Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutational analysis of Kaposica reveals that bridging of MG2 and CUB domains of target protein is crucial for the cofactor activity of RCA proteins

Significance The complement system discriminates self from nonself targets solely owing to the presence of complement regulators on the host cells, which primarily belong to the regulators of complement activation (RCA) protein family. These regulators control complement activation on the host cell surface by two mechanisms termed “cofactor activity” (CFA) and “decay-accelerating activity. ” Here, we have identified the critical structural determinants of an RCA protein responsible for imparting the CFA and show that these determinants bridge MG2 (macroglobulin-2) and CUB (complement C1r-C1s, Uegf, Bmp1) domains of C3b and interact with factor I. As a proof of principle, we show that incorporation of putative membrane cofactor protein (CD46) regions responsible for the bridging and factor I interaction in decay acceleration factor (CD55) results in gain of function. We, thus, define the molecular events that govern CFA. The complement system has evolved to annul pathogens, but its improper regulation is linked with diseases. Efficient regulation of the system is primarily provided by a family of proteins termed regulators of complement activation (RCA). The knowledge of precise structural determinants of RCA proteins critical for imparting the regulatory activities and the molecular events underlying the regulatory processes, nonetheless, is still limited. Here, we have dissected the structural requirements of RCA proteins that are crucial for one of their two regulatory activities, the cofactor activity (CFA), by using the Kaposi’s sarcoma-associated herpesvirus RCA homolog Kaposica as a model protein. We have scanned the entire Kaposica molecule by sequential mutagenesis using swapping and site-directed mutagenesis, which identified residues critical for its interaction with C3b and factor I. Mapping of these residues onto the modeled structure of C3b–Kaposica–factor I complex supported the mutagenesis data. Furthermore, the model suggested that the C3b-interacting residues bridge the CUB (complement C1r-C1s, Uegf, Bmp1) and MG2 (macroglobulin-2) domains of C3b. Thus, it seems that stabilization of the CUB domain with respect to the core of the C3b molecule is central for its CFA. Identification of CFA-critical regions in Kaposica guided experiments in which the equivalent regions of membrane cofactor protein were swapped into decay-accelerating factor. This strategy allowed CFA to be introduced into decay-accelerating factor, suggesting that viral and human regulators use a common mechanism for CFA.
Robust Ferromagnetism of Chromium Nanoparticles Formed in Superfluid Helium

Chromium nanoparticles are formed using superfluid helium droplets as the nanoreactors, which are strongly ferromagnetic. The transition from antiferromagentism to ferromagnetism is attributed to atomic-scale disorder in chromium nanoparticles, leading to abundant unbalanced surface spins. Theoretical modeling confirms a frustrated aggregation process in superfluid helium due to the antiferromagnetic nature of chromium.
Mercury offloaded in Northern elephant seal hair affects coastal seawater surrounding rookery

Significance Mercury is a potent neurotoxin that accumulates in food webs, posing a global threat to environmental health. Marine mammals are common sentinel species for studying marine pollution; however, their potential role as vectors of contaminants to local ecosystems has rarely been addressed. By quantifying the concentration and chemical form of mercury in seawater affected by Northern elephant seal (Mirounga angustirostris) colonization, we demonstrated here that marine mammal behavioral ecology can substantially influence nearshore mercury cycling. Elevated methylmercury (MeHg) levels in seawater adjacent to the rookery during the molting season may become bioavailable to lower trophic levels, indicating that large marine mammal assemblages represent an important source of MeHg to nearshore food chains and coastal marine fisheries, thereby threatening ecosystem health. Methylmercury (MeHg) is a potent neurotoxin that is biomagnified approximately 1–10 million-fold in aquatic carnivores such as the Northern elephant seal (Mirounga angustirostris), whose excreta and molted pelage, in turn, constitute a source of environmental MeHg contamination at the base of marine food chains. The potential for this top-down contamination is greatest in coastal areas with productive marine ecosystems that provide ideal habitats for large marine mammal colonies that can number in the thousands. This recycling of MeHg was evidenced by comparing total mercury (HgT) and MeHg concentrations in seawater, and HgT in molted pelage of M. angustirostris, at the Año Nuevo State Reserve pinniped rookery with concentrations at neighboring coastal sites in Central California. Seawater MeHg concentrations around the rookery (average = 2.5 pM) were markedly higher than those at the comparison coastal sites (average = 0.30 pM), and were as high as 9.5 pM during the M. angustirostris molting season. As a consequence, excreta and molts from this marine mammal colony, and presumably other marine predator populations, constitute a major source of MeHg at the base of the local marine food chain.
Hemophagocytic Syndrome Associated with Hematologic Malignancies

