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The Nun protein of coliphage HK022 arrests RNA polymerase (RNAP) in vivo and in vitro at pause sites distal to phage λ N-Utilization (nut) site RNA sequences. We tested the activity of Nun on ternary elongation complexes (TECs) assembled with templates lacking the λ nut sequence. We report that Nun stabilizes both translocation states of RNAP by restricting lateral movement of TEC along the DNA register. When Nun stabilized TEC in a pretranslocated register, immediately after NMP incorporation, it prevented binding of the next NTP and stimulated pyrophosphorolysis of the nascent transcript. In contrast, stabilization of TEC by Nun in a posttranslocated register allowed NTP binding and nucleotidyl transfer but inhibited pyrophosphorolysis and the next round of forward translocation. Nun binding to and action on the TEC requires a 9-bp RNA–DNA hybrid. We observed a Nun-dependent toe print upstream to the TEC. In addition, mutations in the RNAP β′ subunit near the upstream end of the transcription bubble suppress Nun binding and arrest. These results suggest that Nun interacts with RNAP near the 5′ edge of the RNA–DNA hybrid. By stabilizing translocation states through restriction of TEC lateral mobility, Nun represents a novel class of transcription arrest factors.

BackgroundThe transcription factor FOXN1 is implicated in the differentiation of thymic and skin epithelial cells, and alterations in it are responsible for the Nude/SCID phenotype. During a genetic counselling programme offered to couples at risk in a community where a high frequency of mutated FOXN1 had been documented, the identification of a human FOXN1−/− fetus gave the unique opportunity to study T cell development in utero.ResultsTotal blockage of CD4+ T cell maturation and severe impairment of CD8+ cells were documented. Evaluation of the variable-domain β-chain (Vβ) families' usage among T lymphocytes revealed that the generation of T cell receptor (TCR) diversity occurred to some extent in the FOXN1−/− fetus, although it was impaired compared with the control. A few non-functional CD8+ cells, mostly bearing TCRγδ in the absence of CD3, were found.DiscussionFOXN1 is crucial for in utero T cell development in humans. The identification of a limited number of CD8+ cells suggests an extrathymic origin for these cells, implying FOXN1-independent lymphopoiesis.

Background Myogenous temporomandibular disorders (TMD) are considered to be a common musculoskeletal condition. No studies exist comparing intra-oral myofascial therapies to education, self-care and exercise (ESC) for TMD. This study evaluated short-term differences in pain and mouth opening range between intra-oral myofascial therapy (IMT) and an ESC program. Methods Forty-six participants with chronic myogenous TMD (as assessed according to the Research Diagnostic Criteria Axis 1 procedure) were consecutively block randomised into either an IMT group or an ESC group. Each group received two sessions per week (for five weeks) of either IMT or short talks on the anatomy, physiology and biomechanics of the jaw plus instruction and supervision of self-care exercises. The sessions were conducted at the first author’s jaw pain and chiropractic clinic in Sydney, Australia. Primary outcome measures included pain at rest, upon opening and clenching, using an eleven point ordinal self reported pain scale. A secondary outcome measure consisted of maximum voluntary opening range in millimetres. Data were analysed using linear models for means and logistic regression for responder analysis. Results After adjusting for baseline, the IMT group had significantly lower average pain for all primary outcomes at 6 weeks compared to the ESC group (p < 0.001). These differences were not clinically significant but the IMT group had significantly higher odds of a clinically significant change (p < 0.045). There was no significant difference in opening range between the IMT and ESC groups. Both groups achieved statistically significant decreases in all three pain measures at six weeks (p ≤ 0.05), but only the IMT group achieved clinically significant changes of 2 or more points. Conclusion This study showed evidence of superiority of IMT compared to ESC over the short-term but not at clinically significant levels. Positive changes over time for both IMT and ESC protocols were noted. A longer term, multi-centre study is warranted. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12610000508077 .

The coliphage HK022 protein Nun transcription elongation arrest factor inhibits RNA polymerase translocation. In vivo, Nun acts specifically to block transcription of the coliphage λ chromosome. Using in vitro assays, we demonstrate that Nun cross-links RNA in an RNA:DNA hybrid within a ternary elongation complex (TEC). Both the 5′ and the 3′ ends of the RNA cross-link Nun, implying that Nun contacts RNA polymerase both at the upstream edge of the RNA:DNA hybrid and in the vicinity of the catalytic center. This finding suggests that Nun may inhibit translocation by more than one mechanism. Transcription elongation factor GreA efficiently blocked Nun cross-linking to the 3′ end of the transcript, whereas the highly homologous GreB factor did not. Surprisingly, both factors strongly suppressed Nun cross-linking to the 5′ end of the RNA, suggesting that GreA and GreB can enter the RNA exit channel as well as the secondary channel, where they are known to bind. These findings extend the known action mechanism for these ubiquitous cellular factors.

