Miracle-dz/UniFAR-FTUs huggingface dataset:
Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response*

Translation regulation largely occurs during initiation, which features ribosome assembly onto mRNAs and selection of the translation start site. Short, upstream ORFs (uORFs) located in the 5′-leader of the mRNA can be selected for translation. Multiple transcripts associated with stress amelioration are preferentially translated through uORF-mediated mechanisms during activation of the integrated stress response (ISR) in which phosphorylation of the α subunit of eIF2 results in a coincident global reduction in translation initiation. This review presents key features of uORFs that serve to optimize translational control that is essential for regulation of cell fate in response to environmental stresses.
The Impact of Depression on Functioning in Elderly Patients With Low Vision.

The authors examined the interrelationships between low vision, depression, and functioning in older adults. Seventy patients over age 65 attending a low-vision clinic were interviewed by a geriatric nurse-practitioner, using a structured clinical format to diagnose depression according to DSM-III-R criteria. In all, 38.6% of patients met criteria for major depression. There was no association between depression and severity of visual impairment, but a direct relationship was found between depression and functional impairment. Depression was the most powerful variable associated with functional impairment (adjusted R2 = 0.20; P < 0.0001). Depression frequently co-occurs with visual impairment in this population. Appropriate recognition and treatment may reduce functional disability and improve quality of life.
Gastrointestinal , Hepatobiliary , and Pancreatic Pathology Three-Dimensional Scaffolds Reduce Islet Amyloid Formation and Enhance Survival and Function of Cultured Human Islets

Islet transplantation provides a promising approach for treatment of type 1 diabetes mellitus. Amyloid formation and loss of extracellular matrix are two nonimmune factors contributing to death of isolated human islets. We tested the effects of two types of three-dimensional scaffolds, collagen matrix (CM) and fibroblast-populated collagen matrix (FPCM), on amyloid formation, viability, and function of isolated islets. Islets from cadaveric donors were cultured in FPCM, CM, or two-dimensional plate (2D) for 7 days. After 7 days, compared with the 2D culture condition, CM and FPCM markedly reduced amyloid formation of cultured islets and decreased apoptotic -cell rate by 75%. IL-1 and Fas levels were also reduced in scaffold-embedded islets. Furthermore, / cell ratios were increased by 18% and 36% in CMand FPCMembedded islets, respectively. Insulin content and insulin response to elevated glucose were also enhanced by both three-dimensional scaffolds. Moreover, culture in CM and FPCM (but not 2D) preserved insulin, GLUT-2, and PDX-1 mRNA expression. FPCM-embedded islets had significantly higher insulin response and lower amyloid formation than CM-embedded islets. These findings suggest that three-dimensional scaffolds reduce amyloid formation and improve viability and function of human islets in vitro, and that CM and fibroblasts have additive effects in enhancing islet function and reducing amyloid formation. Using this strategy is likely to improve outcome in human islet transplantation. (Am J Pathol 2012, 181:1296–1305; http:// dx.doi.org/10.1016/j.ajpath.2012.06.032)
The guanine nucleotide exchange factor Arf-like protein 13b is essential for assembly of the mouse photoreceptor transition zone and outer segment

Arf-like protein 13b (ARL13b) is a small GTPase that functions as a guanosine nucleotide exchange factor (GEF) for ARL3-GDP. ARL13b is located exclusively in photoreceptor outer segments (OS) presumably anchored to discs by palmitoylation, whereas ARL3 is an inner segment cytoplasmic protein. Hypomorphic mutations affecting the ARL13b G-domain inactivate GEF activity and lead to Joubert syndrome (JS) in humans. However, the molecular mechanisms in ARL13b mutation–induced Joubert syndrome, particularly the function of primary cilia, are still incompletely understood. Because Arl13b germline knockouts in mouse are lethal, we generated retina-specific deletions of ARL13b in which ARL3-GTP formation is impaired. In mouse retArl13b−/− central retina at postnatal day 6 (P6) and older, outer segments were absent, thereby preventing trafficking of outer segment proteins to their destination. Ultrastructure of postnatal day 10 (P10) central retArl13b−/− photoreceptors revealed docking of basal bodies to cell membranes, but mature transition zones and disc structures were absent. Deletion of ARL13b in adult mice via tamoxifen-induced Cre/loxP recombination indicated that axonemes gradually shorten and outer segments progressively degenerate. IFT88, essential for anterograde intraflagellar transport (IFT), was significantly reduced at tamArl13b−/− basal bodies, suggesting impairment of intraflagellar transport. AAV2/8 vector-mediated ARL13b expression in the retArl13b−/− retina rescued ciliogenesis.
The inducible microRNA-203 in fish represses the inflammatory responses to Gram-negative bacteria by targeting IL-1 receptor-associated kinase 4

