Miracle-dz/UniFAR-FTUs huggingface dataset:
Enrichment of Cdk1-cyclins at DNA double-strand breaks stimulates Fun30 phosphorylation and DNA end resection

DNA double-strand breaks (DSBs) are one of the most cytotoxic types of DNA lesion challenging genome integrity. The activity of cyclin-dependent kinase Cdk1 is essential for DSB repair by homologous recombination and for DNA damage signaling. Here we identify the Fun30 chromatin remodeler as a new target of Cdk1. Fun30 is phosphorylated by Cdk1 on Serine 28 to stimulate its functions in DNA damage response including resection of DSB ends. Importantly, Cdk1-dependent phosphorylation of Fun30-S28 increases upon DNA damage and requires the recruitment of Fun30 to DSBs, suggesting that phosphorylation increases in situ at the DNA damage. Consistently, we find that Cdk1 and multiple cyclins become highly enriched at DSBs and that the recruitment of Cdk1 and cyclins Clb2 and Clb5 ensures optimal Fun30 phosphorylation and checkpoint activation. We propose that the enrichment of Cdk1-cyclin complexes at DSBs serves as a mechanism for enhanced targeting and modulating of the activity of DNA damage response proteins.
Fis1 acts as a mitochondrial recruitment factor for TBC1D15 that is involved in regulation of mitochondrial morphology

Summary In yeast, C-tail-anchored mitochondrial outer membrane protein Fis1 recruits the mitochondrial-fission-regulating GTPase Dnm1 to mitochondrial fission sites. However, the function of its mammalian homologue remains enigmatic because it has been reported to be dispensable for the mitochondrial recruitment of Drp1, a mammalian homologue of Dnm1. We identified TBC1D15 as a Fis1-binding protein in HeLa cell extracts. Immunoprecipitation revealed that Fis1 efficiently interacts with TBC1D15 but not with Drp1. Bacterially expressed Fis1 and TBC1D15 formed a direct and stable complex. Exogenously expressed TBC1D15 localized mainly in cytoplasm in HeLa cells, but when coexpressed with Fis1 it localized to mitochondria. Knockdown of TBC1D15 induced highly developed mitochondrial network structures similar to the effect of Fis1 knockdown, suggesting that the TBC1D15 and Fis1 are associated with the regulation of mitochondrial morphology independently of Drp1. These data suggest that Fis1 acts as a mitochondrial receptor in the recruitment of mitochondrial morphology protein in mammalian cells.
Effects of a 3-month supplementation with a novel soluble highly viscous polysaccharide on anthropometry and blood lipids in nondieting overweight or obese adults.

BACKGROUND High viscosity fibre is known to exert many beneficial effects on appetite and metabolism. It could potentially help in weight management, in dieting or nondieting individuals. The present study investigated the effects of the daily intake of a novel high viscosity polysaccharide (HVP) over 3 months in nondieting obese or overweight men and women. METHODS The study comprised a double-blind, randomised controlled clinical trial. Participants ingested 5-15 g per day of either HVP (n = 29, experimental group) or inulin (n = 30, control group) for 15 weeks. Changes in anthropometry (weight, waist and hip circumferences), blood lipids and glucose tolerance were studied from the beginning to the end of administration. Compliance and tolerance were examined. RESULTS Differences appeared between HVP and inulin supplementation in female participants only. Mean (SD) decreases in body weight [1.6 (3.2) kg; approximately 2% of initial weight] and hip circumference [2.8 (3.6 ) cm] occurred in women of the HVP group but not in controls (Time × Group interactions, P ≤ 0.002). Total, high-density lipoprotein and low-density lipoprotein-cholesterol were lower at the end of supplementation in the women of the HVP group compared to controls (P ≤ 0.021). No effect appeared in waist circumference and triacylglycerol. No difference was noted in the number or severity of the adverse effects reported in both groups. Adverse effects were mild and agreed with commonly reported reactions to intake of dietary fibre. CONCLUSIONS Beneficial although modest effects appeared after several weeks of daily HVP intake in nondieting obese or overweight women. The effects of HVP should be investigated in the context of a weight loss programme.
Winter is Coming – But Not Yet. German Health Policy Under the Third Merkel Chancellorship

