Miracle-dz/UniFAR-FTUs huggingface dataset:
Orai1 Function Is Essential for T Cell Homing to Lymph Nodes

In T lymphocytes, Ca2+ release–activated Ca2+ (CRAC) channels composed of Orai1 subunits trigger Ag-induced gene expression and cell proliferation through the NFAT pathway. We evaluated the requirement of CRAC channel function for lymphocyte homing using expression of a dominant-negative Orai1-E106A mutant to suppress Ca2+ signaling. To investigate homing and motility of human lymphocytes in immunocompromised mouse hosts, we transferred human lymphocytes either acutely or after stable engraftment after a second transfer from the same blood donor. Human and mouse lymphocyte homing was assessed, and cells were tracked within lymph nodes (LNs) by two-photon microscopy. Our results demonstrate that human T and B lymphocytes home into and migrate within the LNs of immunocompromised NOD.SCID mice similar to murine lymphocytes. Human T and B cells colocalized in atrophied or reconstituted mouse LNs, where T cells migrated in a random walk at velocities of 9–13 μm/min and B cells at 6 μm/min. Expression of Orai1-E106A inhibited CRAC channel function in human and mouse T cells, and prevented homing from high endothelial venules into murine LNs. Ca2+ signals induced by CCL21 were also inhibited in T cells expressing Orai1-E106A. With CRAC channels inhibited, the high-affinity form of LFA-1 failed to become active, and T cells failed to migrate across endothelial cells in a transwell model. These results establish a requirement for CRAC channel–mediated Ca2+ influx for T cell homing to LNs mediated by high-affinity integrin activation and chemokine-induced transendothelial migration.
Impact of timely antibiotic administration on outcomes in patients with severe sepsis and septic shock in the emergency department

Objective We aimed to investigate the effect of timely antibiotic administration on outcomes in patients with severe sepsis and septic shock. Methods We analyzed data from a sepsis registry that included adult patients who initially presented to the emergency department (ED) and met criteria for severe sepsis or septic shock. Timely antibiotic use was defined as administration of a broad-spectrum antibiotic within three hours from the time of ED arrival. Multivariable logistic and linear regression analyses were performed to assess associations between timely administration of antibiotics and outcomes, including hospital mortality, 48-hour change in Sequential Organ Failure Assessment (SOFA) score (delta SOFA), and hospital length of stay (LOS). Results A total of 591 patients were included in the study. In-hospital mortality was 16.9% for patients receiving timely antibiotics (n=377) and 22.9% for patients receiving delayed antibiotics (n=214; P=0.04). The adjusted odds ratio for in-hospital survival was 0.54 (95% confidence interval [CI], 0.34 to 0.87; P=0.01) in patients who received timely antibiotics. Timely antibiotic administration was also significantly associated with higher delta SOFA (2 vs. 1) and shorter hospital LOS among survivors (11 days vs. 15 days). Multivariable linear regression analyses showed that timely antibiotic administration was significantly associated with increased delta SOFA and decreased hospital LOS. Conclusion Antibiotic administration within three hours from the time of ED arrival was significantly associated with improved outcomes, including in-hospital survival, reversal of organ failure, and shorter hospital LOS, in patients with severe sepsis and septic shock.
Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats

Abstract 1. This study was designed to evaluate how the absence of P-glycoprotein (Pgp, Mdr1a), breast cancer-resistance protein (Bcrp, Abcg2) or both affects drug distribution into sciatic nerves, brain and cerebrospinal fluid (CSF) in rats. 2. Pgp substrate (loperamide), BCRP substrates (dantrolene and proprietary compound X) and dual substrates (imatinib and proprietary compound Y) were well distributed into sciatic nerves with comparable nerve to plasma concentration ratios between wild-type and knockout (KO) rats. 3. Brain exposure increased substantially in Mdr1a(−/−) rats for loperamide and in Mdr1a(−/−)/Abcg2(−/−) rats for imatinib and compound Y, but minimally to modestly in Abcg2(−/−) rats for dantrolene and compound X. The deletion of Mdr1a or Abcg2 alone had little effect on brain distribution of compound Y. 4. While CSF to unbound brain concentration ratio remained ≥3 in the KO animals for dantrolene, compounds X and Y, it was reduced to 1 in the Mdr1a(−/−)/Abcg2(−/−) rats for imatinib. 5. The data indicate that Pgp and Bcrp do not play significant roles in drug distribution into peripheral nerve tissues in rats, while working in concert to regulate brain penetration. Our results further support that CSF concentration may not be a good surrogate for unbound brain concentration of efflux substrates.
On the Role of Regulatory T Cells during Viral-Induced Inflammatory Lesions