Hemophagocytic syndromes may occur in patients of all age groups. Secondary HS is more frequent than primary (familial) and is usually described in patients with an underlying immune disorder. This clinicopathological entity is the result hemophagocytosis of hemopoetic cells due to activation of morphologically benign macrophages in the bone marrow. Clinical symptoms include fever, hepatosplenomegaly, severe cytopenias, dyslipidemia, and frequent coangulopathy. The prognosis is dismal. Hematologic malignancies are often involved in HS, which may present at any disease phase. Non-Hodgkin lymphomas and less frequently Hodgkin disease have been associated with HS. Lymphoma associated hamophagocytic syndrome (LAHS) accounts for 40-50% of HS where an underlying condition can be defined. NK/T and T peripheral lymphomas are responsible for 80% of LAHS. As far as B-cell lymphomas are concerned, intravascular usually present with LAHS. The pathogenesis of HS is not fully understood, but it seems to differ between T- and B-cell lymphomas. EBV is thought to have an important part in the pathogenetic procedure, since it has been detected both in Hodgkin and Non-Hodgkin lymphomas presenting with HS. Treatment decisions depend upon the underlying condition and its phase. However the most acceptable treatment option is currently immunochemotherapy followed by myeloablative stem cell transplantation.
Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2

Significance Significant controversy persists regarding a hierarchical vs. stochastic model of cancer. Using a microfluidic single-cell culture device, we define for the first time, to our knowledge, the differentiation capacity of primary human ovarian cancer cells. We demonstrate that ovarian cancer follows a hierarchical model with rare stochastic events. Defining the differentiation capacity allowed us to explain apparently paradoxical actions of bone morphologenetic protein 2 (BMP2); BMP2 suppresses growth in vitro by suppressing bulk cell proliferation, but promotes growth in vivo by promoting cancer stem-like cell (CSC) expansion. This work supports BMP2 signaling as a critical therapeutic target regulating ovarian CSC growth. Whether human cancer follows a hierarchical or stochastic model of differentiation is controversial. Furthermore, the factors that regulate cancer stem-like cell (CSC) differentiation potential are largely unknown. We used a novel microfluidic single-cell culture method to directly observe the differentiation capacity of four heterogeneous ovarian cancer cell populations defined by the expression of the CSC markers aldehyde dehydrogenase (ALDH) and CD133. We evaluated 3,692 progeny from 2,833 cells. We found that only ALDH+CD133+ cells could generate all four ALDH+/−CD133+/− cell populations and identified a clear branched differentiation hierarchy. We also observed a single putative stochastic event. Within the hierarchy of cells, bone morphologenetic protein 2 (BMP2) is preferentially expressed in ALDH−CD133− cells. BMP2 promotes ALDH+CD133+ cell expansion while suppressing the proliferation of ALDH−CD133− cells. As such, BMP2 suppressed bulk cancer cell growth in vitro but increased tumor initiation rates, tumor growth, and chemotherapy resistance in vivo whereas BMP2 knockdown reduced CSC numbers, in vivo growth, and chemoresistance. These data suggest a hierarchical differentiation pattern in which BMP2 acts as a feedback mechanism promoting ovarian CSC expansion and suppressing progenitor proliferation. These results explain why BMP2 suppresses growth in vitro and promotes growth in vivo. Together, our results support BMP2 as a therapeutic target in ovarian cancer.
Persistence of the dominant soil phylum Acidobacteria by trace gas scavenging