Background Migraine is the second world’s cause of disability. Among non-pharmacological treatments, nutritional intervention, particularly ketogenic diet, represents one of the most promising approaches. Methods This a prospective, single center, randomized, controlled study aimed at evaluating the efficacy of a very low-calorie ketogenic diet (VLCKD) compared to a hypocaloric balanced diet (HBD) in migraine prophylaxis in patients affected by high-frequency episodic migraine (HFEM) with a Body Mass Index (BMI) > 27 kg/m 2 . Fifty-seven patients were randomly assigned to a VLCKD (group 1) or HBD (group 2). Group 1 patients followed a VLCKD for 8 weeks, followed by a low calorie diet (LCD, weeks 9–12), and a HBD (weeks 13–24), whereas group 2 patients followed a HBD from week 0 to 24. Anthropometric indexes, urine and blood chemistry were assessed at enrollment, baseline, weeks 4, 8, 12, and 24. Migraine characteristics were evaluated at baseline, weeks 8, 12 and 24. Change in monthly migraine days (MMDs) at weeks 5–8 compared to baseline was the primary endpoint. Secondary endpoints encompassed changes in visual analogue scale (VAS), Headache Impact Test-6 (HIT-6) and Short Form Health Survey-36 (SF-36) scores. We also studied effects on circulating lymphocytes and markers of inflammation, changes in plasma aldosterone and renin levels before and after VLCKD or HBD treatment. Results Reduction from baseline in MMDs was greater in VLCKD compared to HBD group at week 8 (p = 0.008), at week 12 (p = 0.007), when ketosis had been interrupted by carbohydrates reintroduction, and at week 24 (p = 0.042), when all patients were following the same dietary regimen. Quality of life scores (SF-36) were improved in VLCKD group at week 8 and 12, and were also improved in HBD group, but only at week 12. Weight-loss was significantly higher in VLCKD group at week 8 (p = 0.002) and week 12 (p = 0.020). At the end of the study weight loss was maintained in VLCKD group whereas a slight weight regain was observed in HBD group. Inflammatory indexes, namely C reactive protein (CRP), neutrophil to lymphocyte ratio (NLR) and total white blood cell count (WBC) were significantly reduced (p < 0.05) in VLCKD group at week 12. Aldosterone plasma level were significantly increased in both groups at week 8, particularly in VLCKD group. However, electrolytes and renin plasma levels were never altered throughout the study in both groups. Conclusions VLCKD is more effective than HBD in reducing MMD in patients with HFEM and represents an effective prophylaxis in patients with overweight/obesity. Trial registration ClinicalTrials.gov identifier: NCT04360148.

In this work we set out to determine if the murine macrophage J774 cell line can be used to produce myogenic growth factors. Activated J774 macrophages were grown in serum-free conditions. The macrophage-conditioned medium (MCM) was then used to treat cultures of primary myoblasts and regenerating muscle tissue, in vitro and in vivo respectively. MCM activity in vitro was tested by analyzing the expression of muscle-specific transcription factors, in parallel with the proliferation and differentiation rates of the cells. The macrophage-secreted factors greatly enhanced the proliferative potential of both rat and human primary myoblasts and were found to be highly muscle-specific. In vivo, MCM administration markedly enhanced the regenerative processes in damaged muscles. The ability to produce large amounts of macrophage-secreted myogenic factor(s) in the absence of serum holds great promise for its biochemical characterization and successive application in therapeutic protocols, both for ex vivo gene therapy and for muscle repair.

Table 1 Patient characteristics Parameter HCV-T0 HCV-T6 HAV HD Age (y) (mean (SD)) 42 (3) 40 (2) 32 (5) 35 (6) Sex (M/F) 10/6 12/12 11/4 7/3 ALT level (U/l <40) 1425 (539) 100 (50) 1418 (543) <40 AST level (U/l <40) 892 (305) 84 (24) 851 (221) <40 HCV-RNA (IU/ml (mean (SD)) 310 (232)x103 Positive na na Genotype 1a/1b 12/16 11/12 0 Non-1 4/16 1/12 Mode of infection Needlestick 1/16 0 Surgery procedure 2/16 0 Alimentary 0 15/15 Unclear 13/16 0 Immunological parameters CD3+ CD4+ 956 (297)[dagger]** 892 (103) 725 (200)** 772 (297)** CD3+ CD4+ CD25+ 130 (50)[dagger]** 111 (12) 46 (26)** 46 (13)** CD3+ CD4+ CD25+ 13.5 (3)[double dagger]** 11.2 (2) 6.3 (1)** 6 (1)** T regulatory functional assay¶ Ratio 1:2¶ 100§** 92 80 79 Ratio 1:20 99** 85** 70 55 HCV-T0, patients with hepatitis C virus at time 0; HCV-T6, patients hepatitis C virus after six months; HAV, patients with acute hepatitis A; HD, healthy donors; na, not applicable; ALT, alanine aminotransferase; AST, aspartate aminotransferase. **Statistically significant (Mann-Whitney U test, p<0.01). [dagger]Total count number (cells/mm3; values are mean (SD)). [double dagger]Percentage.

