Miracle-dz/UniFAR-FTUs huggingface dataset:
PCoM-DB Update: A Protein Co-Migration Database for Photosynthetic Organisms

The identification of protein complexes is important for the understanding of protein structure and function and the regulation of cellular processes. We used blue-native PAGE and tandem mass spectrometry to identify protein complexes systematically, and built a web database, the protein co-migration database (PCoM-DB, http://pcomdb.lowtem.hokudai.ac.jp/proteins/top), to provide prediction tools for protein complexes. PCoM-DB provides migration profiles for any given protein of interest, and allows users to compare them with migration profiles of other proteins, showing the oligomeric states of proteins and thus identifying potential interaction partners. The initial version of PCoM-DB (launched in January 2013) included protein complex data for Synechocystis whole cells and Arabidopsis thaliana thylakoid membranes. Here we report PCoM-DB version 2.0, which includes new data sets and analytical tools. Additional data are included from whole cells of the pelagic marine picocyanobacterium Prochlorococcus marinus, the thermophilic cyanobacterium Thermosynechococcus elongatus, the unicellular green alga Chlamydomonas reinhardtii and the bryophyte Physcomitrella patens. The Arabidopsis protein data now include data for intact mitochondria, intact chloroplasts, chloroplast stroma and chloroplast envelopes. The new tools comprise a multiple-protein search form and a heat map viewer for protein migration profiles. Users can compare migration profiles of a protein of interest among different organelles or compare migration profiles among different proteins within the same sample. For Arabidopsis proteins, users can compare migration profiles of a protein of interest with putative homologous proteins from non-Arabidopsis organisms. The updated PCoM-DB will help researchers find novel protein complexes and estimate their evolutionary changes in the green lineage.
HISTOLOGIC CHANGES IN THE LENS PRODUCED BY GALACTOSE

In the course of a study of galactose cataract in rats by one of us, 1 chiefly from a biochemical standpoint, it seemed advisable to correlate the change in the lens seen with the ophthalmoscope and focal illumination with the histologic changes in the same lenses or with those in the lenses of animals with similar stages of opacity. In the study of galactose cataract white rats were employed which had been placed on a diet of which galactose composed 50 per cent. All essential food factors, including vitamins, were supplied. Lenses were removed one, three, four, six, seven, nine, fourteen, fifteen, eighteen, twenty-five and thirty-two days after feeding was begun. There were also two lenses of animals which had been placed on a normal diet after opacities had developed, to illustrate the apparent clearing of opacities which was observed in vivo. This series included lenses in which no signs
Modulation of the IL‐12/IFN‐γ axis by IFN‐α therapy for hepatitis C

Although IFN‐α forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN‐α alone. The antiviral activities of IFN‐α formed the rationale for its use in viral hepatitis. However, IFN‐α and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN‐γ production by activating STAT4 but can also inhibit production of IL‐12, a potent activator of STAT4 and IFN‐γ production. The efficacy of IFN‐α in the treatment of hepatitis C may therefore depend in part on the balance of IFN‐γ‐inducing and IL‐12‐suppressing effects. We characterized the effects of pegylated IFN‐α therapy for hepatitis C on the capacity of patients’ PBMC to produce IL‐12 and IFN‐γ ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN‐α‐driven IFN‐γ production prior to treatment than those from nonresponding patients. No differences in pretreatment IL‐12 productive capacity were seen between patient groups. However, therapy with IFN‐α led to suppression of inducible IL‐12 production throughout the course of therapy in both groups of patients.
Topoisomerase II Poisoning by ICRF-193*