Significance The mechanisms that the “dormant microbial majority” use to remain energized in nutrient-starved soil ecosystems have long remained elusive. In this work, we used an isolate of the highly abundant but poorly understood soil phylum Acidobacteria as a model for understanding microbial persistence mechanisms. When the bacterium entered a persistent state due to nutrient-exhaustion, we showed it could scavenge the trace concentrations of molecular hydrogen gas (H2) found in ambient air using a specialized high-affinity enzyme. These findings demonstrate that Acidobacteria can consume H2 and contribute to global hydrogen cycling. We propose that consumption of trace gases such as H2 provides a dependable general mechanism for dominant soil phyla to generate the maintenance energy required for long-term survival. The majority of microbial cells in global soils exist in a spectrum of dormant states. However, the metabolic processes that enable them to survive environmental challenges, such as nutrient-limitation, remain to be elucidated. In this work, we demonstrate that energy-starved cultures of Pyrinomonas methylaliphatogenes, an aerobic heterotrophic acidobacterium isolated from New Zealand volcanic soils, persist by scavenging the picomolar concentrations of H2 distributed throughout the atmosphere. Following the transition from exponential to stationary phase due to glucose limitation, the bacterium up-regulates by fourfold the expression of an eight-gene operon encoding an actinobacteria-type H2-uptake [NiFe]-hydrogenase. Whole-cells of the organism consume atmospheric H2 in a first-order kinetic process. Hydrogen oxidation occurred most rapidly under oxic conditions and was weakly associated with the cell membrane. We propose that atmospheric H2 scavenging serves as a mechanism to sustain the respiratory chain of P. methylaliphatogenes when organic electron donors are scarce. As the first observation of H2 oxidation to our knowledge in the Acidobacteria, the second most dominant soil phylum, this work identifies new sinks in the biogeochemical H2 cycle and suggests that trace gas oxidation may be a general mechanism for microbial persistence.
Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies

Significance Genetic mutations of protein tyrosine phosphatase nonreceptor type 11 Ptpn11 (Shp2) are associated with childhood leukemias and solid tumors. The mechanisms by which Ptpn11 mutations induce malignancies are not fully understood. In this study, we demonstrate that Ptpn11 disease mutations disturb mitosis and cytokinesis, causing chromosomal instability and greatly increased susceptibility to DNA damage-induced malignancies. This finding reveals a novel mechanism by which deregulation of Shp2 induces malignancies and has important clinical implications. Given that Ptpn11 mutations enhance DNA damage-induced tumorigenesis, caution should be taken when considering DNA-damaging preconditioning for stem cell transplantation therapy or DNA-damaging chemotherapy for Ptpn11-associated malignancies, especially in Noonan syndrome patients with germ-line Ptpn11 mutations, as the risk of therapy-induced malignancies in these patients may be increased. Gain-of-function (GOF) mutations of protein tyrosine phosphatase nonreceptor type 11 Ptpn11 (Shp2), a protein tyrosine phosphatase implicated in multiple cell signaling pathways, are associated with childhood leukemias and solid tumors. The underlying mechanisms are not fully understood. Here, we report that Ptpn11 GOF mutations disturb mitosis and cytokinesis, causing chromosomal instability and greatly increased susceptibility to DNA damage-induced malignancies. We find that Shp2 is distributed to the kinetochore, centrosome, spindle midzone, and midbody, all of which are known to play critical roles in chromosome segregation and cytokinesis. Mouse embryonic fibroblasts with Ptpn11 GOF mutations show a compromised mitotic checkpoint. Centrosome amplification and aberrant mitosis with misaligned or lagging chromosomes are significantly increased in Ptpn11-mutated mouse and patient cells. Abnormal cytokinesis is also markedly increased in these cells. Further mechanistic analyses reveal that GOF mutant Shp2 hyperactivates the Polo-like kinase 1 (Plk1) kinase by enhancing c-Src kinase-mediated tyrosine phosphorylation of Plk1. This study provides novel insights into the tumorigenesis associated with Ptpn11 GOF mutations and cautions that DNA-damaging treatments in Noonan syndrome patients with germ-line Ptpn11 GOF mutations could increase the risk of therapy-induced malignancies.
Midostaurin (PKC412) inhibits immunoglobulin E‐dependent activation and mediator release in human blood basophils and mast cells

