The human CTF4-orthologue AND-1 interacts with DNA polymerase α/primase via its unique C-terminal HMG box

A dynamic multi-protein assembly known as the replisome is responsible for DNA synthesis in eukaryotic cells. In yeast, the hub protein Ctf4 bridges DNA helicase and DNA polymerase and recruits factors with roles in metabolic processes coupled to DNA replication. An important question in DNA replication is the extent to which the molecular architecture of the replisome is conserved between yeast and higher eukaryotes. Here we describe the biochemical basis for the interaction of the human CTF4-orthologue AND-1 with Pol α/primase, the replicative polymerase that initiates DNA synthesis. AND-1 has maintained the trimeric structure of yeast Ctf4, driven by its conserved SepB domain. However, the primary interaction of AND-1 with Pol α/primase is mediated by its C-terminal HMG box, unique to mammalian AND-1, which binds the B subunit, at the same site targeted by the SV40 T antigen for viral replication. In addition, we report a novel DNA-binding activity in AND-1, which might promote the correct positioning of Pol α/primase on the lagging-strand template at the replication fork. Our findings provide a biochemical basis for the specific interaction between two critical components of the human replisome, and indicate that important principles of replisome architecture have changed significantly in evolution.This work was supported by a Wellcome Trust investigator award to L.P. (104641/Z/14/Z), a Cambridge Gates PhD scholarship to A.C.S., a PhD fellowship of the Boehringer-Ingelheim Fonds and awards from the Janggen-Pöhn-Stiftung and the Swiss National Science Foundation to S.H

Towards understanding startup product development as effectual entrepreneurial behaviors

Software startups face with multiple technical and business challenges, which could make the startup journey longer, or even become a failure. Little is known about entrepreneurial decision making as a direct force to startup development outcome. In this study, we attempted to apply a behaviour theory of entrepreneurial firms to understand the root-cause of some software startup s challenges. Six common challenges related to prototyping and product development in twenty software startups were identified. We found the behaviour theory as a useful theoretical lens to explain the technical challenges. Software startups search for local optimal solutions, emphasise on short-run feedback rather than long-run strategies, which results in vague prototype planning, paradox of demonstration and evolving throw-away prototypes. The finding implies that effectual entrepreneurial processes might require a more suitable product development approach than the current state-of-practice.Comment: This is the author's version of the work. Copyright owner's version can be accessed at https://doi.org/10.1007/978-3-319-69191-6_15, 8th ICSOB 2017, Essen, German

A case of pregnancy with Rhesus antibody and bicornuate uterus - a favourable outcome: a case report

Introduction: In 1% of Rhesus negative women sensitisation occurs without any overt sensitising event during pregnancy. This accounts for late immunisation during a first pregnancy and is responsible for 18-27% of cases of alloimmunisation. The incidence of congenital uterine anomalies in a fertile population is 3.2% of which 5% are bicornuate uterus. Bicornuate uterus can lead to early miscarriages, preterm labor, fetal growth retardation and congenital malformations. Case presentation: A 23-year-old lady in her first pregnancy developed Anti-D antibodies at 28 weeks of gestation without any known sensitising event. In view of increasing anti-D titres, at 36 weeks she was delivered. Incidentally during caesarean section she was found to have bicornuate uterus. The neonate was treated with phototherapy and blood transfusion following delivery. Conclusion: Rhesus antibodies when managed by close monitoring and timely delivery can lead to favourable outcome. Bicornuate uterus does not always lead to complications like miscarriage, growth retardation or preterm labour and does not need any special intervention

Utilité de la biopsie testiculaire dans le bilan de l’infertilité des couples: Usefulness of testicular biopsy in the checkup of infertility couple

