Miracle-dz/UniFAR-FTUs huggingface dataset:
mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition

Significance Rapamycin is an immunosuppressive drug that partially inhibits the cellular kinase mammalian target of rapamycin (mTOR). This study uncovers previously unidentified mechanisms of mTOR signaling in B cells. Antigen recognition and other signals activate mTOR, a central driver of lymphocyte proliferation and differentiation. However, mTOR forms two protein complexes (mTORC1 and mTORC2) whose roles in B-cell differentiation are poorly defined. We found that a new class of ATP-competitive mTOR kinase inhibitors (TOR-KIs) can augment antibody class switching at concentrations that partially inhibit mTOR activity. Mechanistic studies indicate that mTORC1 loss suppresses, whereas mTORC2 loss promotes, class switching. The dominant effect of TOR-KIs is to promote switching through mTORC2 inhibition. These findings establish distinct immunomodulatory activity of TOR-KIs compared with the canonical mTOR inhibitor rapamycin. The mammalian target of rapamycin (mTOR) is a kinase that functions in two distinct complexes, mTORC1 and mTORC2. In peripheral B cells, complete deletion of mTOR suppresses germinal center B-cell responses, including class switching and somatic hypermutation. The allosteric mTORC1 inhibitor rapamycin blocks proliferation and differentiation, but lower doses can promote protective IgM responses. To elucidate the complexity of mTOR signaling in B cells further, we used ATP-competitive mTOR kinase inhibitors (TOR-KIs), which inhibit both mTORC1 and mTORC2. Although TOR-KIs are in clinical development for cancer, their effects on mature lymphocytes are largely unknown. We show that high concentrations of TOR-KIs suppress B-cell proliferation and differentiation, yet lower concentrations that preserve proliferation increase the fraction of B cells undergoing class switching in vitro. Transient treatment of mice with the TOR-KI compound AZD8055 increased titers of class-switched high-affinity antibodies to a hapten–protein conjugate. Mechanistic investigation identified opposing roles for mTORC1 and mTORC2 in B-cell differentiation and showed that TOR-KIs enhance class switching in a manner dependent on forkhead box, subgroup O (FoxO) transcription factors. These observations emphasize the distinct actions of TOR-KIs compared with rapamycin and suggest that TOR-KIs might be useful to enhance production of class-switched antibodies following vaccination.
Relationship between Cerebrospinal Fluid Biomarkers for Inflammation, Demyelination and Neurodegeneration in Acute Optic Neuritis

Background Various inflammatory biomarkers show prognostic potential for multiple sclerosis (MS)-risk after clinically isolated syndromes. However, biomarkers are often examined singly and their interrelation and precise aspects of their associated pathological processes remain unclear. Clarification of these relationships could aid the appropriate implementation of prognostic biomarkers in clinical practice. Objective To investigate the interrelation between biomarkers of inflammation, demyelination and neurodegeneration in acute optic neuritis and to assess their association to measures of MS risk. Material and Methods A prospective study at a tertiary referral centre from June 2011 to December 2012 of 56 patients with optic neuritis as a first demyelinating symptom and 27 healthy volunteers. Lumbar puncture was performed within 28 (median 16) days of onset. CSF levels of CXCL13, matrix metalloproteinase (MMP)-9, CXCL10, CCL-2, osteopontin and chitinase-3-like-1, myelin basic protein (MBP) and neurofilament light-chain (NF-L) were determined. MS-risk outcome measures were dissemination in space (DIS) of white matter lesions on cerebral MRI, CSF oligoclonal bands and elevated IgG-index. Results In the interrelation analysis the biomarkers showed close correlations within two distinct groups: Biomarkers of leukocyte infiltration (CXCL13, MMP-9 and CXCL10) were strongly associated (p<0.0001 for all). Osteopontin and chitinase-3-like-1 were also tightly associated (p<0.0001) and correlated strongly to tissue damage markers (NF-L and MBP). The biomarkers of leukocyte infiltration all associated strongly with MS-risk parameters, whereas CHI3L1 and MBP correlated with MRI DIS, but not with CSF MS-risk parameters and osteopontin and NF-L did not correlate with any MS-risk parameters. Conclusions Our findings suggest two distinct inflammatory processes: one of leukocyte infiltration, represented by CXCL13, CXCL10 and MMP-9, strongly associated with and potentially predicting MS-risk; the other represented by osteopontin and CHI3L1, suggesting tissue damage-related inflammation, potentially predicting residual disabilities after attack and perhaps cumulative damage over time. These hypotheses should be further addressed in follow-up studies.
Structure/Function Analysis of the Interaction of Phosphatidylinositol 4,5-Bisphosphate with Actin-capping Protein

The heterodimeric actin-capping protein (CP) can be inhibited by polyphosphoinositides, which may be important for actin polymerization at membranes in cells. Here, we have identified a conserved set of basic residues on the surface of CP that are important for the interaction with phosphatidylinositol 4,5-bisphosphate (PIP2). Computational docking studies predicted the identity of residues involved in this interaction, and functional and physical assays with site-directed mutants of CP confirmed the prediction. The PIP2 binding site overlaps with the more important of the two known actin-binding sites of CP. Correspondingly, we observed that loss of PIP2 binding correlated with loss of actin binding among the mutants. Using TIRF (total internal reflection fluorescence) microscopy, we observed that PIP2 rapidly converted capped actin filaments to a growing state, consistent with uncapping. Together, these results extend our understanding of how CP binds to the barbed end of the actin filament, and they support the idea that CP can “wobble” when bound to the barbed end solely by the C-terminal “tentacle” of its β-subunit.
Screening of Date Palm (Phoenix dactylifera L.) Cultivars for Salinity Tolerance

Date palm (Phoenix dactylifera L.) is a major fruit tree in the Middle East and it is a plant considered to be tolerant to a variety of abiotic stresses, including salinity. However, the physiological basis of its salinity tolerance is not fully known. The objective of this study was to screen Omani date palm cultivars for tolerance or susceptibility to salt stress. Seedlings from 10 commercially important date palm cultivars were subjected to 240 mM NaCl, and several physiological parameters related to salinity tolerance traits were evaluated upon treatment. The cultivars were divided into two groups based on the dry weight (DW) of their leaf and root tissues, a parameter which was used as an indication of healthy growth. The results revealed that photosynthesis, electrolyte leakage (EL), and the shoot K+/Na+ ratio were all significantly reduced in the susceptible cultivars. In addition, the relative water content was higher in the tolerant cultivars in comparison with the susceptible ones. These results suggest that although date palm is tolerant to high salinity, there is variation in tolerance among different cultivars. Shoot Na+ exclusion, photosynthesis, and membrane stability are apparently the main determinants of tolerance and can be used in salinity tolerance screening of date palm. The results have shown new very tolerant cultivars (Manoma and Umsila) that could serve as genetic resources for improved date palm tolerance to salinity.
Muscle versus Nonmuscle Flaps in the Reconstruction of Chronic Osteomyelitis Defects

Background: Surgical treatment of chronic osteomyelitis requires aggressive debridement followed by wound coverage and obliteration of dead space with vascularized tissue. Controversy remains as to the effectiveness of different tissue types in achieving these goals and in the eradication of disease. Methods: Chronic osteomyelitis was induced in 26 goat tibias using Staphylococcus aureus as an infecting inoculum. In a single stage, debridement followed by reconstruction using either a muscle flap (n = 13) or a fasciocutaneous flap (n = 13) was performed. Flap donor sites were closed primarily and antibiotics were given for 5 days postoperatively. Daily clinical evaluation for 1 year was performed and monthly radiographs were obtained for 9 months and 1 year after the reconstruction. Results: Twenty-five flaps survived completely, and one nonmuscle flap underwent partial flap loss following a period of venous congestion. There were no postoperative complications in the muscle flap group. Two goats (15 percent) in the nonmuscle group developed superficial wounds in the immediate postoperative period that resolved with conservative management. No limbs had recurrent osteomyelitis wounds at 1 year of clinical follow-up examination. Radiographic evidence of osteomyelitis was present in two goats (15 percent) in the muscle group and one goat (8 percent) in the nonmuscle group. There was no statistically significant difference in the incidence of recurrent osteomyelitis between the groups by clinical and radiographic assessment. Conclusions: The findings in this study demonstrate that vascularized tissue flaps in the form of muscle or nonmuscle flaps provide viable options for wound coverage of osteomyelitis defects following adequate surgical debridement.
The Presence and Severity of Chronic Kidney Disease Predicts All-Cause Mortality in Type 1 Diabetes

OBJECTIVES This study aimed to identify clinical features associated with premature mortality in a large contemporary cohort of adults with type 1 diabetes. RESEARCH DESIGN AND METHODS The Finnish Diabetic Nephropathy (FinnDiane) study is a national multicenter prospective follow-up study of 4,201 adults with type 1 diabetes from 21 university and central hospitals, 33 district hospitals, and 26 primary health care centers across Finland. RESULTS During a median 7 years of follow-up, there were 291 deaths (7%), 3.6-fold (95% CI 3.2–4.0) more than that observed in the age- and sex-matched general population. Excess mortality was only observed in individuals with chronic kidney disease. Individuals with normoalbuminuria showed no excess mortality beyond the general population (standardized mortality ratio [SMR] 0.8, 95% CI 0.5–1.1), independent of the duration of diabetes. The presence of microalbuminuria, macroalbuminuria, and end-stage kidney disease was associated with 2.8, 9.2, and 18.3 times higher SMR, respectively. The increase in mortality across each stage of albuminuria was equivalent to the risk conferred by preexisting macrovascular disease. In addition, the glomerular filtration rate was independently associated with mortality, such that individuals with impaired kidney function, as well as those demonstrating hyperfiltration, had an increased risk of death. CONCLUSIONS An independent graded association was observed between the presence and severity of kidney disease and mortality in a large contemporary cohort of individuals with type 1 diabetes. These findings highlight the clinical and public health importance of chronic kidney disease and its prevention in the management of type 1 diabetes.
Extension of the Stöber method to the preparation of monodisperse resorcinol-formaldehyde resin polymer and carbon spheres.

Sphere we go: Monodisperse resorcinol formaldehyde (RF) resin polymer spheres with finely tunable particle size ranging from 200 to 1000 nm (see pictures) are prepared by an extension of the Stober method. Pyrolysis of the RF spheres at 600°C under N atmosphere yields uniform carbon spheres with a volume shrinkage of 19%.
Major mergers of haloes, the growth of massive black holes and the evolving luminosity function of quasars

We construct a physically motivated analytical model for the quasar luminosity function, based on the joint star formation and feeding of massive black holes suggested by the observed correlation between the black hole mass and the stellar mass of the hosting spheroids. The parallel growth of massive black holes and host galaxies is assumed to be triggered by major mergers of haloes. The halo major merger rate is computed within the framework of the extended Press-Schechter model. The evolution of black holes on cosmological time-scales is achieved by the integration of the governing set of differential equations, established from a few reasonable assumptions that account for the distinct (Eddington-limited or supply-limited) accretion regimes. Finally, the typical light curves of the reactivated quasars are obtained under the assumption that, in such accretion episodes, the fall of matter on to the black hole is achieved in a self-regulated stationary way. The predicted quasar luminosity function is compared with the luminosity functions of the 2dF quasi-stellar object sample and other, higher-redshift data. We find good agreement in all cases, except for z < 1 where the basic assumption of our model is likely to break down.
Interaction in Online Courses: More is NOT Always Better

Cognitive theory suggests more interaction in learn ing environments leads to improved learning outcomes and increased student satisfaction, two indicators of s uccess useful to program administrators. Using a sa mple of 359 lower-level online, undergraduate business courses, we investigated course enrollments, student and fa culty time spent in interaction, and course completion rates, all drivers of resource consumption. Our key findin gs indicate that increased levels of interaction, as measured b y time spent, actually decrease course completion r ates. This result is counter to prevailing curriculum design t heory and suggests increased interaction may actual ly diminish desired program reputation and growth.
Adaptive and maladaptive coping strategies predict posttrauma outcomes in ambulance personnel

Attending potentially dangerous and traumatic incidents is inherent in the role of emergency workers, yet there is a paucity of literature aimed at examining variables that impact on the outcomes of such exposure. Coping has been implicated in adjusting to trauma in other contexts, and this study explored the effectiveness of coping strategies in relation to positive and negative posttrauma outcomes in the emergency services environment. One hundred twenty-five paramedics completed a survey battery including the Posttraumatic Growth Inventory (PTGI; Tedeschi & Calhoun, 1996), the Impact of Events Scale–Revised (IES-R; Weiss & Marmar, 1997), and the Revised-COPE (Zuckerman & Gagne, 2003). Results from the regression analysis demonstrated that specific coping strategies were differentially associated with positive and negative posttrauma outcomes. The research contributes to a more comprehensive understanding regarding the effectiveness of coping strategies employed by paramedics in managing trauma, with implications for their psychological well-being as well as the training and support services available.
Evaluation of variation in serum globulin concentrations in dairy cattle.

BACKGROUND Several factors may influence the concentration of serum globulins in healthy cows and thereby affect clinical interpretation; however, few studies have addressed sources of variation in globulin values. OBJECTIVES The purpose of this study was to compare colorimetry-based total serum globulin values with electrophoretically-determined serum globulin fractions and with IgG concentration, and to evaluate diurnal and long-term physiological variation and the effects of lactation and venipuncture site on serum globulin concentrations in Holstein dairy cattle. METHODS Serum total globulin and albumin concentrations were analyzed by colorimetry and electrophoresis in 86 lactating cows; IgG concentrations were determined by radial immunodiffusion in 41 dry and 34 lactating cows. Serum globulins were analyzed hourly for 24 hours in 8 lactating cows and weekly for 15 weeks in 6 additional cows. Globulin concentrations were compared in samples obtained from jugular and coccygeal venipuncture sites in 4 cows. Results were analyzed using parametric statistical tests. RESULTS Colorimetry-based total serum globulin concentrations correlated well with gamma-globulin fractions (r2 = 0.87) and IgG concentrations (r2 = 0.91). Diurnal variation of total serum globulins concentration was significant (P =.01); however, globulins did not vary significantly over a 15-week period. Mean serum globulins concentration in samples obtained from the jugular vein was 2.35 g/L higher than that in samples obtained by coccygeal venipuncture (P <.0001). CONCLUSIONS The colorimetric method used widely in routine laboratory analyses remains a useful test for globulins determination in dairy cattle. However, time of sampling and venipuncture site should be considered in the interpretation of serum globulins on serial or interindividual specimens.
An Empirical Look At Developmental Interventions And Student Performance In The First Intermediate Accounting Course

Due to concerns about student performance in Intermediate Accounting I, our Department of Accounting established an Intermediate Readiness Committee in the spring of 2006 to create a developmental program for students entering Intermediate I, with the goal of improving performance in that course. Over the next two years, the Committee established the Developmental Program with two escalating interventions to improve performance in Intermediate I. These interventions were comprised of readiness testing with study sessions and readiness testing with use of developmental software. This study reports the impact these interventions had on student performance in Intermediate I. The authors control for gender, grades earned in each of the two accounting principles courses, whether the student took Principles II at school of study or transferred the course credit from another school, and overall undergraduate grade point average upon entering Intermediate I. Results indicate that each intervention resulted in significantly higher grades than observed in a Base Period without intervention.
Trends in Tuberculosis Epidemiology among Children in the Democratic Republic of Congo

Setting: The epidemiology of tuberculosis (TB) among children in the Democratic Republic of Congo (DRC) is not well known. Objective: This study aimed to describe the trends in TB epidemiology among children in the DRC and to compare these trends in children and adults. Design: Data from the National TB program, the WHO Global TB Report, and a demographic survey of health in the DRC were retrospectively analyzed. The study period was from 1995 to 2014. The notification rate, absolute incidence and incidence rate of TB per 100,000 population were reported. Results: In 2014, 12,785 (12.6% of adult cases) TB cases were reported in children and 101,303 in adults. Among children, 3438 (26.89%) had PTB+; 2828 (22.11%) had PTB–; and 6519 (50.98%) had extrapulmonary TB (EPTB). Children under 5 years had a lower reported prevalence of TB (184 cases). The incidence rate per 100,000 population was 10 in children and 181 in adults. The TB incidence decreased between 2010 (11.47) and 2014 (10.46). The proportion of children in overall cases of PTB+ was 4% to 5% in all districts. Conclusion: Caring for childhood TB remains a challenge in the DRC. Improved diagnostic procedures and effective training of providers who care for childhood TB are needed.
The theory of planned behaviour in the context of cultural heritage tourism

An emerging body of literature addresses multiple aspects of cultural heritage tourism in multiple environments worldwide. This study seeks to contribute to current knowledge, studying visitors to a heritage building in the UK through the lens of the theory of planned behaviour (TPB). A questionnaire based on the various predictors associated with the TPB was designed to gather participants' motivations to visit the heritage building, including visitation to sightsee, attend events, and experience gastronomy at the building's restaurant. The findings confirm the validity and impact of attitude towards the behaviour, subjective norms, and perceived behavioural control on behavioural intention, in this case, to become involved in heritage building visitation. In addition, it was noticed that respondents' level of agreement suggests their preparedness to invest in terms of travel, time, and financially spending when visiting heritage buildings. Implications of the findings will be discussed and future research avenues suggested.
Risk factors for preschool depression: the mediating role of early stressful life events.

BACKGROUND Family history of mood disorders and stressful life events are both established risk factors for childhood depression. However, the role of mediators in risk trajectories, which are potential targets for intervention, remains understudied. To date, there have been no investigations of mediating relationships between risk factors and very early onset depression, a developmental period during which intervention may be more effective. The current study used regression analyses to examine the relationships between family history of mood disorders and stressful life events as risk factors for depression in a preschool sample. METHOD Preschoolers 3.0 to 5.6 years of age participated in a comprehensive mental health assessment. Caregivers were interviewed about their children using a structured diagnostic measure to derive DSM-IV major depressive disorder (MDD) diagnoses and dimensional depression severity scores. Family history of psychiatric disorders and preschoolers' stressful life events was obtained. RESULTS Both family history and stressful life events predicted depression severity scores 6 months later. Analyses examining the influence of family history of mood disorders and stressful life events on preschoolers' depression severity demonstrated that stressful life events mediated the relationship between family history and preschoolers' depression. CONCLUSIONS Findings outline the key role of exposure to early stressful life events as a mediator of familial mood disorder risk in preschool onset depression. This finding in a preschool sample provides support for the hypothesis that psychosocial factors may have increased importance as mediators of risk in younger age groups. Findings suggest that psychosocial factors should be considered key targets for early intervention in depression.
Transaction-Cost Economics: The Governance of Contractual Relations

THE new institutional economics is preoccupied with the origins, incidence, and ramifications of transaction costs. Indeed, if transaction costs are negligible, the organization of economic activity is irrelevant, since any advantages one mode of organization appears to hold over another will simply be eliminated by costless contracting. But despite the growing realization that transaction costs are central to the study of economics,' skeptics remain. Stanley Fischer's complaint is typical: "Transaction costs have a well-deserved bad name as a theoretical device . [partly] because there is a suspicion that almost anything can be rationalized by invoking suitably specified transaction costs. "2 Put differently, there are too many degrees of freedom; the concept wants for definition.