptor (PPAR) γ coactivator-1 (PGC-1) family members and their binding partners orchestrate remodelling in response to diverse challenges such as diet, temperature and exercise. In this study, we exposed goldfish to three temperatures (4, 20 and 35°C) and to three dietary regimes (food deprivation, low fat and high fat) and examined the changes in mitochondrial enzyme activities and transcript levels for metabolic enzymes and their genetic regulators in red muscle, white muscle, heart and liver. When all tissues and conditions were pooled, there were significant correlations between the mRNA for the PGC-1 coactivators (both α and β) and mitochondrial transcripts (citrate synthase), metabolic gene regulators including PPARα, PPARβ and nuclear respiratory factor-1 (NRF-1). PGC-1β was the better predictor of the NRF-1 axis, whereas PGC-1α was the better predictor of the PPAR axis (PPARα, PPARβ, medium chain acyl CoA dehydrogenase). In contrast to these intertissue/developmental patterns, the response of individual tissues to physiological stressors displayed no correlations between mRNA for PGC-1 family members and either the NRF-1 or PPAR axes. For example, in skeletal muscles, low temperature decreased PGC-1α transcript levels but increased mitochondrial enzyme activities (citrate synthase and cytochrome oxidase) and transcripts for COX IV and NRF-1. These results suggest that in goldfish, as in mammals, there is a regulatory relationship between (i) NRF-1 and mitochondrial gene expression and (ii) PPARs and fatty acid oxidation gene expression. In contrast to mammals, there is a divergence in the roles of the coactivators, with PGC-1α linked to fatty acid oxidation through PPARα, and PGC-1β with a more prominent role in mediating NRF-1-dependent control of mitochondrial gene expression, as well as distinctions between their respective roles in development and physiological responsiveness.
PARENTS' VIEWS OF DIFFERENT RESPITE CARE SERVICES

This paper focuses on one part of a three-year study into respite care services to disabled children. Relevant literature in the field is first reviewed and the aims and methods of the research are outlined. The main findings from semi-structured interviews with 160 parents using different types of respite care—family based schemes, local authority residential homes and health authority provision, including hospitals—are reported and discussed. Certain differences emerged between the characteristics of children using different services, notably in terms of age, weight, and level of dependency. Uneven access to services was identified, with black and low income families apparently having limited choice. Significant variation was found in the perceptions of the various service users. Important features of family based schemes were the child-centred nature of the service, the good relationships generally enjoyed by parents and carers and the informality of arrangements. Some benefits were reported for children receiving respite care in residential homes but widespread difficulty in obtaining bookings and instances of poor physical care were significant drawbacks. Parents using health authority provision reported a range of dissatisfactions, mostly associated with the institutional nature of the service.