Ocular HSV-1 infection can result in stromal keratitis, a blinding immunoinflammatory lesion that represents an immunopathological response to the infection. CD4+ T cells are the main orchestrators, and lesions are more severe if the regulatory T cell (Treg) response is compromised from the onset of infection. Little is known about the role of Foxp3+CD4+ Tregs during ongoing inflammatory reactions, which is the topic of this article. We used DEREG mice and depleted Tregs at different times postinfection. We show that lesions became more severe even when depletion was begun in the clinical phase of the disease. This outcome was explained both by Tregs’ influence on the activity of inflammatory effector T cells at the lesion site and by an effect in lymphoid tissues that led to reduced numbers of effectors and less trafficking of T cells and neutrophils to the eye. Our results demonstrate that Tregs can beneficially influence the impact of ongoing tissue-damaging responses to a viral infection and imply that therapies boosting Treg function in the clinical phase hold promise for controlling a lesion that is an important cause of human blindness.
Innovation exploitation, exploration and supplier relationship management

This paper describes how supplier relationship management facilitates innovation exploitation and exploration in brewing and bus manufacturing. In the two industries examined, strong ties are associated with exploitation whilst mixed features of strong and weak ties benefit exploration. This is in contrast to the findings of Gilsing and Nooteboom (2005) and suggests that tie strength associated with exploitation and exploration differs according to the industrial context in which firms operate. The findings also suggest different streams of capabilities are required to manage supplier relationships. In exploitation strong ties facilitate capabilities to identify new opportunities, to form a collective to pool resources and to work across organisational boundaries. In exploration weak ties are conducive to the search for new ideas but impede firms’ capability to realise potential innovations. Relationship management becomes challenging when innovations are radical, with high complexity in communication and.
Exploring Recall of Physical Activity in Young People using Qualitative Interviewing

Recall of physical activity is a known problem affecting all forms of self-report. Participants age 8? 16 years contributed to 16 focus groups and 24 interviews based on cognitive interviewing (n = 8) and think-aloud (n = 8) and general probing (n = 8) techniques. When unassisted, participants readily described physical activity mode but gave vague descriptions of daily activities. In contrast, the close detail of frequency, intensity, and duration of these activities was only more fully developed through prompting. Talk-based methods can provide considerable insight into developing more reliable and valid physical activity self-reports
Care assistants overlooked?: A cross‐national study of care home staff in England and Germany

Within the context of residential care settings in England and Germany little consideration is given to the role of care assistants. Policies that determine the staffing levels in both countries have resulted in care assistants making a considerable contribution towards the ‘hands‐on’ care of dependent, older people. However, the policies overlook the need to encourage and support care assistants in developing the skills required to provide effective, efficient care to dependent, older people. This paper presents the findings of a small‐scale qualitative study conducted in residential care settings situated in the south east of England and north Germany. The study establishes the connection between the nature of ‘emotional labour’ and the need to provide suitable training to care assistants, thus influencing the quality of care provided to dependent, older people. At present training in both countries is focused on qualified staff. Overlooking care assistants and their contribution towards care could be detrimental to the quality of care provided to older people in both England and Germany.
PATTERNS—A Model for Evaluating Trauma in NICU Music Therapy: Part 1—Theory and Design

While preterm infants are born with survival mechan- isms intact, they lack the protective buffering system of the intrauterine environment. Dysmature neurologi- cal functioning and the absence of coping strategies further impede the preterm infant’s capacity to manage the heightened states of arousal commonly linked to hospitalization in a neonatal intensive care unit (NICU). Music therapy offers a unique capacity to enhance healing across the spectrum of experience, and research in NICU music therapy has shown consis- tent benefit for infants, parents, and caregivers in this environment. Integrating current evidence across disci- plines in developing new models of treatment is key to building fully informed and responsible practices. PAT- TERNS (Preventive Approach to Traumatic Experience by Resourcing the Nervous System) was developed to address this need both by identifying the broad- ranging potential for traumatic experience in the NICU and by utilizing this scope of potential exposure to trauma as a construct for the formation of a preventive music therapy treatment model that is based on latent human resiliency and trauma renegotiation principles.
Genetic polymorphisms analysis of drug-metabolizing enzyme CYP2C9 in the Uyghur population

Abstract Genetic variations in cytochrome P450 2C9 are known to contribute to interindividual and interethnic variability in response to clinical drugs, but little is known about the genetic variation of CYP2C9 in the Uyghur population. We directly sequenced the whole CYP2C9 gene in 96 unrelated, healthy Uyghur from Xinjiang Uygur Autonomous Region of China and screened for genetic variants in the promoter, exons, introns and 3′-UTR. Thirty five previously reported alleles and six genotypes were detected in this study. The allele frequencies of CYP2C9*1, *2, *11, *12, *29 and *33 were 89.58, 7.81, 0.52, 0.52, 1.04 and 0.52%, respectively. We detected one non-synonymous novel variant at position 329 from Arg to Cys and this mutation is predicted to be intolerant by SIFT. Our results provide basic information about CYP2C9 alleles in Uyghur, which may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group.
Systemic Lack of Canonical Histamine Receptor Signaling Results in Increased Resistance to Autoimmune Encephalomyelitis

Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune model of multiple sclerosis. HA exerts its effects through four known G-protein–coupled receptors: H1, H2, H3, and H4 (histamine receptors; H1–4R). Using HR-deficient mice, our laboratory has demonstrated that H1R, H2R, H3R, and H4R play important roles in EAE pathogenesis, by regulating encephalitogenic T cell responses, cytokine production by APCs, blood–brain barrier permeability, and T regulatory cell activity, respectively. Histidine decarboxylase–deficient mice (HDCKO), which lack systemic HA, exhibit more severe EAE and increased Th1 effector cytokine production by splenocytes in response to myelin oligodendrocyte gp35–55. In an inverse approach, we tested the effect of depleting systemic canonical HA signaling on susceptibility to EAE by generating mice lacking all four known G-protein–coupled-HRs (H1–4RKO mice). In this article, we report that in contrast to HDCKO mice, H1–4RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H1–4RKO mice, compared with wild-type mice, produce a lower amount of Th1/Th17 effector cytokines. The opposing results seen between HDCKO and H1–4RKO mice suggest that HA may signal independently of H1–4R and support the existence of an alternative HAergic pathway in regulating EAE resistance. Understanding and exploiting this pathway has the potential to lead to new disease-modifying therapies in multiple sclerosis and other autoimmune and allergic diseases.
Towards the architecture of managed dynamic virtual organisations for e-business communities

This paper explores the challenges of constructing a distributed e-business architecture based on the concept of the Dynamic (Request-Based) Virtual Organisation (RBVO), a B2B value network which is dynamically formed upon demand to meet identified business opportunities. In this paper, we investigate the steps involved in achieving inter-domain end-to-end business collaboration using the structural concepts of the RBVO by presenting a reference architecture and a framework (realisation of that architecture in a particular class of environments). The practical work was done within the framework of EU-sponsored research projects (LAURA, TrustCoM). The LAURA project, which aims to facilitate creation of interregional e-business zones for SMEs uses, where applicable, the potential of the ebXML architecture to support the innovative RBVO concept. The TrustCoM project concentrates on application of Web Services technologies for secure, trusted and manageable business interactions and VO management based on the choreographed collaboration concept.
Tumor Necrosis Factor–α–Converting Enzyme: Its Role in Community-Acquired Pneumonia

Bronchoalveolar lavage fluid recovered from infected and uninvolved lungs of patients with community-acquired pneumonia (CAP; ) on day was analyzed for cytokine, n p 16 6 0.8 soluble receptor, and antagonist levels. The role of tumor necrosis factor (TNF)–a–converting enzyme (TACE) in the resolution of the local inflammatory response was investigated. TNFa, interleukin (IL)–1b, and IL-6 were elevated in the infected versus uninvolved lobe, whereas IL-10 was not. Epithelial lining fluid (ELF) cytokine levels correlated with intracellular cytokine expression. Levels of proTNF-a were reciprocally related to TNF-a ELF levels. Levels of soluble receptors, generated by TACE cleavage of membrane-bound precursors, were compartmentalized to infected ELF. TACE was down-regulated by internalization in cells from the site of infection. These data demonstrate that, in vivo during CAP, TACE has a role in regulating resolution of the local inflammatory response by modulating levels of pro- and counterinflammatory mediators. Community-acquired pneumonia (CAP) is a common condition characterized by a high burden of morbidity and mortality. CAP rates among the 6 most common causes of death in the United States, where 2–3 million cases occur annually. The percentage of mortality among hospitalized patients ranges from 2% to 30% but is ! 1% for patients not requiring hospitalization [1–5]. The critical factors responsible for immunoregulation in the lung and the variation in response and outcome among different patients require a balance between endogenously generated pro- and anti-inflammatory mediators. Among the most important proinflammatory mediators in CAP are tumor necrosis factor (TNF)–a, interleukin (IL)–1b, and IL-6 [6–9], whereas IL-10 has been suggested to be critical in counterbalancing their effects and achieving adequate resolution of the septic process [10]. TNF-a is produced as a 26-kDa membrane-associated protein (proTNF-a), which is cleaved enzymatically by TNF-a–converting enzyme (TACE) into a soluble 17.5-kDa cytokine [11]. It is a pleiotropic early response proinflammatory cytokine capable of inducing IL-1b and IL
Cd72c Is a Modifier Gene that Regulates Faslpr-Induced Autoimmune Disease