To evaluate the gender-related differences in demographic and ocular biometric trends in a defined population presenting for consultation within the Italian public health system and to collect data of several ocular parameters at different stages of life, highlighting the differences between females and males. In this retrospective study, keratometry, corneal astigmatism, and axial eye length of 729 patients (729 eyes; mean age: 58±21 years; range: 18-96 years) were evaluated using partial coherence interferometry. Statistical evaluation was performed utilizing a paired -test and R analysis. In females (396 eyes of 396 patients), mean keratometry ranged between 40.59-47.78 D (44.27±1.36 D), corneal astigmatism ranged between 0-3.82 D (1.13±0.74 D), and axial length ranged between 20.5-31.32 mm (24.07±1.74 mm). In males (333 eyes of 333 patients), mean keratometry ranged between 38.5-46.95 D (43.54±1.35 D; p<0.001), corneal astigmatism ranged between 0.1-3.97 D (1.15±0.79; p=0.75), and axial length ranged between 20.41-31.21 mm (24.57±1.78 mm; p<0.001). Both genders presented a shorter axial length in advanced age. Elderly males presented a higher percentage of against-the-rule astigmatism. Females may have steeper corneas and shorter eyes. A trend toward axial length reduction with age was observed in both genders. This finding is probably due to the difference in growth between generations, as the new ones have an higher size than the old ones.

Thymic tumors represent a unique neoplastic disease associated with various immune-mediated syndromes. Immune impairment is generically recognized to be associated with thymoma. Hypogammaglobulinemia and recurrent pulmonary infections in thymoma patients define Good's syndrome. Apart from sporadic reports focusing on this topic, there is still a lack of knowledge on immune assessment and clinical sequelae in thymoma patients. The present study was performed to evaluate immunoglobulin levels, CD19(+) B lymphocytes, and CD3(+) T lymphocytes in a large series of thymoma patients from a single institution. The occurrence of recurrent severe infections was related to immunological findings to identify the possible correlation with the immunodeficiency status. Eighteen patients (eight males, ten females, mean age: 56 years, range: 19-75) with a pathological diagnosis of thymic tumor were studied. Six patients suffered from clinical recurrent pulmonary infections. Blood samples were collected to measure serum immunoglobulins and analyze immunophenotype. Low T lymphocyte number was found in 22% of the patients. T lymphocytosis was present in one patient. Panhypogammaglobulinemia was found in 4 of 18 patients (22%). Conversely B lymphopenia was a frequent finding in this series of thymoma patients (9 of 18, 50%). Five of six patients (83%) with recurrent infections had B lymphopenia, while only two (33%) had panhypogammaglobulinemia. B lymphopenia often occurred in this series of thymoma patients and was related to susceptibility to recurrent infections more than hypogammaglobulinemia. Therefore, immunophenotype has to be monitored in follow-up of thymoma patients because it may reveal significant abnormalities.

Abstract Background: Ice hockey is an international sport. Injuries occur in a full body fashion, to a number of tissues, commonly through body contact. There is a lack of literature documenting the scope of sports chiropractic practice. Thus, it was the aim to document the type, scope and severity of conditions presenting to, and the treatment provided by, the New Zealand team chiropractor acting as a primary health provider for the duration of the 2007 World Ice Hockey Championships. Methods: All conditions presenting were recorded. Diagnosis was recorded along with clinical parameters of injury: injury type, severity, mechanism and whether referral or advanced imaging was required. All treatment provided was continuously recorded, including information on the number of treatments required and the reason, duration, type and location of treatment. Results: Players presented for diagnosis of injury 50 times. Muscle (34%), joint (24%) and tendon injuries (18%) were most common. Players presented with a new injury 76% of the time. Most injuries had been present for less than one week (84%), with 53% occurring through a contact mechanism. Injuries were common at training and match locations. Only two injuries required the player to stop playing or training, both of which were referred for advanced imaging. During the study, 134 treatment consultations were rendered to 45 player injuries. Eighty per-cent of injuries were managed with four or less treatments. Three quarters of treatment was provided at training locations with treatment duration predominantly being between 11-15 minutes (71%) and 16-20 minutes (27%). Most treatment delivered was passive in nature (71%) although combination active and passive care was provided (27%). Treatment typically involved joint (81%) and soft tissue based therapies (81%) and was delivered in a full body manner. Conclusions: This study documented the injury profile of ice hockey at an international level of competition. It documented the conditions presenting to a chiropractor for diagnosis and the treatment provided. Treatment was consistent with that recommended for chiropractic management of athletic injuries. This documentation of sports chiropractic scope of practice fills a void in the literature and assists in determining a role for sports chiropractors as primary health providers or in multidisciplinary sports management teams.