Miracle-dz/UniFAR-FTUs huggingface dataset:
DNA Polymorphism and Selection at the Melanocortin‐1 Receptor Gene in Normally Pigmented Southern African Individuals

Abstract: Skin pigmentation is a polygenic multifactorial trait determined by the cumulative effects of multiple genetic variants and environmental factors. Melanocortin‐1 receptor (MC1R) is one of the genes involved in pigmentation, and has been implicated in the red hair and pale skin phenotype in human Caucasoid individuals. The present study was undertaken to identify variation at the MC1R locus in normally pigmented individuals in two African populations, sub‐Saharan Negroids (22 unrelated individuals) and the San (17 unrelated individuals). The study showed considerable MC1R gene sequence variation with the detection of eight synonymous and three nonsynonymous mutations. This is the first report of nonsynonymous mutations in African individuals in the MC1R gene: L99I was found in a single San individual, S47I was detected in a single Negroid individual, and F196L was detected in five Negroid individuals (5/44; 0.11). The functional significance of these mutations is not known. Three of the eight synonymous mutations found, L106L (CTG → CTA), F300F (TTC → TTT), and T314T (ACA → ACG) (also known as A942G), have been reported previously. T314T was the only variant that showed a significant difference between the Negroid and San populations (0.477 and 0.059, respectively; P= 1.6× 10−5). Its low frequency in the San may be the result of random genetic drift in a population of small size, or selection. Several tests of neutrality of the MC1R coding region in these and other African populations were significant, suggesting that purifying selection (functional constraint) had occurred at this gene locus in Africans. This demonstrates that although some nonsynonymous MC1R mutations are tolerated in individuals with dark skin, this gene has likely played a significant role in the maintenance of dark pigmentation in Africans and normal pigment variation in non‐African populations.
Outsourcing Risk: A Separate Operational Risk Category?

Financial authorities and supervisors have emphasized concerns about outsourcing risk for about a decade. A recent European Banking Authority consultation paper discusses "outsourcing" as a subtopic within "operational risk arising from outsourced services and activities, and whether these can affect the institution's ability to process transactions". However, it remains open whether there is an additional operational risk if one compares internal and external sourcing, qualifying "outsourcing" as a separate risk category. Starting from the perspective of the boundary of a firm (ie, the boundary between internal and external production), this paper identifies three steps in sourcing. First, there is business risk, linked to the ex ante entrepreneurial decision to "make or buy", with the required due diligence to make the "best" selection with regard to the allocation of resources. Second, all sourcing has intrinsic risk, although this is independent of the selection of internal production or external sourcing, ie, the boundary of the firm. Third, multisourcing generates a new type of risk, which emerges from the complexity of the sourcing ecosystem at either provider or firm level.
Discriminative stimulus effects of zolpidem in pentobarbital-trained subjects: I. Comparison with triazolam in rhesus monkeys and rats.

The present study compared the discriminative stimulus effects of the imidazopyridine, zolpidem, with a triazolobenzodiazepine, triazolam, in pentobarbital-trained rhesus monkeys and rats. Rhesus monkeys (n = 4), trained to discriminate pentobarbital (10 mg/kg intragastric [i.g.]) from saline under a FR 1 discrete-trials shock avoidance procedure, were given zolpidem (0.10-30 mg/kg i.g.) or triazolam (0.01-0.3 mg/kg i.g.). Both zolpidem and triazolam produced dose-dependent increases in pentobarbital-appropriate responding that reached 80% or greater at the highest doses tested. Zolpidem, but not triazolam, increased latency to respond in a dose-dependent manner. Sprague-Dawley rats (n = 12), trained to discriminate pentobarbital (8.0 mg/kg i.p.) from saline under a FR 10 schedule of food reinforcement, were given zolpidem (0.50-4.0 mg/kg i.p.; 5-, 15- and 45-min pretreatment) or triazolam (0.025-0.20 mg/kg i.p., 15-min pretreatment). Zolpidem occasioned intermediate drug-appropriate responding (maximum group mean = 48%) at the 5- and 15-min pretreatment times and no drug-appropriate responding at the 45-min pretreatment time. In contrast, triazolam occasioned > or = 80% pentobarbital-appropriate responding at 0.10 and 0.20 mg/kg. Both zolpidem and triazolam produced dose-dependent decreases in the rate of responding. The rate-decreasing effects of zolpidem were maximal at the 5-min pretreatment time and had dissipated after the 45-min pretreatment time. Further studies were conducted in rats to equate procedural variables between the monkey and rat studies. When the FR was reduced from 10 to 1, zolpidem occasioned 26 to 62% pentobarbital-appropriate responding over a dose range of 1.0 to 6.0 mg/kg i.p. After i.g. administration, zolpidem occasioned 100% drug-appropriate responding at the highest dose tested (6.0 mg/kg); however, only two of seven rats responded. Taken together, these data raise the possibility of a species difference between non-human primates and rats in the pentobarbital-like discriminative stimulus effects of zolpidem.
Biosynthesis of γ-butyrolactone autoregulators that switch on secondary metabolism and morphological development in Streptomyces