Context and objectives. Testicular biopsy is a relevant tool for the management of male’s infertility.However data in Subsaharan Africa are sparce in this field. Histological aspects aspects in case of azoospermia (AZOO) or oligoasthenoterato-spermia (OATS), were described, to sort out main causes of the disturbance. Methods. A retrospective analysis of of patients’ records has been undertaken, covering the period of 2010 to 2015 in 2 hopitals of Kinhasa. Studied parameters included clinical, biological, and morphological data. Histological features were then compared with the results of spermogramme, FSH, and testicular biometry. Results.Out of 60 files, only 47(68/%) met the inclusion criteria. A total of 47 patients was unled out of 60 records. Fibrosis was the main histological pattern observed (70%). Non obstructive AZOO (87%) was predominant compared to obstructive form (12, 7%). All normal or intermediate testicular histology was associated with a FSH level of ≤10.5 IU / mL and normal or hypotrophic testicular appearance on ultrasound. In contrast, testicular atrophy and FSH ≥14UI / mL were significantly associated with fibrosis. Surgical treatment was applied in 15% AZOO and obstructive OATS, 15% AZOO AMP and non-obstructive OATS and insemination with donor sperm or adoption (70%). Conclusion. The study shows histologycally a link between azoospermia and fibrosis as well as non-obstructive abnormalities.Azoospermia in this study is characterized histologically by fibrosis and non-obstructive abnormalities. Systematic testicular biopsy should be recommanded in patients with AZOO or OATS, when the level of FSH is ≥10.5 IU / mL, except in case of testicular atrophy. Contexte et objectifs: En dépit de l’importance de la biopsie testiculaire, très peu de centres d’Andrologie recours à ce moyen dans la prise charge de l’infertilité du couple en Afrique sub-saharienne. La présente étude avait pour objectifs de décrire les aspects histologiques testiculaires en cas d’azoospermie (AZOO) ou d’oligoasthénotératospermie (OATS), et de rechercher les associations éventuelles entre la FSH, la biométrie testiculaire et les aspects histologiques de la biopsie testiculaire (BT). Méthodes. Nous avons colligé tous les dossiers des patients présentant AZOO ou OATS, suivi dans deux hôpitaux de Kinshasa (Cliniques Universitaires de Kinshasa et Clinique Ngaliema), entre 2010 et 2015 pour infertilité. Les paramètres d’intérêt incluaient les données clinique (examen physique), biologique (spermogramme, spermocytogramme, FSH), et morphologiques (échographie et biopsie testiculaire). Les résultats histologiques ont été regroupés en 3 classes: normale, intermédiaire, fibrose. Les aspects histologiques ont été comparés au spermogramme, au taux de FSH, et à la biométrie testiculaire. Résultats. Durant la période de l’étude, 60 patients ont été suivis, mais 47 (AZOO, 68%) seulement ont satisfait aux critères de sélection. La biopsie testiculaire a révélé un aspect de fibrose (70%) et intermédiaire dans 17%. Comparées aux anomalies obstructives (12,7%), les non-obstructives étaient plus fréquentes (87%). Tous les aspects histologiques testiculaires normaux ou intermédiaires étaient associés à un taux de FSH de ≤10,5 UI/ml et un aspect testiculaire normal ou hypotrophique à l’échographie. En revanche, l’atrophie testiculaire et un taux de FSH ≥14 UI/ml semblaient être associés à la fibrose (p > 0,05). De ce qui précède, l’attitude thérapeutique plausible est la chirurgie pour 15% d’AZOO et d’OATS obstructives, AMP 15% d’AZOO et d’OATS non obstructives et l’insémination avec sperme de donneur ou à l’adoption (70%). Conclusion. L’azoospermie dans cette étude est caractérisée histologiquement par une fibrose et des anomalies non-obstructives. Exceptée en cas d’atrophie testiculaire, la biopsie testiculaire devra être systématique chez les patients avec AZOO ou OATS surtout si FSH ≥10,5UI/ml, en vue d’un choix thérapeutique judicieux

Mechanical testing of a device for subcutaneous internal anterior pelvic ring fixation versus external pelvic ring fixation