Health policy in Germany for a long time was considered to be hardly reformable. During the last 25 years, reforms became more frequent, yet substantial major policy change is still rare. When taking a closer look, German health policy follows phases of stability alternating with punctuations of this equilibrium when fundamental structural reforms occur. This contribution analyses the German health policy of the 18th legislative period against the backdrop of this newly emerging pattern of health policy making by applying Punctuated Equilibrium Theory (PET). Marginal reforms without profound reorganisation of the health system were only possible in this period because of the particularly favourable financial situation of sickness funds. Consequently, the conflicting parties and interest groups were able to postpone fundamental solutions to upcoming problems to a later point in time. After explaining the marginal reforms under the third Grand Coalition, it becomes clear that the dominant equilibrium is not going to last: Winter is coming and will bring about concussions in German health policy soon.
MACULAR EPIRETINAL MEMBRANE PEELING TREATMENT OUTCOMES IN YOUNG CHILDREN

Purpose: The purpose of this study was to describe macular epiretinal membrane (ERM) peeling treatment outcomes in young children. Methods: The medical records of all vitrectomies from 1998 through 2010 were retrospectively reviewed. Patients who were selected were 16 years or younger and had primarily macular or posterior pole disease secondary to an ERM. Patients with retinopathy of prematurity, Coats disease, Norrie disease, and incontinentia pigmenti were excluded. Fourteen patients underwent vitrectomy with ERM peeling, and their preoperative and postoperative visual acuities were compared. Results: The mean age at surgery was 8 years, with an average follow-up of 4.2 years (range, 6 months to 11 years). The average presenting visual acuity was 20/258. Average postoperative visual acuity was 20/100, with improvement in 12 patients (86%) and no change of visual acuity in 2 patients (14%). Conclusion: Pediatric ERMs respond well to vitrectomy and membrane peel with a low likelihood of recurrence. Other associated pathology, such as familial exudative retinopathy and combined hamartomas of the retina and retinal pigment epithelium, was associated with complications, such as delayed-onset rhegmatogenous retinal detachment from peripheral traction and recurrence of ERM in 7% of patients.
Transition of Software Maintenance Teams from Scrum to Kanban

Software companies are increasingly moving to use Kanban after Scrum since Kanban claimed to offer improved project visibility, software quality, team motivation, communication and collaboration. However, empirical studies are needed to verify these effects and companies' real motivation for the transition. In particular, underlying reasons leading software companies to start using Kanban in software maintenance must be understood. A multiple-case study was conducted to investigate why two experienced Scrum maintenance teams transitioned to Kanban. We conducted 17 semi-structured interviews with two different teams from two large Finnish software companies. Thematic analysis was applied to identify the most common challenges in Scrum and their solutions in Kanban. The results showed that Scrum maintenance teams faced challenges, such as lack of work visibility, task prioritisation, communication and collaboration, over commitment of sprints, work synchronisation and changing people. We discuss how maintenance teams mitigated these challenges with Kanban and present the lessons learned.
Extrapleural bupivacaine for amelioration of multiple rib fracture pain.

OBJECTIVE The pain associated with multiple rib fractures can be surprisingly variable. The objective of this study was to determine the efficacy of an indwelling, percutaneously placed intercostal catheter in relieving the pain associated with multiple rib fractures. DESIGN Prospective nonrandomized study setting: Surgical intensive care unit in a level 1 trauma center. SUBJECTS Fifteen blunt chest trauma patients with a minimum of three rib fractures who had failed an intravenous patient controlled analgesia protocol. INTERVENTIONS Insertion of an epidural catheter within the intercostal space. Bupivacaine 0.25% with epinephrine was injected in a volume of 20 mL. Subsequent doses were limited to a total of 400 mg per 24 hours. MEASUREMENTS AND MAIN RESULTS Severity of injury was estimated by using the Injury Severity Score. For each patient a preinjection visual analogue scale (VAS) and incentive spirometry (IS) lung volume were determined. Fifteen minutes following injection of 0.25% bupivacaine with epinephrine the VAS and IS were repeated. The Injury Severity Score ranged from 9 to 32 (mean 19.0 +/- 1.6). Overall, mean VAS pain scores improved significantly following the initial bolus of bupivacaine (before VAS = 7.5 +/- 0.6, after VAS = 3.5 +/- 0.5, p < 0.05) and this was associated with significant increase in IS lung volumes (before IS = 0.77 +/- 0.09, after IS = 1.3 +/- 0.13, p < 0.05). No patient experienced either insertion-related or drug administration complications. CONCLUSIONS These results confirm that an indwelling intercostal catheter provides a continuous nerve block resulting in a simple, safe procedure that can ameliorate the pain and splinting associated with multiple rib fractures. Although we experienced no complications, additional investigation is clearly needed.
Auditory Brainstem Implant in Neurofibromatosis Type 2 and Non-Neurofibromatosis Type 2 Patients