A factor (2-isocapryloyl-3R-hydroxymethyl-γ-butyrolactone) is a representative of the γ-butyrolactone autoregulators that trigger secondary metabolism and morphogenesis in the Gram-positive, filamentous bacterial genus Streptomyces. Here, we report the A factor biosynthesis pathway in Streptomyces griseus. The monomeric AfsA, containing a tandem repeat domain of ≈80 aa, catalyzed β-ketoacyl transfer from 8-methyl-3-oxononanoyl-acyl carrier protein to the hydroxyl group of dihydroxyacetone phosphate (DHAP), thus producing an 8-methyl-3-oxononanoyl-DHAP ester. The fatty acid ester was nonenzymatically converted to a butenolide phosphate by intramolecular aldol condensation. The butenolide phosphate was then reduced by BprA that was encoded just downstream of afsA. The phosphate group on the resultant butanolide was finally removed by a phosphatase, resulting in formation of A factor. The 8-methyl-3-oxononanoyl-DHAP ester produced by the action of AfsA was also converted to A factor in an alternative way; the phosphate group on the ester was first removed by a phosphatase and the dephosphorylated ester was converted nonenzymatically to a butenolide, which was then reduced by a reductase different from BprA, resulting in A factor. Because introduction of afsA alone into Escherichia coli caused the host to produce a substance having A factor activity, the reductase(s) and phosphatase(s) were not specific to the A factor biosynthesis but commonly present in bacteria. AfsA is thus the key enzyme for the biosynthesis of γ-butyrolactones.
The ageing Australian firefighter: an argument for age-based recruitment and fitness standards for urban fire services

Currently, there is no enforcement of physical standards within Australian fire services post-recruitment, possibly leading to inappropriate fitness and body composition. This study evaluated the impacts of ageing on physical standards of Australian firefighters. Seventy-three firefighters from three different 10-year age groups [25–34 years (n = 27), 35–44 years (n = 27), 45–54 years (n = 19)] volunteered for physical testing using dual-energy X-ray analysis and existing fitness tests used for recruitment by an Australian fire service. Older (45–54 years) participants demonstrated significantly poorer physical standards compared with younger participants including cardiovascular fitness (p < 0.05), strength (p = 0.001) and simulated operational power testing tasks (p < 0.001). Age-related body composition changes were also observed independent of body mass index. Minimum recruitment standards and fitness programs need to account for age-related declines in physical capabilities to ensure that the minimum standard is maintained regardless of age. Practitioner Summary: Using dual-energy X-ray analysis and established fitness testing protocols, this study aimed to gain an appreciation of the current standards of body composition and fitness of Australian firefighters and the effects of ageing on their physical abilities post-recruitment. The study demonstrated a significant decline in physical standards due to age.
Objective outcome evaluation using inertial sensors in subacromial impingement syndrome: a five-year follow-up study

