Phase variable DNA repeats in 'Neisseria gonorrhoeae' influence transcription, translation, and protein sequence variation

There are many types of repeated DNA sequences in the genomes of the species of the genus Neisseria, from homopolymeric tracts to tandem repeats of hundreds of bases. Some of these have roles in the phase-variable expression of genes. When a repeat mediates phase variation, reversible switching between tract lengths occurs, which in the species of the genus Neisseria most often causes the gene to switch between on and off states through frame shifting of the open reading frame. Changes in repeat tract lengths may also influence the strength of transcription from a promoter. For phenotypes that can be readily observed, such as expression of the surface-expressed Opa proteins or pili, verification that repeats are mediating phase variation is relatively straightforward. For other genes, particularly those where the function has not been identified, gathering evidence of repeat tract changes can be more difficult. Here we present analysis of the repetitive sequences that could mediate phase variation in the Neisseria gonorrhoeae strain NCCP11945 genome sequence and compare these results with other gonococcal genome sequences. Evidence is presented for an updated phase-variable gene repertoire in this species, including a class of phase variation that causes amino acid changes at the C-terminus of the protein, not previously described in N. gonorrhoeae

Amyloidosis: Diagnostic investigations, clinical categories, prognosis and management

BACKGROUND: Amyloidosis is a very rare disorder of protein misfolding characterised by the deposition of certain proteins in an abnormal fibrillary form within the extracellular space, which disrupts the normal structure and function of organs throughout the body. Amyloid deposition may be systemic or localised, though there have been few systematic clinical studies of the latter. Treatment depends on the respective amyloid fibril type, and comprises chemotherapy regimens derived from myeloma for the most prevalent systemic monoclonal immunoglobulin light chain (AL) type. The clinical features of systemic AL amyloidosis are protean, commonly including a variety of poorly understood coagulation abnormalities and fatigue symptoms of uncertain cause. Measurement of serum free light chains (FLC) has been a very important advance in guiding treatment of systemic AL amyloidosis. Novel treatment approaches include the serum amyloid P component (SAP) depleting drug ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2 carboxylic acid which has shown promise in a pilot study in patients with hereditary fibrinogen amyloidosis. AIMS: To compare the performance of two commercially available serum free light chain assays and study the prognostic utility of each in systemic AL amyloidosis. To investigate the underlying bleeding and coagulation abnormalities, associated prognostic implications, endothelial dysfunction and implications for the possibility of light chain toxicity. To explore the sleep disordered breathing morbidity in amyloidosis. To investigate the incidence, patient characteristics and survival outcomes in patients with localised AL amyloidosis. To explore a subgroup of localised amyloidosis: tracheobronchial and laryngeal amyloidosis from a clinical and proteomic perspective. To examine two types of treatment in systemic amyloidosis: the use of lenalidomide based chemotherapy with prior use of Thalidomide/Bortezomib treatment in systemic AL amyloidosis and CPHPC treatment. RESULTS AND CONCLUSIONS: Both FreeliteTM and N Latex assays have high sensitivity for detecting abnormal FLC in patients with systemic light chain amyloidosis, showing an excellent correlation between the assays for identifying the abnormal light chain subtype but with discordance in the absolute values. Coagulation abnormalities in systemic AL amyloidosis were frequent and included the following abnormalities: elevated concentration of fibrinogen in 42 (56.8%), elevated FVIII 67 (90.5%) and vWF Ag 67 (90.5%). Kaplan Meier estimates showed that vWF Ag (p=0.039) and FVIII (p=0.01) thresholds greater than 280IU associated with a significant survival disadvantage. A fall in the vWF Ag levels following chemotherapy in those achieving a clonal response suggests potential light chain toxicity implications. Albumin concentration lower than 25g/L correlated with coagulation factors which are prothrombotic, implying that anticoagulation may be an important consideration in newly diagnosed systemic AL. Thus these findings suggest the potential prognostic utility of vWF Ag levels and thrombotic risks associated with newly diagnosed systemic AL patients. Recurrent overnight oxygen desaturations proved to be frequent in patients with cardiac and/or soft tissue amyloidosis, although the occurrence of sleep disordered breathing (SDB) needs confirmation with formal polysomnography. Patients with poor right heart ventricular systolic function score high with SDB questionnaires, which was associated with adverse outcome in newly diagnosed cardiac AL amyloidosis. Localised AL amyloidosis is a very different disease from systemic AL amyloidosis, with a far superior prognosis. Local surgical resection is adequate in most patients with localised amyloidosis in whom treatment is needed, and radiotherapy can have a useful role in some patients whose disease cannot be controlled by local measures. Progression to systemic AL amyloidosis is extremely rare except among patients with lymph node involvement. Patients with lymph node involvement and those with isotypic specific circulating free light chains warrant closer follow up for development of systemic amyloidosis. Most patients with localised AL have excellent long term outcomes. Laryngeal and tracheobronchial amyloidosis is a subtype of localised amyloidosis, in which hoarseness and dyspnoea are the predominant symptoms, the 2 year OS 93% and 90% respectively. Proteomic analysis of amyloid dissected from biopsies showed the presence of the amyloid signature proteins, apolipoprotein A1 (in greater amounts protein) and insulin-like growth factor binding protein complex in all samples compared with patients with systemic AL or transthyretin amyloidosis. Of interest, apolipoprotein A1 has been described within the respiratory tract and insulin growth factor has been postulated to play a role in inflammation, which may be relevant with respect to the pathogenesis and effects of airways amyloidosis. Lenalidomide and dexamethasone combination treatment following prior proteasome inhibitor based therapy produced an overall haematologic response rate of 61%, including 20% complete responses. Renal responses among patients who received prolonged treatment were surprisingly frequent; twenty one out of 38 (55%) evaluable patients achieved a renal response (40% on an ITT basis) – 7 (18%) at 6 months, 7 (18%) at 12 months and an additional 7 (18%) patients at 18 months by long term follow up. This raises the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits. CPHPC depletes circulating Serum amyloid P (SAP) component as a treatment for systemic amyloidosis.1 Our study of 10 patients suggested a significant reduction in the natural progression of renal decline and renal survival along with an excellent safety profile; this was supported by our QoL assessments using SFv36 questionnaires. The work in this thesis has thus contributed to improved characterisation and clinical management of various types of amyloidosis, and has identified several avenues of therapy that merit further investigation in larger populations and randomised clinical trials

