Miracle-dz/UniFAR-FTUs huggingface dataset:
The adaptor protein CIKS/Act1 is necessary to induce collagen-induced arthritis pathology and it contributes to collagen-specific antibody production

Objective— CIKS/Act1 is an adaptor molecule necessary for signaling by members of the IL-17 cytokine family. Here we aim to determine whether this adaptor is required for collagen-induced arthritis (CIA). If required, CIKS-mediated signaling could be a potential target for therapeutic intervention in rheumatoid arthritis. Methods— CIA model studies were performed with CIKS deficient and sufficient mice on an otherwise wild-type C57BL/6 background or on a background lacking Fc γ RIIb. In addition, wild-type and CIKS deficient mice were subjected to collagen-antibody induced arthritis (CAIA) studies. Arthritis pathology was determined by visual inspection of the paws, by histochemical analysis of tissue sections and by measurements of collagen-specific antibodies. Results— Arthritis pathology could be readily induced with the CIA model in wild-type mice and pathology was exacerbated in Fc γ RIIb-deficient mice. In contrast, CIKS deficient mice were protected from all aspects of CIA pathology, even in Fc γ RIIb deficient mice. The absence of CIKS completely prevented neutrophil infiltration into joints, bone erosion and cartilage damage; furthermore, production of collagen type 2-specific antibodies (CII-Abs) was reduced. In contrast to the CIA model, CIKS deficient mice remained susceptible to arthritis induced with the CAIA model. Conclusion— CIKS-mediated signaling is necessary for the pathogenesis in the CIA model, but not in the CAIA model. These findings suggest critical functions of CIKS during the development of arthritis in the CIA model, including in the formation of CII-Abs, and they mark the CIKS adaptor as a potential therapeutic target
Neutrophil Gelatinase Associated Lipocalin is Instrumental in the Pathogenesis of Antibody-Mediated Nephritis

Objective— The mechanism by which anti-DNA antibodies mediate lupus nephritis has yet to be conclusively determined. Previously, we found that treatment of mesangial cells with anti-DNA antibodies induced high expression of Neutrophil Gelatinase Associated Lipocalin (NGAL), an iron-binding protein upregulated in response to kidney injury. However, whether NGAL is instrumental in pathogenesis, induced as part of repair, or irrelevant to damage/repair pathways, is not known. Methods— To investigate the role of NGAL in antibody-mediated nephritis, we induced nephrotoxic nephritis by passive antibody transfer to B6 or 129 mice. To determine if NGAL upregulation is instrumental, we compared the severity of renal damage in NGAL wild-type and knock-out mice following induction of nephrotoxic nephritis. Results— We found that kidney NGAL expression, as well as urinary NGAL levels, were significantly increased in nephrotoxic nephritis as compared to control injected mice. Tight correlations were observed between NGAL expression, renal histopathology, and urinary NGAL excretion. NGAL knock-out mice had attenuated proteinuria and improved renal histopathology as compared to wild-type mice. Similarly, following nephritis induction, NGAL injection significantly exacerbated nephritis and decreased survival. NGAL induces apoptosis via caspase-3 activation, and upregulates inflammatory gene expression in kidney cells in vitro and when injected in vivo. PA M p t H PA p Conclusion— We conclude that kidney binding of pathogenic antibodies stimulates local expression of NGAL, which plays a crucial role in the pathogenesis of nephritis via promotion of inflammation and apoptosis. NGAL blockade may be a novel therapeutic approach for the treatment of nephritis mediated by pathogenic antibodies, including anti-GBM disease and lupus nephritis. anti-mouse NGAL (R&D Systems, Minneapolis, MN) in 2% BSA in a humid chamber for 1 hour at room temperature. Slides were developed with biotinylated anti-IgG followed by streptavidin-HRP, counterstained with Mayer’s hematoxylin, dehydrated and mounted. The score assigned by a blinded evaluator (including both glomerular and tubular staining) averaging multiple fields was based on intensity: 0, no staining; 1, trace; 2–4, increasing degrees of intensity.
JOURNAL OF THE EXPERIMENTAL ANALYSIS OF BEHAVIOR

