Explore the vast range of titles available.

Background: To date, only a few risk factors for pancreatic cancer have been established. We examined prospectively relations between several medical conditions and pancreatic cancer incidence. Methods: In 1986, 120 852 participants completed a baseline questionnaire on cancer risk factors, including several self-reported physician diagnosed medical conditions. At baseline, a random subcohort of 5000 participants was selected using a case-cohort approach for analysis. After 16.3 years of follow-up, 448 pancreatic cancer cases (63% microscopically confirmed) were available for analysis. Results: Diabetes mellitus type II and hepatitis were positively associated with pancreatic cancer risk (multivariable-adjusted hazard ratio: 1.79; 95% confidence interval: 1.12–2.87 and hazard ratio: 1.37; 95% confidence interval: 1.04–1.81, respectively). Furthermore, a positive trend in risk with increasing years of diagnosis of diabetes ( P =0.004) and of hepatitis ( P =0.02) was observed. However, an inverse association was observed between hypertension and pancreatic cancer risk, this was found among microscopically confirmed cases only (hazard ratio: 0.66; 95% confidence interval: 0.49–0.90), while years since diagnosis of hypertension significantly decreased cancer risk (P for trend=0.02). Conclusion: In this prospective study, a positive association was observed between self-reported physician diagnosed diabetes mellitus type II and hepatitis and pancreatic cancer risk, whereas an inverse association was observed with hypertension.

In a cohort study, ovarian cancer (280 cases) showed no significant association with tea or coffee, the multivariable rate ratios being 0.94 (95% confidence interval (CI): 0.89, 1.00) and 1.04 (95% CI: 0.97, 1.12) per cup per day, respectively. A meta-analysis also produced no significant findings overall, though the cohort studies showed a significant inverse association for tea.

Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ∼1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia ( P =7.6 × 10 −11 ) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants ( P <0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction ( P =2.0 × 10 −4 ), excitability ( P =9.0 × 10 −4 ) and cell adhesion and trans-synaptic signaling ( P =2.4 × 10 −3 ). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.

Background Large comparative studies that have evaluated long-term functional outcome of operatively treated ankle fractures are lacking. This study was performed to analyse the influence of several combinations of malleolar fractures on long-term functional outcome and development of osteoarthritis. Methods Retrospective cohort-study on operated (1995–2007) malleolar fractures. Results were assessed with use of the AAOS- and AOFAS-questionnaires, VAS-pain score, dorsiflexion restriction (range of motion) and osteoarthritis. Categorisation was determined using the number of malleoli involved. Results 243 participants with a mean follow-up of 9.6 years were included. Significant differences for all outcomes were found between unimalleolar (isolated fibular) and bimalleolar (a combination of fibular and medial) fractures (AOFAS 97 vs 91, p  = 0.035; AAOS 97 vs 90, p  = 0.026; dorsiflexion restriction 2.8° vs 6.7°, p  = 0.003). Outcomes after fibular fractures with an additional posterior fragment were similar to isolated fibular fractures. However, significant differences were found between unimalleolar and trimalleolar (a combination of lateral, medial and posterior) fractures (AOFAS 97 vs 88, p  < 0.001; AAOS 97 vs 90, p  = 0.003; VAS-pain 1.1 vs 2.3 p  < 0.001; dorsiflexion restriction 2.9° vs 6.9°, p  < 0.001). There was no significant difference in isolated fibular fractures with or without additional deltoid ligament injury. In addition, no functional differences were found between bimalleolar and trimalleolar fractures. Surprisingly, poor outcomes were found for isolated medial malleolar fractures. Development of osteoarthritis occurred mainly in trimalleolar fractures with a posterior fragment larger than 5 %. Conclusions The results of our study show that long-term functional outcome is strongly associated to medial malleolar fractures, isolated or as part of bi- or trimalleolar fractures. More cases of osteoarthritis are found in trimalleolar fractures.

Generation of neuronal cultures from induced pluripotent stem cells (hiPSCs) serve the studies of human brain disorders. However we lack neuronal networks with balanced excitatory-inhibitory activities, which are suitable for single cell analysis. We generated low-density networks of hPSC-derived GABAergic and glutamatergic cortical neurons. We used two different co-culture models with astrocytes. We show that these cultures have balanced excitatory-inhibitory synaptic identities using confocal microscopy, electrophysiological recordings, calcium imaging and mRNA analysis. These simple and robust protocols offer the opportunity for single-cell to multi-level analysis of patient hiPSC-derived cortical excitatory-inhibitory networks; thereby creating advanced tools to study disease mechanisms underlying neurodevelopmental disorders.