Objective: To evaluate the auditory brainstem implant (ABI) performances in neurofibromatosis type 2 (NF2) and non-NF2 patients. Study Design: Retrospective cohort study. Setting: Tertiary referral center. Patients: Between 1996 and 2006, 31 adult patients (mean age, 41 yr; range, 17-65 yr) were implanted with a 21-electrode Nucleus device (Cochlear Inc., Lane Cove, Australia). The population comprised 23 NF2, 3 postmeningitis bilateral ossified cochleas, 3 solitary vestibular schwannomas on the only hearing ear, 1 inner ear malformation, and 1 bilateral cochlear destruction by otosclerosis. Intervention: Auditory brainstem implant was placed through a translabyrinthine or a retrosigmoid approach. Main Outcome Measures: Auditory brainstem implant was evaluated by open-set words and sentences in sound, vision, and sound-plus-vision modes. Results: In NF2 patients, 16 (70%) were daily users of their implants. In these patients, the open-set dissyllabic word recognition was 36 ± 6.0 % for vision-only mode, 33 ± 6.5 % for sound-only mode, and 65 ± 8.0 % in vision-plus-sound mode with a high interindividual variation. Negative prognostic factors were long duration of total hearing loss (>10 yr), low number of active electrodes (<10), and local complications (meningitis, hematoma). Six non-NF2 patients (75%) were daily ABI users. The performances of patients with ossified cochleas were similar to best NF2 cases. Conclusion: A clear benefit of ABI could be evidenced in NF2 patients, especially in case of small tumor and short duration of hearing loss. Auditory brainstem implant may also be indicated in patients with bilateral profound hearing loss and a predictable failure of cochlear implantation.
East of the West: Repossessing the Past In India

Public history, as it is practised in India, defies easy attempts at classification. This is partially because hardly anything that would be recognised as public history is identified as such by its author(s). For the term, despite its ever-increasing acceptance outside India as a discipline and a practice distinct from history, has yet to gain any currency within India. Any attempt to identify works that are self-consciously public history in the Indian context will likely not yield much fruit. Nor, for that matter, will borrowing any of the many definitions of the term from the West and trying to find works that adhere to it in India. Instead, this chapter will try to highlight the myriad forms that public engagements with the past have taken place in India. This article focuses specifically on museums, arguably the preeminent site of public engagements with the past in India. To that end, it will look at a new generation of museums that are charting new paths towards enabling a better public engagement with the past. It will also analyse a few institutional forms of public engagements with the past.
Effect of pH on metal speciation and resulting metal uptake and toxicity for earthworms

In the present study, relationships between changes in the solubility and speciation of metals in contaminated soils under different pH regimes and their toxicity to earthworms were investigated. Earthworms (Lumbricus rubellus) were exposed in a laboratory bioassay to metalliferous soils under three pH regimes: Unamended pH, pH lowered by one unit (pH — 1), and pH increased by one unit (pH +1). In each soil, total (hot nitric acid‐extractable) and 0.01 M CaCl2–extractable metal concentrations were measured and soil pore‐water chemistry analyzed to allow metal speciation to be modeled using the Windermere Humic Aqueous Model. Earthworm metal accumulation was determined and toxicity assessed by measuring survival and reproduction and at the molecular level by recording expression of the gene encoding metallothionein‐2 (MT‐2) using quantitative reverse transcriptase‐polymerase chain reaction. Both metal solubility and speciation were found to be highly pH dependent. Metal accumulation in earthworms was influenced by soil concentration and, in some cases (e.g., Cd), by pH. Reproduction was affected (reduced up to 90%) by soil metal level, pH, and their interaction. Relationships between analyzed and calculated Zn concentrations and toxicity and between analyzed and calculated Cd concentrations and tissue accumulation and MT‐2 expression were compared by fitting dose‐response models and assessing the fit of the data. This analysis indicated that values based on a pH‐adjusted free ion concentration best explained toxicity (r2 = 0.82) and accumulation (r2 = 0.54). Expression of MT‐2 was, however, poorly correlated (p > 0.05) with all analyzed and modeled soil metal concentrations.
Development and function of metabotropic glutamate receptors in cat visual cortex.

Metabotropic glutamate receptors have been implicated in plasticity in the hippocampus and cerebellum. Are they also involved in plasticity in the visual cortex? This is a complicated question because of the diversity of metabotropic glutamate receptors and the variations in both receptors and plasticity with layer. Inhibition driven by group II metabotropic glutamate receptors is certainly correlated with ocular dominance segregation in layer IV of the cortex. Of the group I metabotropic glutamate receptors, mGluR5 may be involved in plasticity, but mGluR1 is unlikely to be. Both group I and group II receptors produce increases in cyclic adenosine monophosphate which are clearly related to plasticity. Further conclusions await the development of agonists and antagonists specific for individual metabotropic glutamate receptors, as opposed to groups of the receptors.
Investigation of probiotics in multiple sclerosis

None of the disease-modifying therapies (DMTs) currently being used for the management of multiple sclerosis (MS) are 100% effective. In addition, side effects associated with the use of these DMTs have limited the practice of combination therapy. Hence, there is a need for safe immunomodulatory agents to fine-tune the management of MS. The gut microbiome plays an important role in autoimmunity, and several studies have reported alterations in the gut microbiome of MS patients. Studies in animal model of MS have identified members of the gut commensal microflora that exacerbate or ameliorate neuroinflammation. Probiotics represent an oral, non-toxic immunomodulatory agent that could be used in combination with current MS therapy. We designed a pilot study to investigate the effect of VSL3 on the gut microbiome and peripheral immune system function in healthy controls and MS patients. VSL3 administration was associated with increased abundance of many taxa with enriched taxa predominated by Lactobacillus, Streptococcus, and Bifidobacterium species. At the immune level, VSL3 administration induced an anti-inflammatory peripheral immune response characterized by decreased frequency of intermediate monocytes (CD14highCD16low), decreased mean fluorescence intensity (MFI) of CD80 on classical monocytes as well as decreased human leukocyte antigen–antigen D related (HLA-DR) MFI on dendritic cells.
Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells.

These experiments demonstrate that exposure of cultured endothelial cells (EC) to well-defined laminar fluid flow results in an elevated rate of NO production. NO production was monitored by release of NOx (NO2- + NO3(2-) and by cellular guanosine 3',5'-cyclic monophosphate (cGMP) concentration. NO synthase (NOS) inhibitor blocked the flow-mediated stimulation of both NOx and cGMP, indicating that both measurements reflect NO production. Exposure to laminar flow increased NO release in a biphasic manner, with an initial rapid production consequent to the onset of flow followed by a less rapid, sustained production. A similar rapid increase in NO production resulted from an increase in flow above a preexisting level. The rapid initial production of NO was not dependent on shear stress within a physiological range (6-25 dyn/cm2) but may be dependent on the rate of change in shear stress. The sustained release of NO was dependent on physiological levels of shear stress. The calcium (Ca2+) or calmodulin (CaM) dependence of the initial and sustained production of NO was compared with bradykinin (BK)-mediated NO production. Both BK and the initial production were inhibited by Ca2+ and CaM antagonists. In contrast, the sustained shear stress-mediated NO production was not affected, despite the continued functional presence of the antagonists. Dexamethasone had no effect on either the initial or the sustained shear stress-mediated NO production. An inducible NOS does not, therefore, explain the apparent Ca2+/CaM independence of the sustained shear stress-mediated NO production. (ABSTRACT TRUNCATED AT 250 WORDS)
Revisiting the Concept of Targeting Only Bacillus anthracis Toxins as a Treatment for Anthrax

ABSTRACT Protective antigen (PA)-based vaccines are effective in preventing the development of fatal anthrax disease both in humans and in relevant animal models. The Bacillus anthracis toxins lethal toxin (lethal factor [LF] plus PA) and edema toxin (edema factor [EF] plus PA) are essential for the establishment of the infection, as inactivation of these toxins results in attenuation of the pathogen. Since the toxins reach high toxemia levels at the bacteremic stages of the disease, the CDC's recommendations include combining antibiotic treatment with antitoxin (anti-PA) immunotherapy. We demonstrate here that while treatment with a highly potent neutralizing monoclonal antibody was highly efficient as postexposure prophylaxis treatment, it failed to protect rabbits with any detectable bacteremia (≥10 CFU/ml). In addition, we show that while PA vaccination was effective against a subcutaneous spore challenge, it failed to protect rabbits against systemic challenges (intravenous injection of vegetative bacteria) with the wild-type Vollum strain or a toxin-deficient mutant. To test the possibility that additional proteins, which are secreted by the bacteria under pathogenicity-stimulating conditions in vitro, may contribute to the vaccine's potency, we immunized rabbits with a secreted protein fraction from a toxin-null mutant. The antiserum raised against the secreted fraction reacts with the bacteria in an immunofluorescence assay. Immunization with the secreted protein fraction did not protect the rabbits against a systemic challenge with the fully pathogenic bacteria. Full protection was obtained only by a combined vaccination with PA and the secreted protein fraction. Therefore, these results indicate that an effective antiserum treatment in advanced stages of anthrax must include toxin-neutralizing antibodies in combination with antibodies against bacterial cell targets.
Observations of the volume flux of a seafloor hydrothermal plume using an acoustic imaging sonar

We present a 26 day time series (October 2010) of physical properties (volume flux, flow velocity, expansion rate) of a vigorous deep‐sea hydrothermal plume measured using our Cabled Observatory Vent Imaging Sonar (COVIS), which is connected to the Northeast Pacific Time Series Underwater Experiment Canada Cabled Observatory at the Main Endeavour Field on the Juan de Fuca Ridge. COVIS quantitatively monitors the initial buoyant rise of the plume from ∼5 m to ∼15 m above the vents. The time series exhibits temporal variations of the plume vertical volume flux ( 1.93−5.09 m3/s ), centerline vertical velocity component ( 0.11−0.24 m/s ) and expansion rate ( 0.082−0.21 m/m ); these variations have major spectral peaks at semidiurnal ( ∼2 cycle/day) and inertial oscillation ( ∼1.5 cycle/day) frequencies. The plume expansion rate (average ∼0.14 m/m ) is inversely proportional to the plume centerline vertical velocity component (coefficient of determination R2∼0.5 ). This inverse proportionality, as well as the semidiurnal frequency, indicates interaction between the plume and ambient ocean currents consistent with an entrainment of ambient seawater that increases with the magnitude of ambient currents. The inertial oscillations observed in the time series provide evidence for the influence of surface storms on the dynamics of hydrothermal plumes.
Jumping performance profile of male and female gymnasts.

AIM The aim of this study was to establish a more precise jumping performance profile of elite gymnasts than that published in previous studies. METHODS Seventy-six elite male and female competitive gymnasts and 91 moderately active subjects volunteered for the study. The jumping tests performed on a contact mat were: squat jump (SJ) with progressive loads of 0%, 25%, 50 %, 75% and 100% of body mass, counter-movement jump (CMJ), and counter-movement jump with arm swing (CMJA). The parameters used to assess the jumping performance were flight time (FT, ms), FT normalized to body mass (FTbm, ms/kg), estimated elastic component (EC) and arm participation (AP). In SJ, the overload with respect to body mass had a negative impact on reliability in all of the subgroups that were analysed. When overloads were above 50% of body mass in SJ, reliability was poor. Therefore, overloads should not be used with sedentary young females. Gymnasts carry out a large number of jumps from very young ages, which may explain their high jump reliability (ICC>0.91). RESULTS We used FT to estimate the F-v curve through SJ with overloads. The curves for male gymnasts and their controls were practically identical. However, when FT was normalized to body mass (FTbm), the F-v curve showed the advantage of female gymnasts in particular over their control group when overloads were above 50%. Larger, more significant (P<0.001) differences between gymnasts and their control groups were observed in CMJ and CMJA, with FTbm instead of FT. The combination of poor SJ and good CMJ performances explains why the EC was higher in gymnasts than in controls (+27%). CONCLUSION The better AP of the gymnasts (+79%) may be due to better arm strength conditioning and segmental coordination. EC and AP can be considered a suitable complementary parameter of jumping performance in gymnasts.