Miracle-dz/UniFAR-FTUs huggingface dataset:
Resting state functional connectivity of the ventral auditory pathway in musicians with absolute pitch

Absolute pitch (AP) is the ability to recognize pitch chroma of tonal sound without external references, providing a unique model of the human auditory system (Zatorre: Nat Neurosci 6 ( ) 692–695). In a previous study (Kim and Knösche: Hum Brain Mapp ( ) 3486–3501), we identified enhanced intracortical myelination in the right planum polare (PP) in musicians with AP, which could be a potential site for perceptional processing of pitch chroma information. We speculated that this area, which initiates the ventral auditory pathway, might be crucially involved in the perceptual stage of the AP process in the context of the “dual pathway hypothesis” that suggests the role of the ventral pathway in processing nonspatial information related to the identity of an auditory object (Rauschecker: Eur J Neurosci 41 ( ) 579–585). To test our conjecture on the ventral pathway, we investigated resting state functional connectivity (RSFC) using functional magnetic resonance imaging (fMRI) from musicians with varying degrees of AP. Should our hypothesis be correct, RSFC via the ventral pathway is expected to be stronger in musicians with AP, whereas such group effect is not predicted in the RSFC via the dorsal pathway. In the current data, we found greater RSFC between the right PP and bilateral anteroventral auditory cortices in musicians with AP. In contrast, we did not find any group difference in the RSFC of the planum temporale (PT) between musicians with and without AP. We believe that these findings support our conjecture on the critical role of the ventral pathway in AP recognition. Hum Brain Mapp 38:3899–3916, 2017. © 2017 Wiley Periodicals, Inc.
Permissive roles of cytokines interleukin-7 and Flt3 ligand in mouse B-cell lineage commitment

Significance The generation of different blood lineages is regulated by hematopoietic cytokines, either in an instructive or in a permissive manner. The cytokines Interleukin-7 and fms-like tyrosine kinase-3 (Flt3) ligand are required for B-cell development but their precise mode of action remains controversial. Our study has addressed the role of these cytokines in B-cell commitment by analyzing the progenitor stage where B-cell commitment occurs in mice overexpressing one of the two cytokines in the absence of the other. Our results demonstrate a permissive role for both cytokines in B-cell commitment. Interleukin-7 promotes survival of progenitors instead of up-regulation of B-cell commitment factors early B-cell factor 1 (Ebf1) and paired box 5 (Pax5), as previously hypothesized, whereas Flt3 ligand facilitates progenitor expansion by inducing their proliferation. Hematopoietic cells are continuously generated throughout life from hematopoietic stem cells, thus making hematopoiesis a favorable system to study developmental cell lineage commitment. The main factors incorporating environmental signals to developing hematopoietic cells are cytokines, which regulate commitment of hematopoietic progenitors to the different blood lineages by acting either in an instructive or a permissive manner. Fms-like tyrosine kinase-3 (Flt3) ligand (FL) and Interleukin-7 (IL-7) are cytokines pivotal for B-cell development, as manifested by the severely compromised B-cell development in their absence. However, their precise role in regulating B-cell commitment has been the subject of debate. In the present study we assessed the rescue of B-cell commitment in mice lacking IL-7 but simultaneously overexpressing FL. Results obtained demonstrate that FL overexpression in IL-7–deficient mice rescues B-cell commitment, resulting in significant Ebf1 and Pax5 expression in Ly6D+CD135+CD127+CD19− precursors and subsequent generation of normal numbers of CD19+ B-cell progenitors, therefore indicating that IL-7 can be dispensable for commitment to the B-cell lineage. Further analysis of Ly6D+CD135+CD127+CD19− progenitors in IL-7– or FL-deficient mice overexpressing Bcl2, as well as in IL-7 transgenic mice suggests that both FL and IL-7 regulate B-cell commitment in a permissive manner: FL by inducing proliferation of Ly6D+CD135+CD127+CD19− progenitors and IL-7 by providing survival signals to these progenitors.
Performance of Mid-Treatment Breast Ultrasound and Axillary Ultrasound in Predicting Response to Neoadjuvant Chemotherapy by Breast Cancer Subtype.

BACKGROUND The primary objective was to determine whether mid-treatment ultrasound measurements of index breast tumors and index axillary nodes of different cancer subtypes associate with residual cancer burden (RCB). METHODS Patients with invasive breast cancer who underwent neoadjuvant chemotherapy and had pre-treatment and mid-treatment breast and axillary ultrasound were included in this single-institution, retrospective cohort study. Linear regression analysis assessed associations between RCB with (a) change in index breast tumor size, (b) change in index node size, and (c) absolute number of abnormal nodes at mid-treatment. Multivariate linear regression was used to calculate best-fit models for RCB. RESULTS One hundred fifty-nine patients (68 triple negative breast cancer [TNBC], 45 hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-, and 46 HR-/HER2+) were included. Median age at diagnosis was 50 years, range 30-76. Median tumor size was 3.4 cm, range 0.9-10.4. Pathological complete response/RCB-I rates were 36.8% (25/68) for TNBC patients, 24.4% (11/45) for HR+/HER2- patients, and 71.7% (33/46) for HR-/HER2+ patients. Linear regression analyses demonstrated associations between percent change in tumor ultrasound measurements at mid-treatment with RCB index score in TNBC and HR+/HER2- (p < .05) but not in HR-/HER2+ (p > .05) tumors and an association between axillary ultrasound assessment of number of abnormal nodes at mid-treatment with RCB index score across all subtypes (p < .05). CONCLUSION Performance characteristics of breast ultrasound associated with RCB vary by cancer subtype, whereas the performance characteristics of axillary ultrasound associated with RCB are consistent across cancer subtype. Breast and axillary ultrasound may be valuable in monitoring response to neoadjuvant therapy. The Oncologist 2017;22:394-401 IMPLICATIONS FOR PRACTICE: The differential performance characteristics of breast ultrasound by molecular subtype and the consistent performance characteristics of axillary ultrasound across molecular subtypes can have clinical utility in monitoring response to neoadjuvant therapy.
Prescriber Continuity and Disease Control of Older Adults

Background: Medicare beneficiaries with multiple chronic conditions are typically seen by multiple providers, particularly specialists. Clinically appropriate referrals to multiple specialists may compromise the continuity of care for multiple chronic condition beneficiaries and create care plans that patients may find challenging to reconcile, which may impact patient outcomes. Objective: The objective was to examine whether glycemic control or lipid control was associated with the number of prescribers of cardiometabolic medications. Research Design, Subjects, and Measures: A retrospective cross-sectional cohort analysis of 51,879 elderly Medicare fee-for-service beneficiaries with diabetes and 129,762 beneficiaries with dyslipidemia living in 10 east coast states. Glycemic control was defined as having an HbA1c<7.5. Lipid control was defined as an low-density lipoprotein<100 for beneficiaries with heart disease or diabetes or an low-density lipoprotein<130 for all other beneficiaries. We examined the association between the number of prescribers of cardiometabolic medications and disease or lipid control in 2011 through logistic regression, controlling for age, sex, race, Medicaid enrollment, 17 chronic conditions and state-fixed effects. Results: Among beneficiaries with diabetes, 76% with one prescriber had well-controlled diabetes in 2011, which decreased to 65% for beneficiaries with 5+ prescribers. In adjusted analyses, Medicare beneficiaries with 3 or more prescribers were less likely to have glycemic control than beneficiaries with a single prescriber. Among those with dyslipidemia, nearly all (91%–92%) beneficiaries had lipid control. After adjustment for demographics and comorbidity burden, beneficiaries with 3 prescribers were less likely to have lipid control than beneficiaries with a single prescriber. Conclusions: Multiple prescribers were associated with worse disease control, possibly because patients with more severe diabetes or dyslipidemia have multiple prescribers or because care fragmentation is associated with worse disease control.
Effect of hypertension and peroxynitrite decomposition with FeTMPyP on CBF and stroke outcome