Background KIT tyrosine kinase inhibitors (TKI), such as nilotinib or midostaurin (PKC412), are increasingly used in clinical trials to counteract neoplastic cell growth in patients with aggressive mast cell (MC) disorders. However, these patients suffer not only from MC infiltration and consecutive organ damage but also from MC mediator‐related symptoms.
Type II integral membrane protein, TM of J paramyxovirus promotes cell-to-cell fusion

Significance J paramyxovirus represents a group of unclassified paramyxoviruses that encode an integral membrane protein, transmembrane (TM), that is not found in other classified paramyxoviruses. In this work we have found that TM expression is involved in cell-to-cell fusion when coexpressed with the viral fusion protein F or coexpressed with F and the receptor-binding protein G. This work may define a separate class of viral proteins that promote cell-to-cell fusion. Paramyxoviruses include many important animal and human pathogens. Most paramyxoviruses have two integral membrane proteins: fusion protein (F) and attachment proteins hemagglutinin, hemagglutinin–neuraminidase, or glycoprotein (G), which are critical for viral entry into cells. J paramyxovirus (JPV) encodes four integral membrane proteins: F, G, SH, and transmembrane (TM). The function of TM is not known. In this work, we have generated a viable JPV lacking TM (JPV∆TM). JPV∆TM formed opaque plaques compared with JPV. Quantitative syncytia assays showed that JPV∆TM was defective in promoting cell-to-cell fusion (i.e., syncytia formation) compared with JPV. Furthermore, cells separately expressing F, G, TM, or F plus G did not form syncytia whereas cells expressing F plus TM formed some syncytia. However, syncytia formation was much greater with coexpression of F, G, and TM. Biochemical analysis indicates that F, G, and TM interact with each other. A small hydrophobic region in the TM ectodomain from amino acid residues 118 to 132, the hydrophobic loop (HL), was important for syncytial promotion, suggesting that the TM HL region plays a critical role in cell-to-cell fusion.
ANÁLISE CLÍNICA E ULTRASSONOGRÁFICA DOS OMBROS DE PACIENTES LESADOS MEDULARES EM PROGRAMA DE REABILITAÇÃO

SUMMARY The increasing incidence of high energy traumas is associated to a growing prevalence of spinal cord injuries causing motor sequels on limbs. Rehabilitation programs provide an opportunity for improvement of quality of life, helping on integrating those individuals back into social activities. Shoulder pain is more frequent in individuals with spinal cord injury, regardless of the rehabilitation program adopted. In the current study, 32 shoulders of 16 patients with spinal cord injury levels between C4 and T12 submitted to a rehabilitation program at DOT/UNICAMP were evaluated by using ultrasound. Changes on rotator cuff tendons were detected in 56.25%, and 12.50% of the patients presented changes in humeral tuberosities. These changes were more prevalent in quadriplegic patients. Analgesic therapies, rotator cuff muscles’ strengthening whenever possible, and postural rehabilitation may provide shoulder pain reduction, enhancing the advantages of rehabilitation programs and providing a better quality of life.
The impact of tobacco promotion at the point of sale: a systematic review.