Responses of pigeons were maintained by a VI schedule of food reinforcement. Conditioned punishment was programmed by having these responses concurrently produce an originally neutral stimulus. The effectiveness of this response-contingent stimulus was maintained by infrequent and prearranged stimulus-shock pairings delivered independently of responses. This conditioned punishment procedure reduced the overall response rate as long as the procedure was in effect. The extent and durability of the reduction was a function of the intensity of the shock that was paired with the stimulus. Analysis of the reduction in the overall response rate revealed: (1) a reduction of responses occurring in the absence of the responsecontingent stimulus, which was designated as a "punishing" effect, and (2) a reduction of responses during the response-contingent stimulus, which was designated as a "suppressive" effect.
Coping with Breast Cancer: Reflections from Chinese-, Korean-, and Mexican-American Women

Objective— The present study identified and compared the coping strategies of Chinese-, Korean-, and Mexican-American breast cancer survivors (BCS). Methods— Six focus groups were conducted with Chinese- ( n = 21), Korean- ( n = 11), and Mexican-American ( n = 9) BCS. Interviews were audio-recorded, transcribed, and translated for thematic content analysis of coping experiences and strategies. Results— Women reported the use of eight coping strategies (religious/spiritual, benefit finding, fatalism, optimism, fighting spirit, information seeking, denial, and self-distraction). Among Chinese-American BCS, benefit finding was the most referenced coping strategy, whereas religious/spiritual coping was most frequently reported among Korean- and Mexican-American BCS. Denial and self-distraction were the least cited strategies. Conclusions— Survivors draw upon new found inner strength to successfully integrate their cancer experience into their lives. Coping models must consider the diversity of cancer survivors and the variability in coping strategies among cultural ethnic minority BCS. and explore the culturally-relevant coping strategies of and Mexican-American BCS. This study used a qualitative ethnographic approach to about role We conducted
Spatiotemporal patterns of secretomotor neuron generation in the parvicellular neuroendocrine system1

Spatiotemporal patterns of parvicellular neurosecretory neuron generation (birthdates) were determined in the young adult male rat using a triple fluorescence labeling method. The six classic phenotypes were identified in histological sections with rabbit antisera to neurotransmitters (or related enzymes), nuclear bromodeoxyuridine was detected with a mouse monoclonal antibody, and an axonal projection to the median eminence was determined with the fluorescent retrograde tracer fast blue. The vast majority of triply labeled neurons are generated between embryonic days 12–14, during the time when magnocellular neurosecretory neurons are also generated. This pattern of neurogenesis is distinct from the well-known ‘outside-in’ pattern of hypothalamic neurogenesis, where the peak of lateral zone birthdates occurs on embryonic days 12 and 13, the peak of medial zone birthdates occurs on embryonic days 14 and 15, and the peak of periventricular zone birthdates occurs on embryonic days 16 and 17. Thus, neuroendocrine motoneurons may constitute ‘pioneer neurons’ for the various anatomically distinct regions of the periventricular zone. In addition, many intermixed neurons that express the same neurotransmitters as parvicellular neurosecretory neurons but do not send an axon to the median eminence, also appear to be generated sbetween embryonic days 12 and 14. What these results imply about mechanisms underlying neuroendocrine motor zone differentiation is discussed.
Role of TGF β signaling in the pathogenesis of psoriasis

Dysregulation of transformation growth factor β (TGF β ) signaling has been reported in human psoriasis. However, the causal role of TGF β in psoriasis has not been given attention until our recent report that the transgenic mice expressing wild-type TGF β 1 in the epidermis using a keratin 5 promoter (K5.TGF β 1 wt ) developed psoriasis-like skin inflammation. Additional experimental data further support the causal role of TGF β 1 overexpression in psoriasis. First, we temporally induced TGF β 1 expression in keratinocytes in our gene-switch-TGF β 1 wt transgenic mice and found that inflammation severity correlated with on-and-off switch of TGF β 1 wt transgene expression. Second, deletion of T cells in K5.TGF β 1 wt mice significantly delayed the development of psoriatic lesions. Third, therapeutic approaches effective for human psoriasis, i.e. Enbrel and Rosiglitazone (Avandia®), are also effective in relieving the symptoms seen in K5.TGF β 1 wt mice. Future studies will dissect specific mechanisms and identify key factors in the TGF β 1-induced skin inflammation. Our mouse models will provide a useful tool to test novel therapeutic interventions and help to design specific therapeutic approaches for inflammatory skin disorders, including human psoriasis.
Ankylosing spondylitis macrophages produce greater interleukin-23 in response to lipopolysaccharide without significant Unfolded Protein Response induction