Shoulder-related dysfunction is the second most common musculoskeletal disorder and is an increasing burden on health-care systems. Commonly used clinical questionnaires suffer from subjectivity, pain dominance and a ceiling effect. Objective functional measurement has been identified as a relevant issue in clinical rehabilitation. Inertia based motion analysis (IMA) is a new generation of objective outcome assessment tool; it can produce objective movement parameters while being fast, cheap and easy to operate. In this prospective study, an inertial sensor comprising a three-dimensional accelerometer and gyroscope is attached at the humerus to measure shoulder movements during two motion tasks in patients with subacromial impingement syndrome at baseline and at five-year after treatment. One hundred healthy subjects served as healthy reference database and 15 patients were measured pre- and post-treatment. IMA was better able to detect improvement in shoulder movements compared to the clinical questionnaires (Disability of Arm, Shoulder and Hand (DASH) and Simple Shoulder Test (SST); p < 0.05) and was hardly correlated with the clinical questionnaires (Pearson R = 0.39). It may therefore add an objective functional dimension to outcome assessment. The fast assessment (t < 5 min) of a simple motion test makes it suitable for routine clinical follow-up.
Dopamine receptor mechanism(s) and antinociception and tolerance induced by swim stress in formalin test

In the present study, involvement of D1 and D2 dopamine receptors in the antinociception and tolerance induced by water swim stress in the formalin test has been investigated. Water swim stress at 20°C temperature induced antinociception in both phases of the formalin test. Intraperitoneal administration of the D2 dopamine receptor antagonist, sulpiride (25 and 50 mg/kg) reduced swim stress-induced antinociception in the second phase of the formalin test. A higher dose of the D1 dopamine receptor antagonist, SCH23390 (0.1 mg/kg, intraperitoneal) also reduced swim stress-induced antinociception in both phases of the test. Exposure to 3 min water swimming stress, once daily for 3 days, induced tolerance to swim stress-induced antinociception in the second phase of the formalin test. Administration of sulpiride (12.5, 25 and 50 mg/kg), during exposure to water swimming stress (once daily for 3 days), decreased tolerance in the second phase, whereas the antagonist (12.5 and 50 mg/kg) increased pain scores in the first phase of the formalin test. Sulpiride (25 mg/kg) treatment however, once daily for 3 days with no water swimming stress, did not alter swim stress-induced antinociception (0.5, 1 and 3 min tests). Similarly, repeated treatment with SCH23390 (0.05 mg/kg) and water swimming stress did not alter tolerance induced by water swimming stress. Repeated administration of the antagonist in the absence of water swimming stress also did not change swim stress-induced antinociception. The results may indicate a possible involvement of both dopamine D1 and D2 receptors in the antinociception induced by swim stress and D2 receptor mechanism in the tolerance induced by repeated swim stress.
Brain Metabolism and Arterial Acid-Base Balance Following Bilateral Carotid Occlusion in Normotensive and Experimental Hypertensive Rats

SUMMARY: The effects of bilateral common carotid artery occlusion en brain metabolism and arterial acid-base balance were studied in normotensive and experimental renovascular hypertensive rats. One hour after carotid occlusion in hypertensive rats, supratentorial lactate increased to 383% and lactate-pyruvate ratio to 280% of the controls, while adenosine triphosphate (ATP) decreased to 69%. These metabolic changes were thought to be due to cerebral ischemia. Arterial pC02 was lowered and the pH was raised in the hypertensive animals due to cerebral ischemia induced hyperventilation. In the normotensive rats, carotid occlusion had minimal effects on cerebral metabolism and arterial acid-base balance. These results suggest that hypertensive rats are more susceptible to cerebral ischemia caused by carotid occlusion than normotensive rats. Increased cerebrovascular resistance in hypertension is discussed as a casual factor in cerebral ischemia.
Responses of human sensory and motor axons to the release of ischaemia and to hyperpolarizing currents

This study compared directly the post‐ischaemic behaviour of sensory and motor axons in the human median nerve, focusing on the excitability changes produced by ischaemia and its release and by continuous polarizing DC. The decrease in threshold during ischaemia for 13 min was greater, the post‐ischaemic increase in threshold was more rapid, and the return to the pre‐ischaemic excitability took longer in sensory axons. However, a transient depolarizing threshold shift developed in sensory axons a few minutes after release of ischaemia. This pattern could not be reproduced by polarizing currents designed to mimic the probable pump‐induced changes in membrane potential, even though the applied currents produced greater changes in threshold. Hyperpolarizing currents of equivalent intensity produced a greater increase in threshold for motor axons than sensory axons and, in studies of threshold electrotonus using graded hyperpolarizing DC, accommodation was greater in sensory than motor axons. The post‐ischaemic changes in threshold were not uniform for axons of different threshold, whether sensory or motor, the threshold increase was usually less prominent for low‐threshold axons. A transient post‐ischaemic depolarization could be produced in motor axons with ischaemia of 20 min duration. Greater ischaemic and post‐ischaemic changes in threshold for sensory axons could reflect greater dependence on the electrogenic Na+‐K+ pump to maintain resting membrane potential and/or greater extracellular K+ accumulation in ischaemic sensory axons. Inward K+ currents due to extracellular K+ accumulation would then be more likely to trigger a depolarizing shift in membrane potential, the degree of K+ accumulation and pump activity being dependent on the duration of ischaemia. In sensory axons the greater tendency to accommodate to hyperpolarizing stimuli presumably contributes to shaping their post‐ischaemic behaviour but is probably insufficient to explain why their behaviour differs from that of motor axons.
Voltage‐ and ligand‐gated ryanodine receptors are functionally separated in developing C2C12 mouse myotubes