ASSESSMENT OF NATURAL RADIOACTIVITY LEVEL AND ASSOCIATED RADIOLOGICAL HAZARDS IN MARINE SEDIMENT SAMPLES COLLECTED FROM ABYAN BEACH, GULF OF ADEN, YEMEN

تمَّ تجميع 23 عينه بقايا بحرية من ساحل ابين على شاطئ خليج عدن لقياس تركيز الراديوم-226، الثوريوم -232 والبوتاسيوم -40 ومعاملات الاخطار الناتجة عنها بأستخدام كاشف الجرمانيوم عالي النقاوة .HPGe اظهرت النتائج ان اعلى تركيز لفعالية نويدة الراديوم-226 وجدت في العينة ٍS11 والذي تساوي  (36.300±1.41Bq/kg)بينما اقل قيمة وجدت في العينة S23 والذي تساوي (9.44±0.38Bq/kg) بمعدل تركيزيساوي (16.25±0.53Bq/kg). بينما وجدت اعلى تركيزلفعالية نويدة الثوريوم -232المشعة طبيعيا"في العينة S11 والذي تساوي (95.75±5.88Bq/kg) واقل قيمة وجدت في العينة S12 والذي تساوي (12.94±0.79Bq/kg) بمعدل تركيزيساوي (23.80±1.46Bq/kg). اما اعلى تركيز لفعالية نويدة البوتاسيوم -40 فقد وجدت في العينةS5 والتي تساوي (747.72±64.32Bq/kg) واقل قيمة وجدت في العينة S11 والذي تساوي (296.67±25.52Bq/kg) بمعدل تركيزيساوي (518.54±45.84Bq/kg). تم حساب معاملات الاخطار الاشعاعية الناتجة عن تواجد هذه الانوية الطبيعية في عينات البقايا البحرية المقاسة. اظهرت النتائج ان فعالية المعامل الراديومي (Raeq) تقع في المدى (65.58to196.06Bq/kg) بمعدل يساوي (90.21Bq/kg)، معامل الخطورة الخارجي (Hex) يقع في المدى (0.177 to 0.529) بمعدل يساوي 0.243، معامل الخطورة الداخلي (Hin) يقع في المدى (0.203 to 0.627) بمعدل يساوي 0.287. حسبت معدل الجرعة الممتصة الخارجي Dout ومعدل الجرعة الممتصة الداخلي (Din) ووجدت انها تقع في المدى(31.57 to 87.06nGyh-1)، (59.91 to 162.75nGyh-1) بمعدل يساوي 43.66nGyh-1 ,83.13nGyh-1 على التوالي. حسبت الجرعة السنوية المؤثرة الخارجية (AEDout) والداخلية (AEDin) ووجدت انها تقع في المدى (0.294 to 0.798mSvh-1), (0.039 to 0.107mSvh-1) بمعدل يساوي 0.053mSvh-1  و0.407mSvh-1 على التوالي. حسبت قيم الجرعة المكافئة السنوية للغدة التناسلية AGDE ووجدت انها تقع في المدى (226.13 to 605.55μSvh-1) بمعدل يساوي.312.52 μSvh-1-بينما حسبت قيمة كل من ( excess life-time cancer risk (ELCRout الخارجي وكذلك (excess life-time cancer risk (ELCRin الداخلي ووجدت انها تقع في المدى (0.135×10-3 to 0.374×10-3)، (1.029×10-3 to 2.79 ×10-3) بمعدل يساوي (3-10×0.187)، (3-10×1.427) على التوالي. جميع النتائج التي حصلنا عليها للعينات قيد الدراسة اقل من القيمة العليا المسموح بها والموصى بها منThe World Health Organization and EU Council وان الاشعاعات الناتجة عن النويدات الطبيعية لاتشكل خطورة على الحياة البشرية.Twenty three marine sediment samples taken from the side beach from the Abyan beach, Aden Gulf, Yemen to measuring the activity concentration of terrestrial radionuclides radium-226, thorium-232 and potassium-40 and its associated hazard indices using gamma