Innate immune responses are the first defense against pathogenic invaders. Activation and termination of these immune responses are regulated by several mechanisms. MicroRNAs (miRNAs), a group of small non-coding RNAs, have been implicated in the regulation of a spectrum of both physiological and pathological conditions, including immune responses. Although the immune regulatory miRNA networks in higher vertebrates have been well described, regulation of these responses in fish species is poorly understood. In the present study, we investigated the role of the miRNA miR-203 involved in inflammatory responses in miiuy croaker (Miichthys miiuy). We found that the Gram-negative bacterium Vibrio anguillarum and lipopolysaccharide significantly up-regulated host miR-203 expression. The increased miR-203 expression suppressed the production of inflammatory cytokines and thereby prevented mounting of a full immune response. Mechanistically, we identified and validated IL-1 receptor-associated kinase 4 (IRAK4) as a target of miR-203. We observed that miR-203 post-transcriptionally controls IRAK4 expression and thereby inhibits the activation of nuclear factor κB (NF-κB) signaling. In summary, our findings reveal that miR-203 in fish is a critical suppressor of innate immune responses to bacterial infection by suppressing a feedback to IRAK4–NF-κB–mediated signaling.
Highly ordered mesoporous tungsten oxides with a large pore size and crystalline framework for H2S sensing.

An ordered mesoporous WO3 material with a highly crystalline framework was synthesized by using amphiphilic poly(ethylene oxide)-b-polystyrene (PEO-b-PS) diblock copolymers as a structure-directing agent through a solvent-evaporation-induced self-assembly method combined with a simple template-carbonization strategy. The obtained mesoporous WO3 materials have a large uniform mesopore size (ca. 10.9 nm) and a high surface area (ca. 121 m(2) g(-1)). The mesoporous WO3-based H2S gas sensor shows an excellent performance for H2S sensing at low concentration (0.25 ppm) with fast response (2 s) and recovery (38 s). The high mesoporosity and continuous crystalline framework are responsible for the excellent performance in H2S sensing.
Blue light–excited LOV1 and LOV2 domains cooperatively regulate the kinase activity of full-length phototropin2 from Arabidopsis

Phototropin2 (phot2) is a blue-light (BL) receptor that regulates BL-dependent activities for efficient photosynthesis in plants. phot2 comprises two BL-receiving light-oxygen-voltage–sensing domains (LOV1 and LOV2) and a kinase domain. BL-excited LOV2 is thought to be primarily responsible for the BL-dependent activation of the kinase. However, the molecular mechanisms by which small BL-induced conformational changes in the LOV2 domain are transmitted to the kinase remain unclear. Here, we used full-length wild-type and mutant phot2 proteins from Arabidopsis to study their molecular properties in the dark and under BL irradiation. Phosphorylation assays and absorption measurements indicated that the LOV1 domain assists the thermal relaxation of BL-excited LOV2 and vice versa. Using small-angle X-ray scattering and electron microscopy, we observed that phot2 forms a dimer and has a rod shape with a maximum length of 188 Å and a radius of gyration of 44 Å. Under BL, phot2 displayed large conformational changes that bent the rod shape. By superimposing the crystal structures of the LOV1 dimer, LOV2, and a homology model of the kinase to the observed changes, we inferred that the BL-dependent change consisted of positional shifts of both LOV2 and the kinase relative to LOV1. Furthermore, phot2 mutants lacking the photocycle in LOV1 or LOV2 still exhibited conformational changes under BL, suggesting that LOV1 and LOV2 cooperatively contribute to the conformational changes that activate the kinase. These results suggest that BL-activated LOV1 contributes to the kinase activity of phot2. We discuss the possible intramolecular interactions and signaling mechanisms in phot2.
ASTHMA, DIABETES MELLITUS AND HYPERINSULINISM