Tomosyn is a large, non-canonical SNARE protein proposed to act as an inhibitor of SNARE complex formation in the exocytosis of secretory vesicles. In the brain, tomosyn inhibits the fusion of synaptic vesicles (SVs), whereas its role in the fusion of neuropeptide-containing dense core vesicles (DCVs) is unknown. Here, we addressed this question using a new mouse model with a conditional deletion of tomosyn ( Stxbp5 ) and its paralogue tomosyn-2 ( Stxbp5l ). We monitored DCV exocytosis at single vesicle resolution in tomosyn-deficient primary neurons using a validated pHluorin-based assay. Surprisingly, loss of tomosyns did not affect the number of DCV fusion events but resulted in a strong reduction of intracellular levels of DCV cargos, such as neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). BDNF levels were largely restored by re-expression of tomosyn but not by inhibition of lysosomal proteolysis. Tomosyn’s SNARE domain was dispensable for the rescue. The size of the trans-Golgi network and DCVs was decreased, and the speed of DCV cargo flux through Golgi was increased in tomosyn-deficient neurons, suggesting a role for tomosyns in DCV biogenesis. Additionally, tomosyn-deficient neurons showed impaired mRNA expression of some DCV cargos, which was not restored by re-expression of tomosyn and was also observed in Cre-expressing wild-type neurons not carrying lox P sites, suggesting a direct effect of Cre recombinase on neuronal transcription. Taken together, our findings argue against an inhibitory role of tomosyns in neuronal DCV exocytosis and suggests an evolutionary conserved function of tomosyns in the packaging of secretory cargo at the Golgi.

Functional genetic analyses in mice rely on efficient and in-depth characterization of the behavioral spectrum. Automated home-cage observation can provide a systematic and efficient screening method to detect unexplored, novel behavioral phenotypes. Here, we analyzed high-throughput automated home-cage data using existing and novel concepts, to detect a plethora of genetic differences in spontaneous behavior in a panel of commonly used inbred strains (129S1/SvImJ, A/J, C3H/HeJ, C57BL/6J, BALB/cJ, DBA/2J, NOD/LtJ, FVB/NJ, WSB/EiJ, PWK/PhJ and CAST/EiJ). Continuous video-tracking observations of sheltering behavior and locomotor activity were segmented into distinguishable behavioral elements, and studied at different time scales, yielding a set of 115 behavioral parameters of which 105 showed highly significant strain differences. This set of 115 parameters was highly dimensional; principal component analysis identified 26 orthogonal components with eigenvalues above one. Especially novel parameters of sheltering behavior and parameters describing aspects of motion of the mouse in the home-cage showed high genetic effect sizes. Multi-day habituation curves and patterns of behavior surrounding dark/light phase transitions showed striking strain differences, albeit with lower genetic effect sizes. This spontaneous home-cage behavior study demonstrates high dimensionality, with a strong genetic contribution to specific sets of behavioral measures. Importantly, spontaneous home-cage behavior analysis detects genetic effects that cannot be studied in conventional behavioral tests, showing that the inclusion of a few days of undisturbed, labor extensive home-cage assessment may greatly aid gene function analyses and drug target discovery.

In the digital era, start-ups benefit from expanded reach, faster scaling, and access to vast data sets, yet face heightened competition and the challenge of staying current with emerging innovations. Their role in the modern economy is amplified as they collaborate with incubators, investors, and academic institutions to foster innovation and growth. Agile development methods and disruptive innovation bolster their competitiveness against larger incumbents. Leveraging digital technologies and combining resources are further recognised as pivotal success factors driving disruptive innovations in start-ups.

Large oceanic migrants play important roles in ecosystems, yet many species are of conservation concern as a result of anthropogenic threats, of which incidental capture by fisheries is frequently identified. The last large populations of the leatherback turtle, Dermochelys coriacea, occur in the Atlantic Ocean, but interactions with industrial fisheries could jeopardize recent positive population trends, making bycatch mitigation a priority. Here, we perform the first pan-Atlantic analysis of spatio-temporal distribution of the leatherback turtle and ascertain overlap with longline fishing effort. Data suggest that the Atlantic probably consists of two regional management units: northern and southern (the latter including turtles breeding in South Africa). Although turtles and fisheries show highly diverse distributions, we highlight nine areas of high susceptibility to potential bycatch (four in the northern Atlantic and five in the southern/equatorial Atlantic) that are worthy of further targeted investigation and mitigation. These are reinforced by reports of leatherback bycatch at eight of these sites. International collaborative efforts are needed, especially from nations hosting regions where susceptibility to bycatch is likely to be high within their exclusive economic zone (northern Atlantic: Cape Verde, Gambia, Guinea Bissau, Mauritania, Senegal, Spain, USA and Western Sahara; southern Atlantic: Angola, Brazil, Namibia and UK) and from nations fishing in these high-susceptibility areas, including those located in international waters.

Brain function requires precisely orchestrated connectivity between neurons. Establishment of these connections is believed to require signals secreted from outgrowing axons, followed by synapse formation between selected neurons. Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development. However, this does not prevent normal brain assembly, including formation of layered structures, fiber pathways, and morphologically defined synapses. After assembly is completed, neurons undergo apoptosis, leading to widespread neurodegeneration. Thus, synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion probably functions to validate already established synaptic connections.