1 In order to further understand the role of voltage‐ and ligand‐gated ryanodine receptors in the control of intracellular Ca2+ signalling during myogenesis, changes in cytosolic free calcium concentration ([Ca2+]i) were investigated by fura‐2 videoimaging in C2C12 mouse myotubes developing in vitro. 2 A synchronous [Ca2+]i increase was observed after depolarisation with high [K+], while the Ca2+ response propagated as a wave following caffeine administration. Application of the two stimuli to the same myotube often revealed the existence of cellular zones that were responsive to depolarisation but not to caffeine. 3 Focal application of high [K+] promoted a [Ca2+]i response detectable only in the cellular areas close to the pipette tip, while focal application of caffeine elicited a [Ca2+]i increase which spread as a Ca2+ wave. Buffering of [Ca2+]i by BAPTA did not affect the pattern of the depolarisation‐induced [Ca2+]i transient but abolished the Ca2+ waves elicited by caffeine. 4 When high [K+] and caffeine were applied in sequence, reciprocal inhibition of the [Ca2+]i responses was observed. 5 Our results suggest that the different spatial patterns of [Ca2+]i responses are due to uneven distribution of voltage‐ and ligand‐gated ryanodine receptors within the myotube. These two types of receptor control two functionally distinct Ca2+ pools which are part of a common intracellular compartment. Finally, the two differently operated ryanodine receptor channels appear to be independently activated, so that a mechanism of Ca2+‐induced Ca2+ release is not required to sustain the global response in C2C12 myotubes.
AKIP1 Expression Modulates Mitochondrial Function in Rat Neonatal Cardiomyocytes

A kinase interacting protein 1 (AKIP1) is a molecular regulator of protein kinase A and nuclear factor kappa B signalling. Recent evidence suggests AKIP1 is increased in response to cardiac stress, modulates acute ischemic stress response, and is localized to mitochondria in cardiomyocytes. The mitochondrial function of AKIP1 is, however, still elusive. Here, we investigated the mitochondrial function of AKIP1 in a neonatal cardiomyocyte model of phenylephrine (PE)-induced hypertrophy. Using a seahorse flux analyzer we show that PE stimulated the mitochondrial oxygen consumption rate (OCR) in cardiomyocytes. This was partially dependent on PE mediated AKIP1 induction, since silencing of AKIP1 attenuated the increase in OCR. Interestingly, AKIP1 overexpression alone was sufficient to stimulate mitochondrial OCR and in particular ATP-linked OCR. This was also true when pyruvate was used as a substrate, indicating that it was independent of glycolytic flux. The increase in OCR was independent of mitochondrial biogenesis, changes in ETC density or altered mitochondrial membrane potential. In fact, the respiratory flux was elevated per amount of ETC, possibly through enhanced ETC coupling. Furthermore, overexpression of AKIP1 reduced and silencing of AKIP1 increased mitochondrial superoxide production, suggesting that AKIP1 modulates the efficiency of electron flux through the ETC. Together, this suggests that AKIP1 overexpression improves mitochondrial function to enhance respiration without excess superoxide generation, thereby implicating a role for AKIP1 in mitochondrial stress adaptation. Upregulation of AKIP1 during different forms of cardiac stress may therefore be an adaptive mechanism to protect the heart.
More Than a Physical Burden: Women’s Mental and Emotional Work in Preventing Pregnancy