THE LITERATURE of the past decade is replete with reports that asthmatics have a tendency to hypoglycemia. Black (1) found more than half of a large series of asthmatic patients to have low fasting blood sugar levels and increased glucose toler’ ance (low glucose tolerance curves). Ohler, in a personal communication to Joslin (2), said that he found low glucose tolerance curves in 14 asthmatics. Wil-mer, Miller and Beardwood (3), Malone (4) and Waldbott and his collaborators (5) made similar ob’ servations. If hypoglycemia is an essential factor conditioning the appearance of asthmatic seizures in sensitive individuals, we should expect such attacks to be absent, or, at most; very rare in diabetics. Kern (6) has shown that although diabetes mellitus and bronchial asthma often share a common heredity they are to some extent mutually exclusive, both diseases occurring very frequently in members of the same family but only extremely rarely in the same person. He postulated a genetic relationship between the .
Tumorigenesis and Neoplastic Progression Molecular Dissection of Premalignant Colorectal Lesions Reveals Early Onset of the CpG Island Methylator Phenotype

From the First Department of Internal Medicine,* and the Departments of Molecular Biology † and Public Health, and the Department of Medical Genome Science, the Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo; the Department of Gastroenterology, Akita Red Cross Hospital, Akita; the Department of Pathology, Iwate Medical University, Morioka; and The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
The Exercise Assessment and Screening for You (EASY) Tool: Application in the Oldest Old Population

The screening tool, the Exercise Assessment and Screening for You (EASY), was developed to call attention to the benefits of exercise and to assist older adults in selecting safe and effective exercise. The purpose of this study is to describe the use of the EASY in an oldest old population, consider the factors associated with EASY scores, and examine the relationship between exercise and adverse events in this population. The sample comprised 163 oldest old adults with an average age of 86.5 (SD = 5.8), the majority of whom were women (73%) and unmarried (64%). The participants responded affirmatively to approximately 2 of the 6 items on the EASY (mean = 1.9, SD = 1.3). Fear of falling, negative outcome expectations, number of comorbidities, age, and pain were all significantly associated with the total score on the EASY and accounted for 24% of the variance. Those who responded affirmatively to at least 1 item on the EASY were more likely to engage in exercise than those who did not (chi-square = 8.0, P = .01). The findings from this study help establish some baseline evidence of the applicability of the EASY when used as a screening tool to help guide oldest old adults prior to starting an exercise program.
Breast Carcinoma versus Lung Adenocarcinoma: The Immunohistochemical Discrimination of Breast Carcinoma Metastatic in Lung

Abstract: Breast and lung adenocarcinomas are the two neoplasms with the highest incidence in women, and as a result, these tumors are some of the most frequently seen tumors in surgical pathology and fine‐needle aspiration biopsies. The number of patients having both tumors is on the rise. For therapeutic purposes, it is important to be able to distinguish the two in tissues and in fine‐needle aspirates (FNA).
Strategy to Assess the Overall Cytokine Profile of Circulating Leukocytes and its Association with Distinct Clinical Forms of Human Chagas Disease

