Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2*

Background: ER aminopeptidases generate antigenic peptides, but how they recognize their substrates is unclear. Results: We solved crystal structures of ERAP2 in complex with a substrate analogue and a peptide product. Conclusion: The peptides were found trapped inside a large cavity adjacent to the catalytic site. Significance: Interactions of the substrate with the internal cavity can result in both substrate permissiveness and limited sequence bias. Endoplasmic reticulum (ER) aminopeptidases process antigenic peptide precursors to generate epitopes for presentation by MHC class I molecules and help shape the antigenic peptide repertoire and cytotoxic T-cell responses. To perform this function, ER aminopeptidases have to recognize and process a vast variety of peptide sequences. To understand how these enzymes recognize substrates, we determined crystal structures of ER aminopeptidase 2 (ERAP2) in complex with a substrate analogue and a peptidic product to 2.5 and 2.7 Å, respectively, and compared them to the apo-form structure determined to 3.0 Å. The peptides were found within the internal cavity of the enzyme with no direct access to the outside solvent. The substrate analogue extends away from the catalytic center toward the distal end of the internal cavity, making interactions with several shallow pockets along the path. A similar configuration was evident for the peptidic product, although decreasing electron density toward its C terminus indicated progressive disorder. Enzymatic analysis confirmed that visualized interactions can either positively or negatively impact in vitro trimming rates. Opportunistic side-chain interactions and lack of deep specificity pockets support a limited-selectivity model for antigenic peptide processing by ERAP2. In contrast to proposed models for the homologous ERAP1, no specific recognition of the peptide C terminus by ERAP2 was evident, consistent with functional differences in length selection and self-activation between these two enzymes. Our results suggest that ERAP2 selects substrates by sequestering them in its internal cavity and allowing opportunistic interactions to determine trimming rates, thus combining substrate permissiveness with sequence bias.
GABAA Receptors Mediate Excitation in Adult Rat GnRH Neurons1

Abstract Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, has long been implicated in playing key roles in the regulation of GnRH neurons. Two groups reported recently that GABA depolarizes GnRH neurons, although one group reported a hyperpolarizing action of GABA. In this study, we investigated the GABA-induced changes in [Ca2+]i of GnRH neurons from GnRH-enhanced green fluorescent protein (GnRH-EGFP) rats both to confirm the depolarizing action of GABA and to further examine the developmental and estrous cycle-dependent modulations of GABA action. GABA increased [Ca2+]i in GnRH neurons at all developmental stages of both sexes. GABA also increased [Ca2+]i in adult female GnRH neurons prepared in the afternoon at each estrous cycle stage. The percentages of neurons with increased [Ca2+]i were 90% in proestrus, 59% in estrus, 84% in diestrus I, and 89% in diestrus II. In GnRH neurons prepared from adult females in the morning, however, the percentage was significantly lower than in those prepared in the afternoon, except in estrus. The percentage was also lower in adult males than in adult females. GABA responses were mimicked by muscimol and blocked by bicuculline. In addition, removal of extracellular Ca2+ completely suppressed the GABA action, and bumetanide attenuated the response. These results indicate that GABA depolarizes GnRH neurons by activating GABAA receptors, thereby activating voltage-gated Ca2+ channels and facilitating Ca2+ influx. In addition, the response to GABA is modulated according to the estrous cycle stage, diurnal rhythm, and sex.
Polyelectrolyte microcapsules as antigen delivery vehicles to dendritic cells: uptake, processing, and cross-presentation of encapsulated antigens.