BACKGROUND: Although useful in the emergency treatment of pelvic ring injuries, external fixation is associated with pin tract infections, the patient’s limited mobility and a restricted surgical accessibility to the lower abdomen. In this study, the mechanical stability of a subcutaneous internal anterior fixation (SIAF) system is investigated. METHODS: A standard external fixation and a SIAF system were tested on pairs of Polyoxymethylene testing cylinders using a universal testing machine. Each specimen was subjected to a total of 2000 consecutive cyclic loadings at 1 Hz with sinusoidal lateral compression/distraction (+/−50 N) and torque (+/− 0.5 Nm) loading alternating every 200 cycles. Translational and rotational stiffness were determined at 100, 300, 500, 700 and 900 cycles. RESULTS: There was no significant difference in translational stiffness between the SIAF and the standard external fixation when compared at 500 (p = .089), 700 (p = .081), and 900 (p = .266) cycles. Rotational stiffness observed for the SIAF was about 50 percent higher than the standard external fixation at 300 (p = .005), 500 (p = .020), and 900 (p = .005) cycles. No loosening or failure of the rod-pin/rod-screw interfaces was seen. CONCLUSIONS: In comparison with the standard external fixation system, the tested device for subcutaneous internal anterior fixation (SIAF) in vitro has similar translational and superior rotational stiffness

Evaluation and pharmacovigilance of projects promoting cultivation and local use of Artemisia annua for malaria

<p>Abstract</p> <p>Background</p> <p>Several non-governmental organisations (NGOs) are promoting the use of <it>Artemisia annua </it>teas as a home-based treatment for malaria in situations where conventional treatments are not available. There has been controversy about the effectiveness and safety of this approach, but no pharmacovigilance studies or evaluations have been published to date.</p> <p>Method</p> <p>A questionnaire about the cultivation of <it>A. annua</it>, treatment of patients, and side-effects observed, was sent to partners of the NGO Anamed in Kenya and Uganda. Some of the respondents were then selected purposively for more in-depth semi-structured interviews.</p> <p>Results</p> <p>Eighteen partners in Kenya and 21 in Uganda responded. 49% reported difficulties in growing the plant, mainly due to drought. Overall about 3,000 cases of presumed malaria had been treated with <it>A. annua </it>teas in the previous year, of which about 250 were in children and 54 were in women in the first trimester of pregnancy. The commonest problem observed in children was poor compliance due to the bitter taste, which was improved by the addition of sugar or honey. Two miscarriages were reported in pregnant patients. Only four respondents reported side-effects in other patients, the commonest of which was vomiting. 51% of respondents had started using <it>A. annua </it>tea to treat illnesses other than malaria.</p> <p>Conclusions</p> <p>Local cultivation and preparation of <it>A. annua </it>are feasible where growing conditions are appropriate. Few adverse events were reported even in children and pregnant women. Where ACT is in short supply, it would make sense to save it for young children, while using <it>A. annua </it>infusions to treat older patients who are at lower risk. An ongoing pharmacovigilance system is needed to facilitate reporting of any adverse events.</p

Population assessment of future trajectories in coronary heart disease mortality.

Background: Coronary heart disease (CHD) mortality rates have been decreasing in Iceland since the 1980s, largely reflecting improvements in cardiovascular risk factors. The purpose of this study was to predict future CHD mortality in Iceland based on potential risk factor trends. Methods and findings: The previously validated IMPACT model was used to predict changes in CHD mortality between 2010 and 2040 among the projected population of Iceland aged 25–74. Calculations were based on combining: i) data on population numbers and projections (Statistics Iceland), ii) population risk factor levels and projections (Refine Reykjavik study), and iii) effectiveness of specific risk factor reductions (published meta-analyses). Projections for three contrasting scenarios were compared: 1) If the historical risk factor trends of past 30 years were to continue, the declining death rates of past decades would level off, reflecting population ageing. 2) If recent trends in risk factors (past 5 years) continue, this would result in a death rate increasing from 49 to 70 per 100,000. This would reflect a recent plateau in previously falling cholesterol levels and recent rapid increases in obesity and diabetes prevalence. 3) Assuming that in 2040 the entire population enjoys optimal risk factor levels observed in low risk cohorts, this would prevent almost all premature CHD deaths before 2040. Conclusions: The potential increase in CHD deaths with recent trends in risk factor levels is alarming both for Iceland and probably for comparable Western populations. However, our results show considerable room for reducing CHD mortality. Achieving the best case scenario could eradicate premature CHD deaths by 2040. Public health policy interventions based on these predictions may provide a cost effective means of reducing CHD mortality in the future