spectrometer with High-Purity Germanium HPGe detector. The average activity concentration of natural radionuclides 226Ra, 232Th and 40k in marine sediments samples under investigation were 16.25± 0.63Bqkg-1, for Ra-226, 23.80± 1.46Bqkg-1 for Th-232 and 518.54±44.61Bqkg-1 for K-40 respectively. The radiation hazard indices which resulting from the presence of natural radionuclides in marine sediment samples were calculated and the obtained results indicate that the average value of radium equivalent activity was 90.21Bqkg-1. The average value of External hazard index Hex was 0.243 and the average values of internal hazard index Hin was 0.287. The average value of outdoor absorbed dose rate Dout was 43.66nGyh−1 and indoor absorbed dose rate Din was 83.13nGyh−1. The average values of annual outdoor effective dose AEDout was 0.053mSvy-1and the annual indoor effective dose AEDin was 0.407mSvy-1. The average values of the annual gonadal dose equivalent AGDE were 312.52μSvy-1. While the average values of outdoor excess life-time cancer risk ELCRout was 0.187×10−3 and the indoor excess life-time cancer risk ELCRin was 1.427×10−3. They are less than worldwide limits

Functional ectodomain of the hemagglutinin-neuraminidase protein is expressed in transgenic tobacco cells as a candidate vaccine against Newcastle disease virus.

Recently, the use of plants for the production of recombinant proteins has been well demonstrated with promising outcomes. In this study, an efficient Nicotiana tabacum L. cv. Bright Yellow 2 (BY-2) cells system expressing the ectodomain of hemagglutinin-neuraminidase (eHN) protein from Newcastle disease virus (NDV) strain AF2240 was established. Transgenic tobacco BY-2 cell cultures expressing the immunogenic eHN protein were generated and the translation efficiency of eHN protein was enhanced using the 5′-untranslated region of Nicotiana tabacum alcohol dehydrogenase gene (NtADH 5′-UTR) under the control of strong cauliflower mosaic virus (CaMV 35S) promoter. Transgenic lines verified by real-time PCR showed high level of eHN mRNA transcripts and immunoblotting confirmed the presence of 66 kD eHN protein. The eHN protein was stably produced in an average of 0.2–0.4 % total soluble protein. Green fluorescent protein-tagged eHN protein was expressed and localized at the cytosol of BY-2 cell. All mice receiving purified eHN protein from transgenic tobacco BY-2 cells produced specific anti-NDV antibodies. We concluded that plant made eHN elicit immune response and can serve as candidate vaccine against NDV