INTRODUCTION Tobacco promotion increases the likelihood that adolescents will start smoking. Much of the tobacco industry's promotional budget is spent on point of sale (PoS) promotion in many jurisdictions. Consequently, tobacco is an eye-catching feature at the PoS in many places. METHODS We reviewed the evidence that PoS tobacco promotion influences key smoking-related behaviors and beliefs, increases susceptibility to smoking in youth, undermines smokers' quit attempts, and promotes relapse among ex-smokers. RESULTS We found 12 peer-reviewed studies, 10 of which were focused on children. Seven of 8 observational studies found statistically significant associations between exposure to tobacco promotion at the PoS and smoking initiation or susceptibility to smoking. Two experimental studies of children found statistically significant associations between exposure to PoS tobacco promotions and beliefs about ease of getting tobacco and smoking prevalence among their peers. An experimental study with adults found that a picture of collected tobacco pack elicited cravings for cigarettes among smokers. A cross-sectional study found that 25% of adult smokers reported impulse purchasing and a third of recent ex-smokers reported urges to start smoking after seeing tobacco displayed. DISCUSSION More prospective studies are needed to clarify the temporal relationship between exposure to PoS tobacco and outcome. However, given the addictiveness of tobacco, the severity of the health hazards posed by smoking, the evidence that tobacco promotion encourages children to start smoking, and the consistency of the evidence that PoS promotion influences children's smoking, we believe that ample justification exists for banning PoS advertising and displays of smoked tobacco products.
Information-theoretic model comparison unifies saliency metrics

Significance Where do people look in images? Predicting eye movements from images is an active field of study, with more than 50 quantitative prediction models competing to explain scene viewing behavior. Yet the rules for this competition are unclear. Using a principled metric for model comparison (information gain), we quantify progress in the field and show how formulating the models probabilistically resolves discrepancies in other metrics. We have also developed model assessment tools to reveal where models fail on the database, image, and pixel levels. These tools will facilitate future advances in saliency modeling and are made freely available in an open source software framework (www.bethgelab.org/code/pysaliency). Learning the properties of an image associated with human gaze placement is important both for understanding how biological systems explore the environment and for computer vision applications. There is a large literature on quantitative eye movement models that seeks to predict fixations from images (sometimes termed “saliency” prediction). A major problem known to the field is that existing model comparison metrics give inconsistent results, causing confusion. We argue that the primary reason for these inconsistencies is because different metrics and models use different definitions of what a “saliency map” entails. For example, some metrics expect a model to account for image-independent central fixation bias whereas others will penalize a model that does. Here we bring saliency evaluation into the domain of information by framing fixation prediction models probabilistically and calculating information gain. We jointly optimize the scale, the center bias, and spatial blurring of all models within this framework. Evaluating existing metrics on these rephrased models produces almost perfect agreement in model rankings across the metrics. Model performance is separated from center bias and spatial blurring, avoiding the confounding of these factors in model comparison. We additionally provide a method to show where and how models fail to capture information in the fixations on the pixel level. These methods are readily extended to spatiotemporal models of fixation scanpaths, and we provide a software package to facilitate their use.
Susceptibility-Weighted MR Imaging for the Detection of Developmental Venous Anomaly: Comparison with T2 and FLAIR Imaging

Developmental venous anomaly (DVA), which is also called venous angioma, is the most common cerebral vascular malformation (1, 2). DVA exhibits radially arranged, dilated veins (so-called caput medusae) that drain into an enlarged transcortical or a subependymal collecting vein (3). DVA is usually asymptomatic and it’s often incidentally found on contrast-enhanced (CE) CT or MR imaging. Recent investigations have reported that parenchymal signal abnormality on T2/FLAIR MR imaging could be INTRODUCTION �Received; May 15, 2014�Revised; August 5, 2014 �Accepted; September 11, 2014 Corresponding author : Dae Seob Choi, M.D. Department of Radiology, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, 90 Chilam-dong, Jinju 660-702, Korea. Tel. 82-55-750-8211, Fax. 82-55-758-1568 E-mail : choids@gnu.ac. kr This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Susceptibility-Weighted MR Imaging for the Detection of Developmental Venous Anomaly: Comparison with T2 and FLAIR Imaging