OBJECTIVE— Previous work from the HLA-B27 transgenic rat model of ankylosing spondylitis (AS) suggests that macrophages develop an intracellular stress response called the Unfolded Protein Response (UPR) and as a result secrete increased cytokines in response to Toll like receptor agonists such as lipopolysaccharide (LPS). Our objective was to determine if macrophages from AS patients also undergo an UPR and secrete increased cytokines/chemokines in response to LPS. METHODS— Peripheral blood monocytes isolated from 10 AS patients and healthy controls were differentiated in vitro with M-CSF. Select samples were treated with IFN- γ to up-regulate MHC class I (HLA-B) expression prior to stimulation with LPS for 3h (for RNA collection), or 8–24h (for supernatant collection). UPR induction was assessed by expression of ERdj4, BiP and CHOP mRNA. RESULTS— Although IFN- γ treatment up-regulated HLA-B expression 2-fold(p=0.0094), neither IFN- γ nor LPS enhanced BiP or CHOP expression substantially (<1.3 fold). ERdj4 expression increased weakly but insignificantly in IFN- γ +LPS AS samples (2.2 fold, p=0.31). In response to LPS, AS macrophages secreted more CXCL9, IL-10, IL-12p70, IL-23, and TNF- α than controls(p ≤ 0.025)The most striking difference was observed for IL-23 (median AS patient 265 pg/mL vs. control 9 pg/mL, p=0.0007). We did not detect significant differences in IL-6, IL-8, or IFN- β production. CONCLUSIONS— Greater IL-23 production by AS patient macrophages in response to LPS than controls. These results have implications for AS pathogenesis and further support the development and application of anti-IL23 therapeutics to AS.
Postterm Newborn with Lissencephaly Presented with Seizure: Case Report and Review of Literature

INTRODUCTION Malformations of cortical development include a wide range of anomalies that commonly lead to developmental delay and epilepsy. Lissencephaly, literally ‘‘smooth brain,’’ is a rare genetic brain malformation characterized by the absence of normal convolutions (folds) in the cerebral cortex. A normal brain structure has folds and grooves on the gray matter surface or on the cerebrum. However, sometimes during pregnancy the structure of the brain does not develop properly, resulting in a smooth surface. The abnormality is caused by defective neuronal migration during weeks 8-14 of gestation. Lissencephaly encompasses a continuous spectrum of malformations—from complete agyria (smoothness) to variable degrees of agyria and pachygyria to subcortical band heterotopia (SBH). Lissencephaly can occur as an autosomal dominant, recessive, or X-linked inheritance, and the condition is subdivided into two types: classic (type 1) and cobblestone (type 2). Classic lissencephaly has a prevalence of 11.7 per million births (1 of 85,470), but the prevalence of milder phenotypes is unknown. Mutations involving the LIS1 and TUBA1A genes result in the classic form of lissencephaly, whereas mutations of the DCX gene cause lissencephaly in males and SBH in females. Affected children present with microcephaly, developmental delay, mental retardation, and early-onset epileptic seizures. We report a case of lissencephaly in a postterm newborn who presented with seizure after delivery.
Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South Africa1

BACKGROUND— The efficacy of BCG may be enhanced by heterologous vaccination strategies that boost the BCG-primed immune response. One leading booster vaccine, MVA85A, has shown promising safety and immunogenicity in UK human trials. We investigated the safety and immunogenicity of MVA85A in mycobacteria-exposed, but Mycobacterium tuberculosis-uninfected, healthy adults from a TB-endemic region of South Africa. METHODS— Twenty-four adults were vaccinated with MVA85A. All subjects were followed up for one year for adverse events and for immunological assessment. RESULTS— MVA85A vaccination was well tolerated and induced potent T cell responses, measured by IFN- γ ELISPOT assay, which exceeded pre-vaccination levels up to 364 days after vaccination. BCG-specific CD4 + T cells boosted by MVA85A comprised of multiple populations expressing combinations of IFN- γ , TNF- α , IL-2 and IL-17, as measured by polychromatic flow cytometry. IFN- γ expressing and polyfunctional IFN- γ + TNF- α + IL-2 + CD4 + T cells were boosted during the peak BCG-specific response 7 days post-vaccination. CONCLUSION— The excellent safety profile and quantitative and qualitative immunogenicity data strongly support further trials to assess the efficacy of MVA85A as a boosting vaccine in TB endemic countries.
Roles for Ca2+ Stores Release and Two Ca2+ Influx Pathways in the FcER1-activated Ca2+ Responses of RBL-2H3 Mast Cells

Cross-linking the high affinity IgE receptor, FcER1, with multivalent antigen induces inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]-dependent release of intracellular Ca2+ stores, Ca2+ influx, and secretion of inflammatory mediators from RBL-2H3 mast cells. Here, fluorescence ratio imaging microscopy was used to characterize the antigen-induced Ca2' responses of sin§le fura-2-loaded RBL-2H3 cells in the presence and absence of extracellular Ca2+ (Ca +). As antigen concentration increases toward the optimum for secretion, more cells show a Ca2+ spike or an abrupt increase in [Ca2 ]i and the lag time to onset of the response decreases both in the presence and the absence of Ca+. When Ca 2 is absent, fewer cells respond to low antigen and the lag times to response are longer than those measured in the presence of Cao, indicating that Cao+ contributes to Ca stores release. Ins(1,4,5)P3 production is not impaired by the removal of Cao I suggesting that extracellular Ca2+ influences Ca2+ stores release via an effect on the Ins(1,4,5)P3 receptor. Stimulation with low concentrations of antigen can lead, only in the presence of Cao , to a small, gradual increase in [Ca2 ]i before the abrupt spike response that indicates stores release. We propose that this small, initial [Ca2+]i increase is due to receptor-activated Ca2+ influx that precedes and may facilitate Ca2+ stores release. A mechanism for capacitative Ca2+ entry also exists in RBL-2H3 cells. Our data su est that a
Utilizing Project-Based Learning to Increase Engagement and Performance in the High School Classroom

Abstract Project-based learning was incorporated into a high school American History course unit where students were expected to write an original history of the Vietnam War based exclusively on primary sources. Throughout the school year, students working as a collective unit worked to raise funds at school events for the purpose of surprising a class guest speaker, a Vietnam veteran, with a sponsored flight to Washington D.C. through Kansas Honor Flights. In addition to creating an experience of civic participation, student engagement (as measured by rate of completion of the project) and performance (as measured by average grade on the project) were tracked. Statistically significant improvements with a moderate effect size were found in student engagement as compared to previous school years. No statistically significant improvements in student performance were demonstrated. Results support previous literature linking project-based learning to increased student engagement but potentially indicate that student performance is best manipulated by an alternative mechanism.
PAH o -quinones produced by the Aldo-Keto-Reductases (AKRs) generate abasic sites, oxidized pyrimidines and 8-oxo-dGuo via reactive oxygen species