Antineoplastic bis(dioxopiperazine)s, such as meso-2,3-bis(2,6-dioxopiperazin-4-yl)butane (ICRF-193), are widely believed to be only catalytic inhibitors of topoisomerase II. However, topoisomerase inhibitors have little or no antineoplastic activity unless they are topoisomerase poisons, a special subclass of topoisomerase-targeting drugs that stabilize topoisomerase-DNA strand passing intermediates and thus cause the topoisomerase to become a cytotoxic DNA-damaging agent. Here we report that ICRF-193 is a very significant topoisomerase II poison. Detection of topoisomerase II poisoning by ICRF-193 required the use of a chaotropic protein denaturant in the topoisomerase poisoning assays. ICRF-193 caused dose-dependent cross-linking of human topoisomerase IIβ to DNA and stimulated topoisomerase IIβ-mediated DNA cleavage at specific sites on 32P-end-labeled DNA. Human topoisomerase IIα-mediated DNA cleavage was stimulated to a lesser extent by ICRF-193. In vivo experiments with MCF-7 cells also showed the requirement of a chaotropic protein denaturant in the assays and selectivity for the β-isozyme of human topoisomerase II. Studies with two topoisomerase IIβ-negative cell model systems confirmed significant topoisomerase II poisoning by ICRF-193 in the wild type cells and were consistent with β-isozyme selectivity. Common use of only the detergent, SDS, in assays may have led to failure to detect topoisomerase II poisoning by ICRF-193 in earlier studies.
Global disease transmission - What if SARS would have been more lethal?

Global disease transmission is an important area, since knowledge of the time of the onset of an epidemic in a region might help authorities to save many lives. In this thesis I have used a deterministic model with eight parameters, of which two were time dependent, for spreading of the SARS disease. My model is an extension of a model by Colizza and co-workers, where I have added a Heaviside step function, that prevent latent people to interact if they are to few. I have also added a ”repulsion factor”, that reduces the traﬃc to an infected city. In my model I used data on how 3,147 of the airports of the world are connected. The strength of the connections were not given, so they were estimated, using the population sizes of the cities. The corresponding rate equations was solved by computer programs, written by me in Java, one of which displayed the result on a map. A major ﬁnding of this thesis is that vaccination can be used to prevent an epidemic from fully break out, and the doses are preferably concentrated to well connected regions, although the eﬀect is not dramatical. This is demonstrated by comparing the effect of vaccinating London, with the eﬀect of vaccinating Tianjin, and with the effect of vaccinating New York. I also demonstrate that the latency of a disease is an important factor for mortality of a disease.
Effect of pronounced weight loss on visceral fat, liver steatosis and adiponectin isoforms

Background Weight loss induced by bariatric surgery is an effective method to reverse obesity and comorbidities. The aim of this prospective weight loss study was to investigate changes of body fat distribution in relation to adiponectin and its isoforms and further to investigate the influence of both body fat distribution and adiponectin on the degree of liver steatosis.
Checkpoint Kinase ATR Promotes Nucleotide Excision Repair of UV-induced DNA Damage via Physical Interaction with Xeroderma Pigmentosum Group A*

In response to DNA damage, eukaryotic cells activate a series of DNA damage-dependent pathways that serve to arrest cell cycle progression and remove DNA damage. Coordination of cell cycle arrest and damage repair is critical for maintenance of genomic stability. However, this process is still poorly understood. Nucleotide excision repair (NER) and the ATR-dependent cell cycle checkpoint are the major pathways responsible for repair of UV-induced DNA damage. Here we show that ATR physically interacts with the NER factor Xeroderma pigmentosum group A (XPA). Using a mass spectrometry-based protein footprinting method, we found that ATR interacts with a helix-turn-helix motif in the minimal DNA-binding domain of XPA where an ATR phosphorylation site (serine 196) is located. XPA-deficient cells complemented with XPA containing a point mutation of S196A displayed a reduced repair efficiency of cyclobutane pyrimidine dimers as compared with cells complemented with wild-type XPA, although no effect was observed for repair of (6-4) photoproducts. This suggests that the ATR-dependent phosphorylation of XPA may promote NER repair of persistent DNA damage. In addition, a K188A point mutation of XPA that disrupts the ATR-XPA interaction inhibits the nuclear import of XPA after UV irradiation and, thus, significantly reduced DNA repair efficiency. By contrast, the S196A mutation has no effect on XPA nuclear translocation. Taken together, our results suggest that the ATR-XPA interaction mediated by the helix-turn-helix motif of XPA plays an important role in DNA-damage responses to promote cell survival and genomic stability after UV irradiation.
Suppressing Type 2C Protein Phosphatases Alters Fruit Ripening and the Stress Response in Tomato

Although ABA signaling has been widely studied in Arabidopsis, the roles of core ABA signaling components in fruit remain poorly understood. Herein, we characterize SlPP2C1, a group A type 2C protein phosphatase that negatively regulates ABA signaling and fruit ripening in tomato. The SlPP2C1 protein was localized in the cytoplasm close to AtAHG3/AtPP2CA. The SlPP2C1 gene was expressed in all tomato tissues throughout development, particularly in flowers and fruits, and it was up-regulated by dehydration and ABA treatment. SlPP2C1 expression in fruits was increased at 30 d after full bloom and peaked at the B + 1 stage. Suppression of SlPP2C1 expression significantly accelerated fruit ripening which was associated with higher levels of ABA signaling genes that are reported to alter the expression of fruit ripening genes involved in ethylene release and cell wall catabolism. SlPP2C1-RNAi (RNA interference) led to increased endogenous ABA accumulation and advanced release of ethylene in transgenic fruits compared with wild-type (WT) fruits. SlPP2C1-RNAi also resulted in abnormal flowers and obstructed the normal abscission of pedicels. SlPP2C1-RNAi plants were hypersensitized to ABA, and displayed delayed seed germination and primary root growth, and increased resistance to drought stress compared with WT plants. These results demonstrated that SlPP2C1 is a functional component in the ABA signaling pathway which participates in fruit ripening, ABA responses and drought tolerance.
Identification of Critical Residues of the MyD88 Death Domain Involved in the Recruitment of Downstream Kinases*

MyD88 couples the activation of the Toll-like receptors and interleukin-1 receptor superfamily with intracellular signaling pathways. Upon ligand binding, activated receptors recruit MyD88 via its Toll-interleukin-1 receptor domain. MyD88 then allows the recruitment of the interleukin-1 receptor-associated kinases (IRAKs). We performed a site-directed mutagenesis of MyD88 residues, conserved in death domains of the homologous FADD and Pelle proteins, and analyzed the effect of the mutations on MyD88 signaling. Our studies revealed that mutation of residues 52 (MyD88E52A) and 58 (MyD88Y58A) impaired recruitment of both IRAK1 and IRAK4, whereas mutation of residue 95 (MyD88K95A) only affected IRAK4 recruitment. Since all MyD88 mutants were defective in signaling, recruitment of both IRAKs appeared necessary for activation of the pathway. Moreover, overexpression of a green fluorescent protein (GFP)-tagged mini-MyD88 protein (GFP-MyD88-(27–72)), comprising the Glu52 and Tyr58 residues, interfered with recruitment of both IRAK1 and IRAK4 by MyD88 and suppressed NF-κB activation by the interleukin-1 receptor but not by the MyD88-independent TLR3. GFP-MyD88-(27–72) exerted its effect by titrating IRAK1 and suppressing IRAK1-dependent NF-κB activation. These experiments identify novel residues of MyD88 that are crucially involved in the recruitment of IRAK1 and IRAK4 and in downstream propagation of MyD88 signaling.
Identifying contributory factors leading to the suboptimal management of constipation and the development of a nurse-led clinic to improve constipation management in patients with cancer: an action research study.

Constipation in cancer and palliative care is frequent, poorly managed and has a profound adverse effect on patients' lives. This qualitative study explores factors contributing to the suboptimal management of constipation and identifies strategies to alleviate it. In a three-staged action research study data were collected from 11 patient interviews, 26 health care professionals (HCPs) during six focus group meetings and a Constipation Management Clinic (CMC), comprising a cohort of 29 patients, which was developed as part of this study. The findings from stage one, patient interviews, confirm that the management of constipation in patients with cancer and palliative care is suboptimal partly due to HCPs’ poor knowledge and ambivalent attitudes, inadequate patient education and a lack of a concordant approach to management. Patients described feeling abandoned, their condition trivialised and many suffered considerable distress and embarrassment. In stage two, focus groups of HCPs were questioned on their understanding of the condition, its impact and their strategies for treatment. Findings from the patient interviews were fed back as a means of education and to facilitate discussion. The focus groups confirmed the findings from the patient interviews. It was therefore possible to postulate that constipation management would be improved by redressing the educational needs of HCPs, imparting knowledge to patients and working to develop a partnership approach. To test this a CMC was developed during stage three. Patients with severe and intractable constipation were recruited to a nurse-led clinic that adopted a patient-focused, education-based management strategy which also encompassed a concordant approach to laxative recommendations. Following attendance there was an immediate improvement in bowel function in all patients who became more autonomous and concordant with their treatment regimens. Aims of the study were to improve the research’s skills and knowledge in research methodology in the cancer and palliative care setting, identify factors leading to the suboptimal management of constipation and to explore ways in which to alleviate the condition in patients with cancer. Throughout the project the action research methodology incorporated concurrent dissemination of findings to HCPs allowing them to discuss and assist with the evolution of the research and to modify their own practices to the benefit of patients generally. This research demonstrates the advantages of adopting an action research approach when identifying strategies to reduce the incidence of constipation in patients with cancer and the importance of paying attention to detail when trying to manage this frequent and distressing problem.
Retinopathy in type 2 diabetes mellitus is associated with increased intima‐media thickness and endothelial dysfunction

Background Microangioathy and macroangiopathy in type 2 diabetes mellitus (T2DM) frequently coexist. Both types of vascular complications share traditional risk factors. It is not clear whether the presence of microangiopathy, such as diabetic retinopathy (DR), constitutes a predictor of atherosclerosis in T2DM. Here we described the search for the association between DR and intima‐media thickness (IMT) in T2DM. We also compared endothelial function in subjects with and without DR.
TodoFirGene: Developing Transcriptome Resources for Genetic Analysis of Abies sachalinensis

Todo-matsu (Abies sachalinensis) is one of the most important forestry species in Hokkaido, Japan and is distributed from near sea level to the alpine zone. Due to its wide spatial distribution, the species adapts to its environment, displaying phenotypes of ecological relevance. In order to identify candidate genes under natural selection, we collected the transcriptome from the female and male flower, leaf and inner bark. De novo assembly with 34.7 Gb of sequencing reads produced 158,542 transcripts from 69,618 loci, whose estimated coverage reached 95.6% of conserved eukaryotic genes. Homology searches against publicly available databases identified 134,190 (84.6%) transcripts with at least one hit. In total, 28,944 simple sequence repeats (SSRs) and 80,758 single nucleotide variants (SNVs) were detected from 23,570 (14.9%) and 25,366 (16.0%) transcripts, which were valuable for use in genetic analysis of the species. All the annotations were included in a relational database, TodoFirGene, which provides an interface for various queries and homology search, and can be accessed at http://plantomics.mind. meiji.ac. jp/todomatsu/. This database hosts not only the A. sachalinensis transcriptome but also links to the proteomes of 13 other species, allowing a comparative genomic study of plant species.
Defining the human endothelial transcriptome

Advances in microarray technology facilitate the study of biological systems at a genome-wide level. Meaningful analysis of these transcriptional profiling studies, however, demands the concomitant development of novel computational techniques that take into account the size and complexity of the data. We have devised statistical algorithms that use replicate microarrays to define a genome-wide expression profile of a given cell type and to determine a list of genes that are significantly differentially expressed between experimental conditions. Applying these algorithms to the study of cultured human umbilical vein endothelial cells (HUVEC), we have found approximately 54% of all genes to be expressed at a detectable level in HUVEC under basal conditions. The set of highest expressed genes is enriched in nucleic acid binding proteins, cytoskeletal proteins and isomerases as well as certain known markers of endothelium, and the complete list of genes can be found at http://vessels. bwh.harvard. edu/ software/endo_xcriptome . We have also studied the effect of a 4-hour exposure of HUVEC to 10 U/mL of IL-], and detected 491 upregulated and 259 downregulated statistically significant genes, including several chemokines and cytokines, as well as members of the TNFAIP3 family, the KLFfamily and the Notch pathway. Applying these rigorous statistical techniques to genome-wide expression datasets underscores known patterns of endothelial inflammatory gene regulation and unveils new pathways as well. Finally, we performed a direct comparison of direct-labeled microarrays with amplified RNA microarrays for an initial assessment of the effect of the additional noise of amplification on the outputs of the statistical algorithms. These techniques can be applied to additional genome-wide profiling studies of endothelium and other cell types to refine our understanding of transcriptomes and the gene regulatory network governing cellular function and pathophysiology. Thesis Supervisor: Guillermo Garcia-Cardefia, Ph.D. Title: Assistant Professor of Pathology, Harvard Medical School
Individual, Housing, and Neighborhood Predictors of Psychological Integration Among Vulnerably Housed and Homeless Individuals.

The current longitudinal study evaluated the individual, housing, and neighborhood characteristics predictive of feeling psychologically integrated within one's neighborhood among a population of homeless and vulnerably housed individuals. Participants were recruited at homeless shelters, meal programs, and rooming houses in Ottawa, Canada and participated in three in-person interviews, each approximately 1 year apart. Prospective and cross-sectional predictors of psychological integration at Follow-up 1 and Follow-up 2 were examined. There were 397 participants at baseline, 341 at Follow-up 1 and 320 at Follow-up 2. A hierarchical multiple regression uncovered several significant predictors of psychological integration. The most salient and common predictors were being older, having greater social support, living in high quality housing, and residing in a neighborhood with a positive impact. Implications for service provision and policy advancements are discussed.
BRCA1 Interaction of Centrosomal Protein Nlp Is Required for Successful Mitotic Progression*♦

Breast cancer susceptibility gene BRCA1 is implicated in the control of mitotic progression, although the underlying mechanism(s) remains to be further defined. Deficiency of BRCA1 function leads to disrupted mitotic machinery and genomic instability. Here, we show that BRCA1 physically interacts and colocalizes with Nlp, an important molecule involved in centrosome maturation and spindle formation. Interestingly, Nlp centrosomal localization and its protein stability are regulated by normal cellular BRCA1 function because cells containing BRCA1 mutations or silenced for endogenous BRCA1 exhibit disrupted Nlp colocalization to centrosomes and enhanced Nlp degradation. Its is likely that the BRCA1 regulation of Nlp stability involves Plk1 suppression. Inhibition of endogenous Nlp via the small interfering RNA approach results in aberrant spindle formation, aborted chromosomal segregation, and aneuploidy, which mimic the phenotypes of disrupted BRCA1. Thus, BRCA1 interaction of Nlp might be required for the successful mitotic progression, and abnormalities of Nlp lead to genomic instability.
Lumbar Mobility and Performance-Based Function: An Investigation in Older Adults with and without Chronic Low Back Pain

Objective. To explore potential differences in lumbar mobility between older adults with and without chronic low back pain, and to determine if lumbar mobility contributes to physical performance in both groups. We hypothesized that older adults with pain would have greater lumbar mobility impairments than pain-free peers, and that lumbar mobility would be associated with performance in both groups, with stronger relationships among those with pain. Design. Matched case-control. Setting. Research laboratory. Patients. Community-dwelling older adults, aged 60–85 years, with (N = 54) and without (N = 54) chronic low back pain. Methods. Inclinometer-measured maximal angles of lumbar flexion, extension, and average side-bending, as well as time to complete performance measures, Repeated Chair Rise and Timed-Up-and-Go, were measured in both groups. Analysis of variance was used to explore the difference in lumbar mobility between groups. Adjusted linear regression was used to assess the independent relationship between lumbar mobility and physical function in both groups. Results. Those with pain had smaller angles of flexion (P = 0.029) and extension (P = 0.013). In the pain group, flexion explained 19% (P = 0.001) and 8.9% (P = 0.006) of the variance for time to complete the Repeated Chair Rise and Timed Up-and-Go tests, respectively. In the pain-free group, extension explained 12.7% (P = 0.007) and 10.3% (P = 0.008) of the variance for time to complete Repeated Chair Rise and Timed Up-and-Go tests, respectively. Conclusion. Older adults with chronic low back pain have more lumbar mobility impairments. Lumbar mobility may be a contributing factor to decreased performance in older adults. Flexion may be most important to performance in those with pain, while extension may be vital in those without pain.