Gravitational detection of a low-mass dark satellite at cosmological distance

The mass-function of dwarf satellite galaxies that are observed around Local Group galaxies substantially differs from simulations based on cold dark matter: the simulations predict many more dwarf galaxies than are seen. The Local Group, however, may be anomalous in this regard. A massive dark satellite in an early-type lens galaxy at z = 0.222 was recently found using a new method based on gravitational lensing, suggesting that the mass fraction contained in substructure could be higher than is predicted from simulations. The lack of very low mass detections, however, prohibited any constraint on their mass function. Here we report the presence of a 1.9 +/- 0.1 x 10^8 M_sun dark satellite in the Einstein-ring system JVAS B1938+666 at z = 0.881, where M_sun denotes solar mass. This satellite galaxy has a mass similar to the Sagittarius galaxy, which is a satellite of the Milky Way. We determine the logarithmic slope of the mass function for substructure beyond the local Universe to be alpha = 1.1^+0.6_-0.4, with an average mass-fraction of f = 3.3^+3.6_-1.8 %, by combining data on both of these recently discovered galaxies. Our results are consistent with the predictions from cold dark matter simulations at the 95 per cent confidence level, and therefore agree with the view that galaxies formed hierarchically in a Universe composed of cold dark matter.Comment: 25 pages, 7 figures, accepted for publication in Nature (19 January 2012

Scaling Laws in Human Language

Zipf's law on word frequency is observed in English, French, Spanish, Italian, and so on, yet it does not hold for Chinese, Japanese or Korean characters. A model for writing process is proposed to explain the above difference, which takes into account the effects of finite vocabulary size. Experiments, simulations and analytical solution agree well with each other. The results show that the frequency distribution follows a power law with exponent being equal to 1, at which the corresponding Zipf's exponent diverges. Actually, the distribution obeys exponential form in the Zipf's plot. Deviating from the Heaps' law, the number of distinct words grows with the text length in three stages: It grows linearly in the beginning, then turns to a logarithmical form, and eventually saturates. This work refines previous understanding about Zipf's law and Heaps' law in language systems.Comment: 6 pages, 4 figure

Taurolidine-citrate lock solution (TauroLock) significantly reduces CVAD-associated grampositive infections in pediatric cancer patients

<p>Abstract</p> <p>Background</p> <p>Taurolidin/Citrate (TauroLock™), a lock solution with broad spectrum antimicrobial activity, may prevent bloodstream infection (BSI) due to coagulase-negative staphylococci (CoNS or 'MRSE' in case of methicillin-resistant isolates) in pediatric cancer patients with a long term central venous access device (CVAD, Port- or/Broviac-/Hickman-catheter type).</p> <p>Methods</p> <p>In a single center prospective 48-months cohort study we compared all patients receiving anticancer chemotherapy from April 2003 to March 2005 (group 1, heparin lock with 200 IU/ml sterile normal saline 0.9%; Canusal^®Wockhardt UK Ltd, Wrexham, Wales) and all patients from April 2005 to March 2007 (group 2; taurolidine 1.35%/Sodium Citrate 4%; TauroLock™, Tauropharm, Waldbüttelbrunn, Germany).</p> <p>Results</p> <p>In group 1 (heparin), 90 patients had 98 CVAD in use during the surveillance period. 14 of 30 (47%) BSI were 'primary Gram positive BSI due to CoNS (n = 4) or MRSE (n = 10)' [incidence density (ID); 2.30 per 1000 inpatient CVAD-utilization days].</p> <p>In group 2 (TauroLock™), 89 patients had 95 CVAD in use during the surveillance period. 3 of 25 (12%) BSI were caused by CoNS. (ID, 0.45). The difference in the ID between the two groups was statistically significant (P = 0.004).</p> <p>Conclusion</p> <p>The use of Taurolidin/Citrate (TauroLock™) significantly reduced the number and incidence density of primary catheter-associated BSI due to CoNS and MRSE in pediatric cancer patients.</p