Degradable polyelectrolyte microcapsules (PMs; see picture) as antigen delivery vehicles are taken up by dendritic cells (DCs) by macropinocytosis. Following uptake, the shell of the microcapsules ruptures, resulting in the invasion of the capsules by the cellular cytoplasm, thus allowing DCs to efficiently process encapsulated antigen.
Developments in home help for elderly people in Denmark: the changing concept of home and institution

The official figures on provision of home help in Denmark are compromised in that they include figures for help delivered to people living in assisted-living dwellings, facilities that were formerly considered nursing homes. Furthermore, many municipalities have integrated home help and nursing-home care and report this as home help. This article examines the effect of these administrative arrangements on the provision of home help and the distribution of home help in terms of hours per week. There has been a polarisation in size of care packages: a smaller group of recipients composed largely of people residing in assisted-living dwellings receive larger care packages, whereas the care packages to people living in their own dwellings have decreased in size. However, a sleight of hand of definitions regarding the concept of home has made the official figures on provision of home help look even more generous than they are.
DNA Damage in Human Spermatozoa Is Highly Correlated with the Efficiency of Chromatin Remodeling and the Formation of 8-Hydroxy-2′-Deoxyguanosine, a Marker of Oxidative Stress1

DNA damage in human spermatozoa has been associated with a range of adverse clinical outcomes, including infertility, abortion, and disease in the offspring. We have advanced a two-step hypothesis to explain this damage involving impaired chromatin remodeling during spermiogenesis followed by a free radical attack to induce DNA strand breakage. The objective of the present study was to test this hypothesis by determining whether impaired chromatin protamination is correlated with oxidative base damage and DNA fragmentation in human spermatozoa. DNA fragmentation, chromatin protamination, mitochondrial membrane potential, and formation of the oxidative base adduct, 8-hydroxy-2′-deoxyguanosine (8OHdG), were monitored by flow cytometry/fluorescence microscopy. Impairment of DNA protamination during late spermatogenesis was highly correlated (P < 0.001) with DNA damage in human spermatozoa. The disruption of chromatin remodeling also was associated with a significant elevation in the levels of 8OHdG (P < 0.001), and the latter was itself highly correlated with DNA fragmentation (P < 0.001). The significance of oxidative stress in 8OHdG formation was demonstrated experimentally using H2O2/Fe2+ and by the correlation observed between this base adduct and superoxide generation (P < 0.001). That 8OHdG formation was inversely associated with mitochondrial membrane potential (P < 0.001) suggested a possible role for these organelles in the creation of oxidative stress. These results clearly highlight the importance of oxidative stress in the induction of sperm DNA damage and carry significant implications for the clinical management of this condition.
Control of hepatitis B virus at the level of transcription

Summary. Hepatitis B virus (HBV) is tightly controlled by a number of noncytotoxic mechanisms. This control occurs within the host hepatocyte at different steps of the HBV replication cycle. HBV persists by establishing a nuclear minichromosome, HBV cccDNA, serving as a transcription template for the viral pregenome and viral mRNAs. Nucleoside/nucleotide analogues widely used for antiviral therapy as well as most antiviral cytokines act at steps after transcription of HBV RNAs and thus can control virus replication but do not directly affect its gene expression. Control of HBV at the level of transcription in contrast is able to restrict both, HBV replication and gene expression. In the review, we focus on how HBV is controlled at the level of transcription. We discuss how the composition of transcription factors determines HBV gene expression and replication and how this may be influenced by antivirally active substances, e.g. the cytokine IL‐6 or helioxanthin analogues, or by the differentiation state of the hepatocyte.
Health potential of female candidates to the professional military service

Health potential of female candidates to the professional military service Study aim: To assess health and social characteristics of female candidates for professional officers and non-commissioned officers of Polish Army. Material and methods: All female students of officer and non-commissioned officer Military Academies (16 each) were studied in 2009. Two questionnaires were applied in the study: IPAQ (short) for assessing the level of physical activity of the respondents and a specially designed questionnaire for assessing social situation, perceived health and pro-health behaviours. Results: The influence of the society on the respondents' decision to join the army is significantly higher among NCOS students than in the group of OS respondents (p<0.05). OS students perceive their health better than their NCOS mates (p<0.05). Among students' pro-health behaviours that were assessed in the research, the most advantageously presented is their physical activity. NCOS students are more resilient mentally (p<0.01), yet their inclination to make use of health service is much lower (p<0.01). Conclusions: The modern educational trends in health promotion call for modifying the existing military school curricula by including health education issues so that the superiors acquire not only commanding skills but become also exemplary health educators.
Retinoblastoma 1 Protein Modulates XY Germ Cell Entry into G1/G0 Arrest During Fetal Development in Mice1

Abstract During mouse germ cell development, the first sign of sex differentiation occurs when XY germ cells enter G1/G0 arrest from 12.5 days postcoitum (dpc). Retinoblastoma 1 (RB1), a potent cell cycle regulator, was investigated in XY germ cell arrest by studying germ cell proliferation in Rb1−/− mutant mouse embryos. Because mice homozygous for the Rb1 deletion die in utero around 14.5 dpc, we used ex vivo culture techniques to allow analysis of developing gonads to 16.5 dpc. In Rb1−/− gonads, we observed normal somatic cell development, assessed by immunofluorescence for markers HSD3B1 and anti-Müllerian hormone. However, at 14.5 dpc, when wild-type XY germ cells had arrested, we could detect actively proliferating germ cells using the proliferation markers MKI67, pHH3, and bromodeoxyuridine incorporation. The increased proliferation was reflected with a trend of increased germ cell number and expression of germ cell markers Ddx4 and Pou5f1 in the Rb1−/− testes. By 16.5 dpc, this phenotype was resolved such that the entire germ cell population had entered G1/G0 arrest, although the total germ cell number remained elevated. At each stage analyzed, we saw no increase in expression of RB1 family members Rbl1 and Rbl2 in the Rb1−/− testes, but we saw a significant increase of cyclin-dependent kinase (CDK) inhibitor Cdkn1b and Cdkn2b expression. We conclude that Rb1 is required for correct germ cell entry into G1/G0 arrest in the wild-type gonad at 14.5 dpc, but in its absence, upregulation of other cell cycle suppressors, including Cdkn1b and Cdkn2b, can induce delayed germ cell arrest.
Intravenous drug use: not a barrier to achieving a sustained virological response in HCV infection

Summary. Hepatitis C virus (HCV) is commonly transmitted by intravenous drug use (IDU) but drug users are under represented in many treatment cohorts, this is because of the assumption of lowered treatment success. We assessed HCV treatment outcomes in active intravenous drug users and patients on opiate substitution therapy. The Tayside HCV treatment database was retrospectively analysed for consecutively treated patients based on risk factor for acquisition of HCV. Primary end point was sustained virological response (SVR). Two hundred and ninety‐one consecutively treated patients were assessed. The overall SVR rate was 55.3%. The SVR rates by risk factor were; Non‐IDU 61.4%, Ex‐IDU 54.8% and Active IDU 47.1% (P = n/s). In the groups G1 patients SVR was; Non‐IDU 52.7%, Ex–IDU 30.7% and active IDU 35.4% (P = n/s). In the non‐G1 patients: non‐IDU 65.1%, Ex‐IDU 76.7% and active IDU 53.5%. Ex‐IDU had a significantly better SVR than active IDU, other differences were not significant. Our results demonstrate that SVR rates in the active drug users and those on opiate substitution therapy can be achieved which are comparable with non‐IDU infected individuals. Intravenous drug use in those engaged with treatment services should not be seen as a barrier to treatment of HCV.
Long‐term outcome of chronic hepatitis C in a population‐based cohort and impact of antiviral therapy: a propensity‐adjusted analysis

Summary. This population‐based study aimed to assess the determinants of the outcome of chronic hepatitis C with analysis of the impact of antiviral therapy with or without sustained virological response (SVR) on cirrhosis decompensation, hepatocellular carcinoma, liver‐related and non‐liver‐related mortality. A total of 1159 HCV‐positive patients newly detected between 1994 and 2001 were included. For each outcome, the prognostic effect of patients’ baseline characteristics was estimated by time‐dependent Cox models using age as the time‐scale and adjusting for treatment received during follow‐up. The impact of antiviral therapy was assessed by using a propensity score in a sample including 184 patients treated in the first 24 months following diagnosis who were matched to 184 untreated patients. At the end of a 59‐month median follow‐up, 100 cases of compensated disease, 58 liver cancer and 163 deaths (55 liver related) were recorded. The 5‐year rates of decompensated cirrhosis, hepatocellular carcinoma, liver‐related and non‐liver‐related death were 4.4%, 2.7%, 5.0% and 8.9%, respectively. Multivariate analyses identified two variables with pejorative influence: alcohol consumption (RR = 4.29 for CD; RR = 5.76 for HCC; RR = 6.69 for liver‐related death; P < 0.0001); HCV diagnosis unrelated to systematic screening (RR = 2.25 for CD; RR = 3.05 for HCC; RR = 4.31 for liver‐related death, P < 0.03). In the matched subset, no significant benefit of antiviral therapy was observed. Nevertheless, among the 144 patients who achieved SVR, no death was observed. This population‐based study showed substantial rates of decompensated cirrhosis, hepatocellular carcinoma and non‐liver‐related mortality. Alcohol consumption and absence of systematic screening were significant determinants of poor outcome, whereas treatment did not have significant influence.
The Perception of Emojis for Analyzing App Feedback

When analyzing textual user feedback, the challenge today is that automation is only possible in a non-satisfactory way due to the limitations of understanding natural language. However, manual evaluation is not possible for products with a large amount of user feedback, as this is neither efficient nor effective. Internet texts are full of emojis. Emojis tell how a user feels about certain aspects of a product. We conducted a survey on the perception of emojis and used the results from 107 participants. The core result is that people perceive emojis in a very homogenous way regarding their sentiments and the emotions they represent This means that emojis give us a tool for analyzing the users’ perspectives on a product by looking at the emojis contained in their feedback.
Seroprevalence of Human Herpes Virus 8 (HHV8) Infection among Commercial Sex Workers in Jos

A study of HHV8 seropositivity was conducted among commercial sex workers in Jos aimed at determining the prevalence in relation to history of STD, duration of prostitution, age and number of sexual partners per day. Antibodies to HHV8 were detected by enzyme linked - immunosorbent assay (ELISA) (Advanced biotechnologies Inc USA) in serum samples of 90 commercial sex workers, 41 (45%) of cases were positive for HHV8, 15 (17%) of the women were HIV Seropositive. Furthermore eight (8) among the HHV8 seropositive women were HIV seropositive given a co-infection rate of 20%. Of the risk factors evaluated, HIV seropositivity and history of sexually transmitted diseases were found to be significantly associated with HHV8 infection using chi’s square. ( P 0.05.) we expect that this important seroepidemiologic baseline data will become a powerful tool for evaluating interventions and control measures.
Interleukin‐28B (IL‐28B) single‐nucleotide polymorphisms and interferon plus ribavirin treatment outcome in Italian chronically HCV‐infected patients

Summary. To determine the single or combined effect of both rs12979860 and rs8099917 SNPs on HCV treatment response, these variants were genotyped in samples from a cohort of 170 patients infected with different HCV genotypes (HCVGT). The favourable rs12979860 CC genotype was found only in patients with sustained or rapid virological responses (SVR/RVR) and at significantly high proportions in HCVGT1/4 SVR patients. A significant association was also found between the rs8099917 TT genotype and SVR in both HCVGT1/4 and HCVGT2/3 groups of patients. In contrast, we found that there was significantly more of the rs8099917 GG genotype in nonresponders (NR) than in SVR patients which suggests a good association of the minor homozygote GG with the lack of treatment response. The combination of rs12979860/rs8099917 CC/TT favourable genotypes was found only in SVR patients and matched the frequency observed for their rs12979860 CC genotypes alone. By contrast, the inverse unfavourable correlate rs12979860/rs8099917 TT/GG genotype was seen more in NR than in SVR patients as observed for the single GG genotype. This study confirms the impact of both rs12979860 and/or rs8099917 IL‐28B SNPs on treatment‐induced clearance of HCV‐RNA and demonstrates that the rs12979860 CC genotype is stronger than rs8099917 TT genotype in predicting a positive treatment response in HCVGT1/4 patients. The unfavourable rs8099917 GG genotype seems to be more important in predicting the failure of treatment response independently from HCV genotype.
Glucose Parameters Are Altered in Mouse Offspring Produced by Assisted Reproductive Technologies and Somatic Cell Nuclear Transfer1

Fortunately, the majority of children conceived through assisted reproductive technologies (ARTs) appear healthy; however, metabolic abnormalities, including elevated glucose and increased and altered adipose tissue deposition, have been reported in adolescents. To parse out factors that may be responsible, we investigated the effects of two different ARTs—in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI)—as well as somatic cell nuclear transfer (SCNT) on glucose clearance, body weight, and body composition of young adult mice. Female and male mice generated through ART weighed more than control (naturally conceived [STOCK]) mice at birth. No differences in body weight were observed in males up to 8 wk of age. ART females took longer than control mice to clear a glucose bolus, with glucose clearance most impaired in SCNT females. IVF females secreted more insulin and had a higher insulin peak 15 min after glucose injection compared with all other groups. Male mice exhibited no differences in glucose clearance, but IVF males required more insulin to do so. SCNT females weighed more than IVF, ICSI, and STOCK females, and they had higher fat content than ICSI females and higher leptin levels than all other groups. These results show that glucose parameters are altered in young adult mice conceived through techniques associated with ART before onset of obesity and may be responsible for its development later in life. The present study suggests that more investigation regarding the long-term effects of manipulations associated with ART is warranted.
Dimerization of Bacterial Diaminopimelate Decarboxylase Is Essential for Catalysis*

Diaminopimelate decarboxylase (DAPDC) catalyzes the final step in the diaminopimelate biosynthesis pathway of bacteria. The product of the reaction is the essential amino acid l-lysine, which is an important precursor for the synthesis of the peptidoglycan cell wall, housekeeping proteins, and virulence factors of bacteria. Accordingly, the enzyme is a promising antibacterial target. Previous structural studies demonstrate that DAPDC exists as monomers, dimers, and tetramers in the crystal state. However, the active oligomeric form has not yet been determined. We show using analytical ultracentrifugation, small angle x-ray scattering, and enzyme kinetic analyses in solution that the active form of DAPDC from Bacillus anthracis, Escherichia coli, Mycobacterium tuberculosis, and Vibrio cholerae is a dimer. The importance of dimerization was probed further by generating dimerization interface mutants (N381A and R385A) of V. cholerae DAPDC. Our studies indicate that N381A and R385A are significantly attenuated in catalytic activity, thus confirming that dimerization of DAPDC is essential for function. These findings provide scope for the development of new antibacterial agents that prevent DAPDC dimerization.
The prevalence, burden and cognizance of migraine in adolescent girls

Abstract Migraine represents a common neurological condition, which frequently affects adolescent girls. This cross sectional study aimed to evaluate the prevalence, impact and fund of migraine knowledge among adolescent girls. Students attending randomly selected high schools were recruited into the study by signing a consent form and completing a validated survey designed for this purpose. The survey assessed the participants fund of knowledge about migraine in five domains: migraine epidemiology, symptoms, triggers, auras and treatment options. The participants were evaluated for headache characteristics according to the International Classification of Headache Disorders, 2nd edition criteria, and categorized as having definite migraine or probable migraine. Additionally, the survey evaluated headache disability by implementing the headache impact test-6, and collected information regarding the use of over-the-counter medication. In a cohort of 309 girls, 14–18 years old, 18% fulfilled the criteria for definite migraine and 25% for probable migraine, with mean headache impact test-6 scores of 62.5 and 55.2, respectively (P < 0.0001). Furthermore, the students fund of knowledge was substantially limited in regards to migraine auras and moderately limited in regards to symptoms, triggers and treatments. A significant portion of the migraineurs self-medicated using over-the-counter medications. The prevalence of migraine in late adolescent girls is very close to that of adult women. The information regarding the cognizance of migraine ought to be used as a guideline for designing educational tools for this population.