Reactive and redox-active polycyclic aromatic hydrocarbon (PAH) o -quinones produced by Aldo-Keto Reductases (AKRs) have the potential to cause depurinating adducts leading to the formation of abasic sites and oxidative base lesions. The aldehyde reactive probe (ARP) was used to detect these lesions in calf thymus DNA treated with three PAH o -quinones (BP-7,8-dione, 7,12-DMBA-3,4-dione and BA-3,4-dione) in the absence and presence of redox-cycling conditions. In the absence of redox-cycling a modest amount of abasic sites were detected indicating the formation of a low level of covalent o -quinone depurinating adducts (> 3.2 × 10 6 dNs). In the presence of NADPH and CuCl 2 , the three PAH o -quinones increased the formation of abasic sites due to ROS derived lesions destabilizing the N-glycosidic bond. The predominant source of AP sites, however, was revealed by coupling the assay with human 8-oxoguanine glycosylase (hOGG1) treatment showing that 8-oxo-dGuo was the major lesion caused by PAH o -quinones. The levels of 8-oxo-dGuo formation were independently validated by HPLC-ECD analysis. Apyrimidinic sites were also revealed by coupling the assay with -deoxyguanosine; 7,12-DMBA-3,4-dione, 7,12-dimethylbenz[ anthracene-3,4-dione; Endo III, Escherichia endonuclease Fapy-Gua, 2,6-diamino-4-hydroxy-5-formamidopyrimidine; human 8-oxoguanine glycosylase; HRP, horse radish peroxidase; M1-dGuo, 3-(2 ′ -deoxy- β -D- erythro -pentofuranosyl)pyrimido[1,2- purin-10(3H)one; NADPH, β -nicotinamide adenine dinucleotide phosphate (reduced); NP-1,2-dione, naphthalene-1,2-dione; -quinones including BP-7,8-dione, benz[ a ]anthracene-3,4-dione (BA-3,4-dione) and 7,12-dimethylbenz[ a ]anthracene-3,4-dione (7,12-DMBA-3,4-dione) were tested for their ability to produce AP sites. We show that in the absence of redox-cycling PAH o -quinones produced a modest number of heat-labile depurinating adducts. In the presence of NADPH and Cu(II) three PAH o -quinones produced significant amounts of the AP sites, 8-oxo-dGuo and oxidized pyrimidines. This represents the first report of PAH o quinone generated ROS to cause abasic sites and form oxidized pyrimidines. The mechanism responsible for formation of three types of oxidative DNA damage generated by PAH o quinone was different depending on whether Cu(II) or Fe(III) was added to the redox-cycling conditions. Those lesions caused in the presence of Cu(II)-mediated PAH o -quinone redox-cycling were produced by singlet oxygen whereas those lesions caused in the presence of Fe (III)-mediated redox-cycling were produced by hydroxyl radical. of three types of 8-oxo-dGuo These provide a good correlation with the mutation pattern seen in the p53 tumor suppressor gene when with PAH o -quinones under These arise due to either singlet oxygen or hydroxyl which is determined by the transition metal used. These are more than those that arise due to the of o -quinone These add to the hypothesis that formation o -quinones mutagenesis
Molecular and Genetic Analysis of the DrosophilaModel of Fragile X Syndrome

The Drosophila genome contains most genes known to be involved in heritable disease. The extraordinary genetic malleability of Drosophila, coupled to sophisticated imaging, electrophysiology and behavioral paradigms, has paved the way for insightful mechanistic studies on the causes of developmental and neurological disease as well as many possible interventions. Here, we focus on one of the most advanced examples of Drosophila genetic disease modeling, the Drosophila model of Fragile X Syndrome, which for the past decade has provided key advances into the molecular, cellular and behavioral defects underlying this devastating disorder. We discuss the multitude of RNAs and proteins that interact with the disease-causing FMR1 gene product, whose function is conserved from Drosophila to human. In turn, we consider FMR1 mechanistic relationships in non-neuronal tissues (germ cells and embryos), peripheral motor and sensory circuits, and central brain circuits involved in circadian clock activity and learning/memory.
Nonischemic Myocardial Changes Detected by Cardiac Magnetic Resonance in Critical Care Patients with Sepsis

neutrophils. PCR-based detection of cytomegalovirus, herpes virus, Aspergillus sp. , Mycobacterium tuberculosis, and Pneumocystis jiroveci were negative. Specific PCR, targeting repeated sequences, detected T. whipplei in significant concentrations (83 10/ml), as those observed among patients (2, 3). T. whipplei genotyping, all of which corresponds to the concatenation of four spacers, identified a new genotype (5) related to two genotypes that have been previously only identified in Senegal. Amplification and sequencing of 16S rDNA gene (4) performed on the BAL fluid identified mainly Prevotella oralis and Haemophilus influenzae among the 96 clones screened but not T. whipplei. Specific PCR detected 10/ml of H. influenzae. Aero/ anaerobic culture and Ziehl-Neelsen staining were negative. The patient was initially treated with 2 g ceftriaxone per day. Cotrimoxazole was added at Day 5 as there was no clinical improvement. The patient subsequently improved and was discharged 2 weeks later. T. whipplei in vitro is resistant to ceftriaxone, but it is susceptible to sulfamethoxazole, and infections caused by this bacterium may be treated by cotrimoxazole (6). The clinical response to cotrimoxazole suggests a role for T. whipplei in the patient’s pneumonia. In a Senegalese population, we have reported that T. whipplei is a relatively common cause of bacteremia, fever, and cough (5). The recent work of Lozupone and colleagues revealed surprisingly high rates of lung colonization with T. whipplei in patients with HIV infection (1). This case extends those findings by suggesting that T. whipplei can be a cause of pneumonia in this population. We suggest that T. whipplei be considered in the differential diagnosis of pneumonia in patients with advanced HIV infection.