In the United States, responsibility for preventing pregnancy in heterosexual relationships disproportionately falls on women. While the biotechnological landscape of available methods may explain the assignment of the physical burden for contraception to women, this does not mean the concomitant time, attention, and stress that preventing pregnancy requires must also be primarily assumed by women. Building on work identifying health care providers as contributors to the construction of normative ideas about reproduction, this study analyzed 52 contraceptive counseling visits with women who reported they did not want future children for the construction of responsibility for the mental and emotional aspects of contraception. Offering a case of how gender inequality is (re)produced through clinical encounters, findings demonstrate that clinicians discursively constructed these responsibilities as women’s and point to structural aspects of the visit itself that reify this unequal burden as normal. Results are consistent with research identifying the broader feminization of family health work in heterosexual relationships. To the extent that the distribution of the mental and emotional responsibilities of preventing pregnancy is both a product of and contributor to gender inequality, this analysis yields insight into the production—and possible deconstruction—of (reproductive) health care as a gendered social structure.
Build Grid Enabled Scientific Workflows Using gRAVI and Taverna

Scientific communities are increasingly exposing information and tools as online services in an effort to abstract complex scientific processes and large data sets. Clients are then able to access services without knowledge of their internal workings therefore simplifying the process of replicating scientific research. Taking a service-oriented approach to science (SOS) facilitates reuse, extension, and scalability of components, whist also making information and tools available to a wider audience. Scientific workflows play a key role in realizing SOS by orchestrating services into well formed logical pipelines created to model the requirements of complex scientific experiments. The task of developing such service-oriented infrastructures is not trivial as developers must create and deploy Web services and then coordinate multiple services into workflows. This paper presents an end-to-end approach for developing SOS-based workflows with the aim of simplifying development, deployment, and execution. In particular, we use gRAVI to wrap applications as WSRF Web services and Taverna to compose and execute workflows. The process is validated through the creation of a real world bioinformatics workflow involving multiple services and complex execution paths.
Simultaneous Parenchyma-Preserving Liver Resection, Cytoreductive Surgery and Intraperitoneal Chemotherapy for Stage IV Colorectal Cancer

Abstract Background: The outcome of stage IV colorectal cancer (CRC) has improved with modern systemic therapy. However, the concomitant presence of liver metastases (LM) and peritoneal carcinomatosis (PC) remains associated with a dismal prognosis and surgery in this context remains exceptional. Methods: Stage IV CRC patients with LM and PC undergoing simultaneous cytoreductive surgery, intraperitoneal chemotherapy (IPC) and liver resection/ablation were identified from prospectively collected databases. We assessed response to neoadjuvant chemotherapy (NACT), postoperative complications, progression free survival (PFS), and overall survival (OS). Results: Twenty-one patients with resectable disease were treated between 2007 and 2014. In 16 patients (76%), NACT was administered and tumour response defined their selection. The remaining 5 (24%) were selected according to the pattern of recurrence. Median peritoneal cancer index was 5 (range: 3–10.5). Liver surgery included 34 wedge resections, 5 ablations and one bisectionectomy to treat a total of 45 hepatic lesions with a median of 2 per patient (range: 1–2) and a median size of 1.35 cm (range: 0.8–2). Tumour regression grade 4 (fibrosis but residual cancer cells predominate) was seen in 50% of the resected metastases after NACT. Median hospital stay was 17 days (range: 14-24); severe morbidity (Clavien-Dindo grade 3-4) occurred in 24% and no perioperative mortality (0-90 days) was recorded. The median OS was 44 months (range: 31-57) while the median PFS was 10 months (range: 8-12). Conclusion: Combined parenchyma-preserving liver resection, cytoreductive surgery and IPC in patients with LM and PC from CRC can be performed safely and results in promising mid-term overall survival.
Comparison of losses and efficiency in alternate flux-switching permanent magnet machines

The performance of the optimized conventional, novel E- and C-core flux-switching permanent magnet (FSPM) machines having different combination of stator and rotor pole numbers is compared by finite element analyses, with particular reference to the conductor and magnet eddy current loss and iron loss. Both iron loss and conductor eddy current loss increase with the rotor pole number, while the 11- and 13-rotor pole machine always exhibit lower magnet eddy current loss than those of the 10- and 14-rotor pole machine, respectively. The E- and C-core machines use half number and volume of magnets but exhibit higher efficiency than those of the conventional FSPM machine.