Resin-rich volumes ( RRV ) and the performance of fibre-reinforced composites: a review

This review considers the influence of Resin-Rich Volumes (RRV) on the static and dynamic mechanical and physical behaviour of fibre-reinforced composites. The formation, shape and size, and measurement of RRV in composites consequent upon different fabric architectures and manufacturing processes is discussed. The majority of studies show a negative effect of the RRV on the mechanical behaviour of composite materials. The main factors that cause the RRV are (a) the clustering of fibres as bundles in textiles, (b) the stacking sequence, (c) the consolidation characteristics of the reinforcement, (d) the resin flow characteristics as a function of tempera-ture, and (e) the composite manufacturing process and cure cycle. RRV are stress concentrations that lead to a disproportionate fall in composite strength. Anyone considering moving from autoclave consolidation to out-of-autoclave (OOA) processes should be cautious of the potential effects of the change

Data driven contagion risk management in low-income countries using machine learning applications with COVID-19 in South Asia

In the absence of real-time surveillance data, it is difficult to derive an early warning system and potential outbreak locations with the existing epidemiological models, especially in resource-constrained countries. We proposed a contagion risk index (CR-Index)—based on publicly available national statistics—founded on communicable disease spreadability vectors. Utilizing the daily COVID-19 data (positive cases and deaths) from 2020 to 2022, we developed country-specific and sub-national CR-Index for South Asia (India, Pakistan, and Bangladesh) and identified potential infection hotspots—aiding policymakers with efficient mitigation planning. Across the study period, the week-by-week and fixed-effects regression estimates demonstrate a strong correlation between the proposed CR-Index and sub-national (district-level) COVID-19 statistics. We validated the CR-Index using machine learning methods by evaluating the out-of-sample predictive performance. Machine learning driven validation showed that the CR-Index can correctly predict districts with high incidents of COVID-19 cases and deaths more than 85% of the time. This proposed CR-Index is a simple, replicable, and easily interpretable tool that can help low-income countries prioritize resource mobilization to contain the disease spread and associated crisis management with global relevance and applicability. This index can also help to contain future pandemics (and epidemics) and manage their far-reaching adverse consequences

An examination of the long-term business value of investments in information technology

In this paper, we examine the effects of investments in Information Technology (IT) on the long term business values of organizations. The regression discontinuity design is used in this research to examine eight hundred and ten IT investment announcements collected from the period 1982–2007. Our results found that press releases can affect the market value of a firm by possibly providing investors with a better idea of a firm’s current and future operations and strategy. On the other hand, these press releases also appear to attract more transient investors. The attraction of transient investors likely suggests the market believes the IT investing firm is serious about its potential for growth and expansion

Testing for an effect of a mindfulness induction on child executive functions

Several sessions of mindfulness practice can exert positive gains for child executive functions (EF); however, the evidence for effects of a mindfulness induction, on EF for adults, is mixed and this effect has not been tested in children. The immediate effect of an age appropriate 3-min mindfulness induction on EF of children aged 4–7 years was tested. Participants (N = 156) were randomly assigned to a mindfulness induction or dot-to-dot activity comparison group before completing four measures of EF. A composite score for EF was calculated from summed z scores of the four EF measures. A difference at baseline in behavioural difficulties between the mindfulness induction and comparison group meant that data was analysed using a hierarchical regression. The mindfulness induction resulted in higher average performance for the composite EF score (M = 0.12) compared to the comparison group (M = − 0.05). Behavioural difficulties significantly predicted 5.3% of the variance in EF performance but participation in the mindfulness or comparison induction did not significantly affect EF. The non-significant effect of a mindfulness induction to exert immediate effects on EF fits within broader evidence reporting mixed effects when similar experimental designs have been used with adults. The findings are discussed with consideration of the extent to which methodological differences may account for these mixed effects and how mindfulness inductions fit within broader theoretical and empirical understanding of the effects of mindfulness on EF

Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities