Miracle-dz/UniFAR-FTUs huggingface dataset:
1,25(OH)2D3 Alters Growth Plate Maturation and Bone Architecture in Young Rats with Normal Renal Function

Whereas detrimental effects of vitamin D deficiency are known over century, the effects of vitamin D receptor activation by 1,25(OH)2D3, the principal hormonal form of vitamin D, on the growing bone and its growth plate are less clear. Currently, 1,25(OH)2D3 is used in pediatric patients with chronic kidney disease and mineral and bone disorder (CKD-MBD) and is strongly associated with growth retardation. Here, we investigate the effect of 1,25(OH)2D3 treatment on bone development in normal young rats, unrelated to renal insufficiency. Young rats received daily i.p. injections of 1 µg/kg 1,25(OH)2D3 for one week, or intermittent 3 µg/kg 1,25(OH)2D3 for one month. Histological analysis revealed narrower tibial growth plates, predominantly in the hypertrophic zone of 1,25(OH)2D3-treated animals in both experimental protocols. This phenotype was supported by narrower distribution of aggrecan, collagens II and X mRNA, shown by in situ hybridization. Concomitant with altered chondrocyte maturation, 1,25(OH)2D3 increased chondrocyte proliferation and apoptosis in terminal hypertrophic cells. In vitro treatment of the chondrocytic cell line ATDC5 with 1,25(OH)2D3 lowered differentiation and increased proliferation dose and time-dependently. Micro-CT analysis of femurs from 1-week 1,25(OH)2D3-treated group revealed reduced cortical thickness, elevated cortical porosity, and higher trabecular number and thickness. 1-month administration resulted in a similar cortical phenotype but without effect on trabecular bone. Evaluation of fluorochrome binding with confocal microscopy revealed inhibiting effects of 1,25(OH)2D3 on intracortical bone formation. This study shows negative effects of 1,25(OH)2D3 on growth plate and bone which may contribute to the exacerbation of MBD in the CKD pediatric patients.
Recovery from Severe Arsenic-Induced Peripheral Neuropathy with 2,3-Dimercapto-l-propanesulphonic Acid

Case Report: A 33-year-old female with a 1.5-year history of multisystem illness was diagnosed with arsenic poisoning. Twenty-four-hour urine arsenic was 1030 μg/dL (normal 0–99) and root hair arsenic was 130 μg/g (normal 0–3). Despite treatment with succimer meso-2,3-dimercaptosuccinic acid, her neuropathy progressed to ventilator dependence and quadriplegia. Subsequent intravenous treatment with 2,3-dimercapto-1-propanesulfonic acid sodium salt was associated with arsenic diuresis, marked neuropathic improvement, and extubation. At 1-year follow-up, neuropathy was limited to mild distal lower extremity weakness and sensory loss. The use of 2,3-dimercapto-l-propanesulphonic acid in the treatment of severe arsenic neuropathy was associated with increased urinary elimination of arsenic and dramatic clinical recovery.
Apo‐Hsp90 coexists in two open conformational states in solution

Background information. Hsp90 (90 kDa heat‐shock protein) plays a key role in the folding and activation of many client proteins involved in signal transduction and cell cycle control. The cycle of Hsp90 has been intimately associated with large conformational rearrangements, which are nucleotide‐binding‐dependent. However, up to now, our understanding of Hsp90 conformational changes derives from structural information, which refers to the crystal states of either recombinant Hsp90 constructs or the prokaryotic homologue HtpG (Hsp90 prokaryotic homologue).
A population-based study of cardiovascular disease risk in sexual-minority women.

OBJECTIVES We sought to determine if sexual-minority women were at greater risk for cardiovascular disease (CVD) than their heterosexual counterparts. METHODS We aggregated data from the 2001-2008 National Health and Nutrition Examination Surveys to examine differences in CVD risk between heterosexual and sexual-minority women by using the Framingham General CVD Risk Score to calculate a ratio of vascular and chronological age. We also examined differences in the prevalence of various CVD risk factors. RESULTS Sexual-minority women were more likely to be current or former smokers, to report a history of drug use, to report risky drinking, and to report a family history of CVD. On average, sexual-minority women were 13.9% (95% confidence interval [CI] = 8.5%, 19.3%) older in vascular terms than their chronological age, which was 5.7% (95% CI = 1.5%, 9.8%) greater than that of their heterosexual counterparts. Family history of CVD and history of drug use were unrelated to increased CVD risk, and this risk was not fully explained by either risky drinking or smoking. CONCLUSIONS Sexual-minority women are at increased risk for CVD compared with heterosexual women.
Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function

Hospitalization of the elderly for invasive pneumococcal disease is frequently accompanied by the occurrence of an adverse cardiac event; these are primarily new or worsened heart failure and cardiac arrhythmia. Herein, we describe previously unrecognized microscopic lesions (microlesions) formed within the myocardium of mice, rhesus macaques, and humans during bacteremic Streptococcus pneumoniae infection. In mice, invasive pneumococcal disease (IPD) severity correlated with levels of serum troponin, a marker for cardiac damage, the development of aberrant cardiac electrophysiology, and the number and size of cardiac microlesions. Microlesions were prominent in the ventricles, vacuolar in appearance with extracellular pneumococci, and remarkable due to the absence of infiltrating immune cells. The pore-forming toxin pneumolysin was required for microlesion formation but Interleukin-1β was not detected at the microlesion site ruling out pneumolysin-mediated pyroptosis as a cause of cell death. Antibiotic treatment resulted in maturing of the lesions over one week with robust immune cell infiltration and collagen deposition suggestive of long-term cardiac scarring. Bacterial translocation into the heart tissue required the pneumococcal adhesin CbpA and the host ligands Laminin receptor (LR) and Platelet-activating factor receptor. Immunization of mice with a fusion construct of CbpA or the LR binding domain of CbpA with the pneumolysin toxoid L460D protected against microlesion formation. We conclude that microlesion formation may contribute to the acute and long-term adverse cardiac events seen in humans with IPD.
A long‐range RNA‐RNA interaction forms a pseudoknot required for translational control of the IF3‐L35‐L20 ribosomal protein operon in Escherichia coli.

In the IF3‐L35‐L20 operon encoding translation initiation factor 3 (IF3) and the two ribosomal proteins L35 and L20, the expression of the genes that code for the two ribosomal proteins is negatively regulated at the translational level by the cellular concentration of L20. This translational repressor directly regulates the expression of the gene encoding L35 and, via translational coupling, that of its own gene. Mutations that affect the control of the L35 gene were found exclusively at two sites: the first is located approximately 300 nucleotides upstream, and the second immediately 5′ of the translation initiation site of the L35 gene. Mutations that fall between these two sites have little or no effect on the control, and the lack of effect of a deletion in the intervening region confirms this finding. RNA structure mapping in vitro suggests that the first site pairs with the second. We show that this pairing is also likely to occur in vivo because single mutations in either of these sites affect control, but base pair compensatory mutations re‐establish control. We propose that these two distant sites can base‐pair to form a long‐range pseudoknot which is required for the control of the expression of the L35 gene.
Selective blockade of B7‐H3 enhances antitumour immune activity by reducing immature myeloid cells in head and neck squamous cell carcinoma

Immature myeloid cells including myeloid‐derived suppressor cells (MDSCs) and tumour‐associated macrophages (TAMs) promote tumour growth and metastasis by facilitating tumour transformation and angiogenesis, as well as by suppressing antitumour effector immune responses. Therefore, strategies designed to reduce MDSCs and TAMs accumulation and their activities are potentially valuable therapeutic goals. In this study, we show that negative immune checkpoint molecule B7‐H3 is significantly overexpressed in human head and neck squamous cell carcinoma (HNSCC) specimen as compared with normal oral mucosa. Using immunocompetent transgenic HNSCC models, we observed that targeting inhibition of B7‐H3 reduced tumour size. Flow cytometry analysis revealed that targeting inhibition of B7‐H3 increases antitumour immune response by decreasing immunosuppressive cells and promoting cytotoxic T cell activation in both tumour microenvironment and macroenvironment. Our study provides direct in vivo evidence for a rationale for B7‐H3 blockade as a future therapeutic strategy to treat patients with HNSCC.
Different digestion of caprine whey proteins by human and porcine gastrointestinal enzymes

The objective of the present study was twofold: first to compare the degradation patterns of caprine whey proteins digested with either human digestive juices (gastric or duodenal) or commercial porcine enzymes (pepsin or pancreatic enzymes) and second to observe the effect of gastric pH on digestion. An in vitro two-step assay was performed at 37°C to simulate digestion in the stomach (pH 2, 4 or 6) and the duodenum (pH 8). The whey proteins were degraded more efficiently by porcine pepsin than by human gastric juice at all pH values. Irrespective of the enzyme source, gastric digestion at pH 2 followed by duodenal digestion resulted in the most efficient degradation. Lactoferrin, serum albumin and the Ig heavy chains were highly degraded with less than 6 % remaining after digestion. About 15, 56 and 50 % Ig light chains, β-lactoglobulin (β-LG) and α-lactalbumin remained intact, respectively, when digested with porcine enzymes compared with 25, 74 and 81 % with human digestive juices. For comparison, purified bovine β-LG was digested and the peptide profiles obtained were compared with those of the caprine β-LG in the digested whey. The bovine β-LG seemed to be more extensively cleaved than the caprine β-LG in the whey. Commercial enzymes appear to digest whey proteins more efficiently compared with human digestive juices when used at similar enzyme activities. This could lead to conflicting results when comparing human in vivo protein digestion with digestion using purified enzymes of non-human species. Consequently the use of human digestive juices might be preferred.
On the possibility of observing H2 emission from primordial molecular cloud kernels

We study the prospects for observing H2 emission during the assembly of primordial molecular cloud kernels. The primordial molecular cloud cores, which resemble those at the present epoch, can emerge around 1þ z , 20 according to recent numerical simulations. The kernels form inside the cores, and the first stars will appear inside the kernels. A kernel typically contracts to form one of the first generation stars with an accretion rate that is as large as ,0.01 M( yr. This occurs owing to the primordial abundances, which result in a kernel temperature of order 1000 K, and the collapsing kernel emits H2 line radiation at a rate ,10 erg s. Predominantly J 1⁄4 5 2 3 ðv 1⁄4 0Þ rotational emission of H2 is expected. At redshift 1þ z , 20, the expected flux is ,0.01mJy for a single kernel. While an individual object is not observable by any facilities available in the near future, the expected assembly of primordial star clusters on subgalactic scales can result in fluxes at the sub-mJy level. This is marginally observable with ASTRO-F and ALMA. We also examine the rotational J 1⁄4 2 2 0 ðv 1⁄4 0Þ and vibrational dv 1⁄4 1 emission lines. The former may possibly be detectable with
“If I Take My Medicine, I Will Be Strong:” Evaluation of a Pediatric HIV Disclosure Intervention in Namibia

Background:Despite known benefits, only a small proportion of HIV-infected children in sub-Saharan Africa know their status and limited disclosure interventions exist. Namibia's Ministry of Health and Social Services developed and implemented a multipronged intervention to support health care workers (HCWs) and caregivers in the disclosure process. Methods:The intervention included a staged disclosure cartoon book, child and caregiver readiness assessment tools, a monitoring form to track progress over visits, and HCW training curriculum. We conducted qualitative interviews with 35 HCWs and 46 caregivers of HIV-positive children at 4 high volume HIV clinics. Interviews elicited detailed information about intervention uptake and impact. HCWs also participated in a self-efficacy survey. Results:The intervention improved HCW and caregiver confidence and communication skills in pediatric disclosure. The most valuable intervention component was the disclosure cartoon book, which provided structure, language, and guidance for a gradual disclosure process. HCWs reported it greatly reduced caregiver resistance to disclosure. Both caregivers and HCWs reported improved knowledge and ability to support the pediatric patient, improved child understanding of how HIV medications work, increased child hopefulness for their future, and improved child adherence to care and treatment. HCW self-efficacy surveys found that HCWs who received training felt more confident in their ability to engage in the disclosure process. Conclusions:HCWs and caregivers highly endorsed the intervention. Given the urgency to address pediatric HIV disclosure in Africa, and the utility and low cost of the locally-produced disclosure tool, this approach may be useful in other similar settings.
The Recycling of Apolipoprotein E in Primary Cultures of Mouse Hepatocytes

Internalization of apoE-containing very low density protein (VLDL) by hepatocytes in vivo and in vitro leads to apoE recycling and resecretion. Because of the role of apoE in VLDL metabolism, apoE recycling may influence lipoprotein assembly or remnant uptake. However, apoE is also a HDL protein, and apoE recycling may be related to reverse cholesterol transport. To investigate apoE recycling, apoE−/− mouse hepatocytes were incubated (pulsed) with wild-type mouse lipoproteins, and cells and media were collected at chase periods up to 24 h. When cells were pulsed with VLDL, apoE was resecreted within 30 min. Although the mass of apoE in the media decreased with time, it could be detected up to 24 h after the pulse. Intact intracellular apoE was also detectable 24 h after the pulse. ApoE was also resecreted when cells were pulsed with HDL. When apoA-I was included in the chase media after a pulse with VLDL, apoE resecretion increased 4-fold. Furthermore, human apoE was resecreted from wild-type mouse hepatocytes after a pulse with human VLDL. Finally, apoE was resecreted from mouse peritoneal macrophages after pulsing with VLDL. We conclude that 1) HDL apoE recycles in a quantitatively comparable fashion to VLDL apoE; 2) apoE recycling can be modulated by extracellular apoA-I but is not affected by endogenous apoE; and 3) recycling occurs in macrophages as well as in hepatocytes, suggesting that the process is not cell-specific.
cAMP-dependent activation of protein kinase A attenuates respiratory syncytial virus-induced human airway epithelial barrier disruption

Airway epithelium forms a barrier to the outside world and has a crucial role in susceptibility to viral infections. Cyclic adenosine monophosphate (cAMP) is an important second messenger acting via two intracellular signaling molecules: protein kinase A (PKA) and the guanidine nucleotide exchange factor, Epac. We sought to investigate effects of increased cAMP level on the disruption of model airway epithelial barrier caused by RSV infection and the molecular mechanisms underlying cAMP actions. Human bronchial epithelial cells were infected with RSV-A2 and treated with either cAMP releasing agent, forskolin, or cAMP analogs. Structure and functions of the Apical Junctional Complex (AJC) were evaluated by measuring transepithelial electrical resistance and permeability to FITC-dextran, and determining localization of AJC proteins by confocal microscopy. Increased intracellular cAMP level significantly attenuated RSV-induced disassembly of AJC. These barrier-protective effects of cAMP were due to the activation of PKA signaling and did not involve Epac activity. Increased cAMP level reduced RSV-induced reorganization of the actin cytoskeleton, including apical accumulation of an essential actin-binding protein, cortactin, and inhibited expression of the RSV F protein. These barrier-protective and antiviral-function of cAMP signaling were evident even when cAMP level was increased after the onset of RSV infection. Taken together, our study demonstrates that cAMP/PKA signaling attenuated RSV-induced disruption of structure and functions of the model airway epithelial barrier by mechanisms involving the stabilization of epithelial junctions and inhibition of viral biogenesis. Improving our understanding of the mechanisms involved in RSV-induced epithelial dysfunction and viral pathogenesis will help to develop novel anti-viral therapeutic approaches.
Activation of Human Monocyte-Derived Dendritic Cells in Vitro by the Biological Response Modifier Arabinoxylan Rice Bran (MGN-3/BIOBRAN)

Arabinoxylan rice bran (MGN-3/Biobran) is a potent biological response modifier (BRM) that activates natural killer (NK) cells, T cells and monocytes. Currently, little is known regarding the effects of MGN-3 on dendritic cells (DCs), the cell type that bridges innate and adaptive immunity. Therefore, we examined the stimulatory effects of MGN-3 on DCs. Human monocyte-derived DCs were treated with MGN-3 at different concentrations (5–20 μg/ml) for 24 hours in vitro. Activation of DCs was determined by assessing the expression of co-stimulatory and maturation markers (CD40, CD80, CD83, CD86 and HLA-DR) by flow cytometry, and production of cytokines by ELISA. DC function was determined by assessing their ability to activate naïve T cells. Activation of T cells was assessed by measuring cell proliferation and cytokine production. MGN-3 treatment, in a dose-dependent manner, resulted in: 1) up-regulation of the surface expression of CD83 and CD86, on DCs; 2) an increase in the production of pro-inflammatory and immuno-regulatory cytokines (IL-1β, IL-6, IL-10, TNF-α, IL-12p40 and low levels of IL-12p70 and IL-2) by DCs; and 3) MGN-3 stimulated DC induced CD4+T cell proliferation and their production of cytokines, IFN-γ, IL-10, IL-17. Results suggest that MGN-3 functions as a natural adjuvant for DC activation and thus may be used in DC-based vaccine strategies against infections and cancer.
Factor analysis and validity of the Conners Parent and Teacher Rating Scales in childhood cancer survivors.

OBJECTIVE To examine the factor structure of the Conners Parent Rating Scale-Revised: Short Form (CPRS-R:S) and the Conners Teacher Rating Scale-Revised: Short Form (CTRS-R:S) in children who are long-term survivors of acute lymphocytic leukemia (ALL) or brain tumors (BT)and who have received central nervous system directed treatment. METHOD Parents and teachers of 150 long-term survivors completed the CPRS-R:S or CTRS-R:S as part of a screening battery. The data were submitted to a maximum likelihood confirmatory factor analysis to test the construct validity of the scales and the forms were compared. The CPRS-R:S was also compared to selected subscales of the Achenbach Child Behavior Checklist (CBCL) for further validation. RESULTS The analyses demonstrated an adequate fit of the original three-factor structure of the CTRS-R:S [oppositional, cognitive problems/inattention, hyperactivity]. The analyses of the CPRS-R:S suggested a less adequate fit of the original three-factor structure but principal components factor analysis yielded a three-factor solution with factors similar to those of Conners' original factor structure. Significant correlations were found between the CPRS-R:S and the selected subscales of the CBCL. CONCLUSIONS These findings support the similar construct validity of the original CTRS-R:S and CPRS-R:S. Although significantly correlated, the CPRS-R:S and CTRS-R:S are not interchangeable in the assessment of survivors of childhood cancer.
Therapeutic aspects of oxygen delivery

In the critically ill patient with circulatory failure, an imbalance between oxygen uptake (VO,) and supply (DOz) can lead to tissue hypoxia and has been related to the development of organ failure. The maintenance of adequate oxygen delivery to the tissues is now widely accepted as essential in the care of the critically ill (1,2). However, there is less agreement on the definition of ‘adequate’ oxygen delivery. DO, can be increased by altering any of its three components, hemoglobin, PaOz or cardiac output. A hemoglobin of at least lOg/dl with a hematocrit of at least 30% is generally recommended. The PaO, should be kept greater than 8kPa but levels much higher than this have little effect on global DO, and carry the risk of oxygen toxicity. CO can be increased by fluid administration and the use of inotropes. Patient’s who a p pear by all global hemodynamic parameters to be adequately resuscitated, may in fact still have areas of residual tissue hypoxia which can lead to the development of organ failure and its often fatal consequences. The need for further therapy in such patients is therefore obvious but the means to achieve this has been hotly debated.
Dietary Restraint Partially Mediates the Relationship between Impulsivity and Binge Eating Only in Lean Individuals: The Importance of Accounting for Body Mass in Studies of Restraint

Binge eating is characteristic of eating and weight-related disorders such as binge eating disorder, bulimia nervosa, and obesity. In light of data suggest impulsivity is associated with overeating specifically in restrained eaters, this study sought to elucidate the exact nature of the associations between these variables, hypothesizing that the relationship between impulsivity and binge eating is mediated by restrained eating. We further hypothesized that the role of dietary restraint as a mediator would be moderated by body mass index (BMI). Study participants (n = 506, 50.6% female) were categorized based on self-reported BMI as under- and normal-weight (BMI < 25, 65.8%, n = 333) or overweight and obese (BMI ≥ 25, 34.2%, n = 173) and completed the “restrained eating” subscale of the Dutch Eating Behavior Questionnaire, the “impulse control difficulties” subscale of the Difficulties with Emotion Regulation Scale, and the Binge Eating Scale. Findings provide initial evidence for the hypothesized moderated mediation model, with dietary restraint partially mediating the relationship between impulsivity and binge eating severity only in lean respondents. In respondents with overweight or obesity, impulsivity was significantly correlated with binge eating severity, but not with dietary restraint. Findings inform our conceptualization of dietary restraint as a possible risk factor for binge eating and highlight the importance of accounting for body mass in research on the impact of dietary restraint on eating behaviors.