Herein we have employed an alternative strategy to assess the cytokine patterns of circulating leukocytes and correlate dominant cytokine profiles with indeterminate‐IND and cardiac‐CARD clinical forms of Chagas disease. We have first calculated median percentages of cytokine‐positive leukocytes of our study sample to establish, for each cytokine‐positive cell population, the cut‐off edge that would segregate ‘low’ and ‘high’ cytokine producers to build colour diagrams and draw a panoramic cytokine chart. Using this approach we demonstrated that most IND individuals presented a dominant regulatory cytokine profile, whereas CARD individuals displayed a dominant inflammatory cytokine pattern. In addition, radar chart analysis confirmed the dichotomic cytokine balance between IND and CARD groups and further allowed the identification of the relative contribution of each cell population for the global cytokine pattern. Data analysis demonstrated that CD4+ T cells were the major cell population defining the regulatory profile in IND, whereas monocytes and CD4+ T cells determined the inflammatory cytokine pattern in CARD individuals. Interestingly, in vitro stimulation with trypomastigote Trypanosoma cruzi antigen was able to invert the cytokine balances in IND and CARD groups. Upon antigenic stimulation, changes in the frequencies of IL‐10‐producing CD4+ T cells and monocytes drove IND individuals towards an inflammatory pattern and CARD towards a regulatory cytokine profile. A similar inversion could be found after in vivo treatment of IND and CARD individuals with benzonidazole. Altogether, these findings shed some light into the complex cytokine network underlying the immunopathogenesis of Chagas disease and provide putative immunological biomarkers of disease severity and therapeutic response.
Anti‐CD20 treatment in Primary Sjögren’s Syndrome

We performed a search for publications on rituximab (Rtx) in the treatment of primary Sjögren’s syndrome (pSS), and assessed the reports for the efficacy of the drug on complaints like sicca symptoms, systemic manifestations and pSS associated lymphoma. We also reviewed the effects on laboratory parameters and potential adverse effects. From the published literature there is little evidence supporting Rtx to have an effect on sicca symptoms, and there is particularly lack of objective improvements in measures of oral and ocular dryness. Systemic manifestations such as fatigue, synovitis, arthralgia, cryoglobulinaemia‐related vasculitis, neurological, renal and pulmonary involvement all seem to react favourably to Rtx treatment. The effect on pSS associated non‐Hodgkin’s lymphoma is also beneficial. Rheumatoid factor concentration is decreasing during Rtx treatment. The levels of anti‐SSA and ‐SSB antibodies are, however, unaltered according to the majority of the studies. The most common complications to Rtx treatment are mild and transient infusion related reactions. Delayed moderate‐to‐severe reactions are less common, and occur mostly in patients who develop human anti‐chimeric antibodies. In conclusion, Rtx is a promising treatment option for severe pSS with systemic complications, but more data from randomized controlled trials are warranted before conclusions on the drug’s role can be made with more accuracy.
Distinctive phosphoinositide- and Ca2+-binding properties of normal and cognitive performance–linked variant forms of KIBRA C2 domain

Kidney- and brain-expressed protein (KIBRA), a multifunctional scaffold protein with around 20 known binding partners, is involved in memory and cognition, organ size control via the Hippo pathway, cell polarity, and membrane trafficking. KIBRA includes tandem N-terminal WW domains, a C2 domain, and motifs for binding atypical PKC and PDZ domains. A naturally occurring human KIBRA variant involving residue changes at positions 734 (Met-to-Ile) and 735 (Ser-to-Ala) within the C2 domain affects cognitive performance. We have elucidated 3D structures and calcium- and phosphoinositide-binding properties of human KIBRA C2 domain. Both WT and variant C2 adopt a canonical type I topology C2 domain fold. Neither Ca2+ nor any other metal ion was bound to WT or variant KIBRA C2 in crystal structures, and Ca2+ titration produced no significant reproducible changes in NMR spectra. NMR and X-ray diffraction data indicate that KIBRA C2 binds phosphoinositides via an atypical site involving β-strands 5, 2, 1, and 8. Molecular dynamics simulations indicate that KIBRA C2 interacts with membranes via primary and secondary sites on the same domain face as the experimentally identified phosphoinositide-binding site. Our results indicate that KIBRA C2 domain association with membranes is calcium-independent and involves distinctive C2 domain–membrane relative orientations.
CARDIOVASCULAR , PULMONARY , AND RENAL PATHOLOGY A Lymphocyte-Dependent Mode of Action for Imatinib Mesylate in Experimental Pulmonary Hypertension

opyright a 2013 American Society for Inve ublished by Elsevier Inc. All rights reserved ttp://dx.doi. org/10.1016/j.ajpath. 2013.01. 031 The capacity of imatinib mesylate to reverse established pulmonary arterial hypertension (PAH) has been attributed to a reduction in pulmonary arterial muscularization via inhibition of platelet-derived growth factor receptor-b on vascular smooth muscle cells. However, there is also a significant immunomodulatory component to the action of imatinib that may account for its efficacy in PAH. We found that monocrotaline-induced pulmonary hypertension was associated with a significant decrease in pulmonary natural killer (NK) cells and T lymphocytes and the accumulation of macrophages in the lungs of F344 rats. The prevention of pulmonary hypertension by imatinib blocked these changes in pulmonary leukocyte content and induced elevations in pulmonary interferon-g, tumor necrosis factor a, and IL-10, corresponding to the enhanced activity of splenic NK cells ex vivo. Treatment with antie asialo GM1 antiserum (ASGM1), which ablated circulating NK cells and depleted T cells, eliminated the therapeutic benefit of imatinib. ASGM1-treated animals also exhibited significant pulmonary arteriolar muscularization in response to monocrotaline challenge compared with immunocompetent controls despite daily imatinib administration to both groups. In the athymic rat, imatinib decreased right ventricular hypertrophy and pulmonary arteriolar muscularization in monocrotaline-challenged animals versus saline-treated controls but did not prevent pulmonary macrophage accumulation or the development of pulmonary hypertension. These data demonstrate that the immunomodulatory effects of imatinib are critical to its therapeutic action in experimental PAH. (Am J Pathol 2013, 182: 1541e1551; http:// dx.doi.org/10.1016/j.ajpath.2013.01.031)
Assessing the economic impact of HIV/AIDS on Nigerian households: a propensity score matching approach

Objectives:We used a novel approach to assess the impact of HIV/AIDS on individuals' healthcare utilization and spending in the Oyo and Plateau states of Nigeria and income foregone from work time lost. Methods:Data from a 2004 random survey of over 6400 individuals were compared with a sample of 482 individuals living with HIV/AIDS. Estimating the effect of HIV is complicated by the fact that our sample of HIV-positive individuals was non-random; there are selection effects, both in acquiring HIV and being in our sample of HIV-positive people, which was based on contacts through non-governmental organizations. To overcome these, we compared HIV-positive people with a control group with similar observed characteristics, using propensity score matching. The matched HIV-negative individuals had worse health and greater health spending than the full HIV-negative group. This suggests that our HIV sample would not have had ‘average’ outcomes even if they had not acquired HIV. Results:Compared with our matched control group, HIV is associated with significantly increased morbidity, healthcare utilization, public health facility use, lost work time and family time devoted to care-giving. Direct private healthcare costs and indirect income loss per HIV-positive individual were 36 065 Naira, approximately 56% of annual income per capita in affected households. Approximately 40% of these costs were income losses associated with sickness and care-giving. 10% of the cost of HIV is accounted for by public subsidies for health. The largest single cost, representing 54% of the total economic burden of HIV, is for out-of-pocket expenses for healthcare.
Visualizing an ultra-weak protein-protein interaction in phosphorylation signaling.

Proteins interact with each other to fulfill their functions. The importance of weak protein-protein interactions has been increasingly recognized. However, owing to technical difficulties, ultra-weak interactions remain to be characterized. Phosphorylation can take place via a K(D)≈25 mM interaction between two bacterial enzymes. Using paramagnetic NMR spectroscopy and with the introduction of a novel Gd(III)-based probe, we determined the structure of the resulting complex to atomic resolution. The structure accounts for the mechanism of phosphoryl transfer between the two enzymes and demonstrates the physical basis for their ultra-weak interaction. Further, molecular dynamics (MD) simulations suggest that the complex has a lifetime in the micro- to millisecond regimen. Hence such interaction is termed a fleeting interaction. From mathematical modeling, we propose that an ultra-weak fleeting interaction enables rapid flux of phosphoryl signal, providing a high effective protein concentration.