We investigated the effect of peroxynitrite decomposition catalyst FeTMPyP treatment on perfusion deficit, vascular function and stroke outcome in Wistar (n = 26) and spontaneously hypertensive rats stroke-prone (SHRSP; n = 26) that underwent tMCAO for 2 h or Sham operation. Peri-infarct CBF was measured by hydrogen clearance in the absence or presence of FeTMPyP (10 mg/kg, i.v.) or vehicle 10 min before reperfusion. Myogenic tone of parenchymal arterioles (PAs) was measured as an indication of small vessel resistance (SVR). Baseline CBF was similar between Wistar and SHRSP (114 ± 12 vs. 132 ± 9 mL/100 g/min); however, MCAO caused greater perfusion deficit in SHRSP (24 ± 6 vs. 7 ± 1 mL/100 g/min; p < 0.05) and increased infarct volume by TTC (12 ± 6 vs. 32 ± 2%; p < 0.05). Reperfusion CBF was decreased from baseline in both SHRSP and Wistar (54 ± 16 and 46 ± 19 mL/100 g/min; p < 0.05), suggesting increased infarction in SHRSP was related to greater perfusion deficit. PAs from SHRSP had increased tone vs. Wistar that was enhanced after tMCAO. FeTMPyP treatment did not affect CBF during ischemia or reperfusion, or tone of PAs, but decreased the incidence of hemorrhage in SHRSP by 50%. Thus, increased tone in PAs from SHRSP could increase perfusion deficit during MCAO that was not alleviated by FeTMPyP.
Systemic activation of Toll-like receptor 2 suppresses mitochondrial respiration and exacerbates hypoxic–ischemic injury in the developing brain

Infection and inflammation are known risk factors for neonatal brain injury. Mycoplasma and Gram-positive bacteria, for which Toll-like receptor 2 (TLR2) plays a key role in recognition and inflammatory response, are among the most common pathogens in the perinatal period. Here, we report that systemic activation of TLR2 by Pam3CSK4 (P3C) increases neural tissue loss and demyelination induced by subsequent hypoxia–ischemia (HI) in neonatal mice. High-resolution respirometry of brain isolated mitochondria revealed that P3C suppresses ADP-induced oxidative phosphorylation, the main pathway of cellular energy production. The results suggest that infection and inflammation might contribute to HI-induced energy failure.
Pathology in Permissive Syrian Hamsters after Infection with Species C Human Adenovirus (HAdV-C) Is the Result of Virus Replication: HAdV-C6 Replicates More and Causes More Pathology than HAdV-C5

ABSTRACT Syrian hamsters are permissive for the replication of species C human adenoviruses (HAdV-C). The virus replicates to high titers in the liver of these animals after intravenous infection, while respiratory infection results in virus replication in the lung. Here we show that two types belonging to species C, HAdV-C5 and HAdV-C6, replicate to significantly different extents and cause pathology with significantly different severities, with HAdV-C6 replicating better and inducing more severe and more widespread lesions. The virus burdens in the livers of HAdV-C6-infected hamsters are higher than the virus burdens in HAdV-C5-infected ones because more of the permissive hepatocytes get infected. Furthermore, when hamsters are infected intravenously with HAdV-C6, live, infectious virus can be isolated from the lung and the kidney, which is not seen with HAdV-C5. Similarly to mouse models, in hamsters, HAdV-C6 is sequestered by macrophages to a lesser degree than HAdV-C5. Depletion of Kupffer cells from the liver greatly increases the replication of HAdV-C5 in the liver, while it has only a modest effect on the replication of HAdV-C6. Elimination of Kupffer cells also dramatically increases the pathology induced by HAdV-C5. These findings indicate that in hamsters, pathology resulting from intravenous infection with adenoviruses is caused mostly by replication in hepatocytes and not by the abortive infection of Kupffer cells and the following cytokine storm. IMPORTANCE Immunocompromised human patients can develop severe, often lethal adenovirus infections. Respiratory adenovirus infection among military recruits is a serious problem, in some cases requiring hospitalization of the patient. Furthermore, adenovirus-based vectors are frequently used as experimental viral therapeutic agents. Thus, it is imperative that we investigate the pathogenesis of adenoviruses in a permissive animal model. Syrian hamsters are susceptible to infection with certain human adenoviruses, and the pathology accompanying these infections is similar to what is observed with adenovirus-infected human patients. We demonstrate that replication in permissive cells in a susceptible host animal is a major part of the mechanism by which systemic adenovirus infection induces pathology, as opposed to the chiefly immune-mediated pathology observed in nonsusceptible hosts. These findings support the use of compounds inhibiting adenovirus replication as a means to block adenovirus-induced pathology.
Racial Discrimination Mediates Race Differences in Sleep Problems: A Longitudinal Analysis