Although modifier genes are extensively studied in various diseases, little is known about modifier genes that regulate autoimmune diseases. Autoimmune disease caused by the Faslpr mutation depends on the genetic background of mouse strains, suggesting a crucial role of modifier genes. MRL/MpJ-Faslpr (MRL/lpr) and AKR/lpr mice develop severe and mild lupus-like autoimmune disease, respectively, whereas this mutation does not cause disease on C57BL/6 (B6) or C3H background. Both MRL and AKR carry the same haplotype of the Cd72 gene encoding an inhibitory BCR coreceptor (CD72c), and CD72c contains several amino acid substitutions and a deletion in the extracellular region compared with CD72a and CD72b. To address the role of Cd72c locus in the regulation of Faslpr-induced autoimmune disease, we generated B6.CD72c/lpr and MRL.CD72b/lpr congenic mice. Introduction of the chromosomal interval containing Cd72c did not cause disease in B6 mice by itself, but caused development of lupus-like disease in the presence of Faslpr on B6 background, clearly demonstrating that this interval contains the modifier gene that regulates Faslpr-induced autoimmune disease. Conversely, MRL.CD72b/lpr congenic mice showed milder disease compared with MRL/lpr mice. We further demonstrated that Cd72c is a hypofunctional allele in BCR signal inhibition and that CD72 deficiency induces severe autoimmune disease in the presence of Faslpr. These results strongly suggest that the Cd72c is a crucial modifier gene that regulates Faslpr-induced autoimmune disease due to its reduced activity of B cell signal regulation.
Health education services in developing countries: the case of Zimbabwe

The authors combine a checklist approach with an historical analysis to assess the effectiveness of Zimbabwes health education service. Data come from interventions with key staff of the Department of Community Medicine and observations from one of the authors during work as a district doctor. The 1st section on policy and strategy briefly describes the political context in which strategy briefly describes the political context in which services have been developed. Organization and management are described in the 2nd section while resources services and operations are assessed in parts 3 and 4. A 5th section reviews the role and impact of health education in disease control. Findings are summarized and an historical analysis of health education in Zimbabwe since independence is presented in the closing pages. Generally policy formulation organization and management and resources have been developed to a medium level but only weak support exists for peripheral health workers and services on the ground are unsatisfactory. Successful service delivery programs like immunization account for the majority of improvements in health status. No improvement was observed however in diseases which requires behavior change; conditions have even worsened in the area of AIDS. Finally it was observed that health education services have evolved from the village educator to the diploma educator stage but service delivery needs to be elevated to the level of specialist and be combined with more training and a reorientation of health workers at district level.
Active Caspase-3 Is Stored within Secretory Compartments of Viable Mast Cells

Caspase-3 is a main executioner of apoptotic cell death. The general notion is that, in viable cells, caspase-3 is found as a cytosolic inactive proenzyme and that caspase-3 activation is largely confined to processes associated with cell death. In this study, we challenge this notion by showing that enzymatically active caspase-3 is stored in viable mast cells. The enzymatically active caspase-3 was undetectable in the cytosol of viable cells, but was recovered in subcellular fractions containing secretory granule-localized proteases. Moreover, active caspase-3 was rapidly released into the cytosolic compartment after permeabilization of the secretory granules. Using a cell-permeable substrate for caspase-3, the presence of active caspase-3–like activity in granule-like compartments close to the plasma membrane was demonstrated. Moreover, it was shown that mast cell activation caused release of the caspase-3 to the cell exterior. During the course of mast cell differentiation from bone marrow cells, procaspase-3 was present in cells of all stages of maturation. In contrast, active caspase-3 was undetectable in bone marrow precursor cells, but increased progressively during the process of mast cell maturation, its accumulation coinciding with that of a mast cell–specific secretory granule marker, mouse mast cell protease 6. Together, the current study suggests that active caspase-3 can be stored within secretory compartments of viable mast cells.
Culture, corruption, suicide, happiness and global social media use: a cross-cultural perspective

This study was conducted to answer this simple question: 'Can cultural values explain global social media use? ' Along with cultural dimensions introduced by past studies we also added several demographic, socio-economic and personality variables into this study that generated quite interesting findings. We found that there are low levels of suicide, more happiness and more corruption in societies that use social media heavily. We also observed that GDP per capita and median age are negatively related with social media use. Self-esteem stood out as important variable related to social media use intensity along with emotional expressiveness, openness and conscientiousness. Contrary to the common view, nation-level social capital achievement was negatively related with social media use and there was absolutely no relationship between high-context and low-context communication characteristics and local social media use. Some other findings also indicated that conservative and collectivistic countries use social media more often than do individualistic and developed countries. Schwartz's cultural dimensions and the results of the GLOBE study accounted for a considerable amount of variation in country-level social media use where Hofstede and Trompenaars' cultural dimensions were insignificant. Since most of the cultural values failed to explain the intensity of social media use, we also developed a cross-cultural online communication framework called cross-cultural self and others' worth.