Objectives: To examine changes in sleep problems over a 1.5-year period among Black or African American (AA) and White or European American (EA) college students and to consider the role of racial discrimination as a mediator of race differences in sleep problems over time. Method: Students attending a large, predominantly White university (N = 133, 41% AA, 57% female, mean age = 18.8, SD = .90) reported on habitual sleep characteristics and experiences of racial discrimination at baseline and follow-up assessments. A latent variable for sleep problems was assessed from reports of sleep latency, duration, efficiency, and quality. Longitudinal models were used to examine race differences in sleep problems over time and the mediating role of perceived discrimination. Covariates included age, gender, parent education, parent income, body mass index, self-rated physical health, and depressive symptoms. Each of the individual sleep measures was also examined separately, and sensitivity analyses were conducted using alternative formulations of the sleep problems measure. Results: AAs had greater increases in sleep problems than EAs. Perceived discrimination was also associated with increases in sleep problems over time and mediated racial disparities in sleep. This pattern of findings was similar when each of the sleep indicators was considered separately and held with alternative sleep problems measures. Conclusions: The findings highlight the importance of racial disparities in sleep across the college years and suggest that experiences of discrimination contribute to group disparities.
Mutations in Argonaute5 Illuminate Epistatic Interactions of the K1 and I Loci Leading to Saddle Seed Color Patterns in Glycine max

The epistatic interaction between two classically defined loci operates via a mutation in an Argonaute protein affecting the small RNA pathway. The soybean (Glycine max) seed coat has distinctive, genetically programmed patterns of pigmentation, and the recessive k1 mutation can epistatically overcome the dominant I and ii alleles, which inhibit seed color by producing small interfering RNAs (siRNAs) targeting chalcone synthase (CHS) mRNAs. Small RNA sequencing of dissected regions of immature seed coats demonstrated that CHS siRNA levels cause the patterns produced by the ii and ik alleles of the I locus, which restrict pigment to the hilum or saddle region of the seed coat, respectively. To identify the K1 locus, we compared RNA-seq data from dissected regions of two Clark isolines having similar saddle phenotypes mediated by CHS siRNAs but different genotypes (homozygous ik K1 versus homozygous ii k1). By examining differentially expressed genes, mapping information, and genome resequencing, we identified a 129-bp deletion in Glyma.11G190900 encoding Argonaute5 (AGO5), a member of the Argonaute family. Amplicon sequencing of several independent saddle pattern mutants from different genetic backgrounds revealed independent lesions affecting AGO5, thus establishing Glyma.11G190900 as the K1 locus. Nonfunctional AGO5 from k1 alleles leads to altered distributions of CHS siRNAs, thus explaining how the k1 mutation reverses the phenotype of the seed coat regions from yellow to pigmented, even in the presence of the normally dominant I or ii alleles.
Drug‐induced liver injury: Advances in mechanistic understanding that will inform risk management

Drug‐induced liver injury (DILI) is a major public health problem. Intrinsic (dose‐dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However, the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.
Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States

Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at −120 mV (3% inhibition by 100 µM lacosamide) but greatly enhanced at −80 mV (43% inhibition by 100 µM lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at −120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at −40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slow-inactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 µM lidocaine or 300 µM carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding.
Now You Have My Attention: Empathic Accuracy Pathways in Couples and the Role of Conflict

Recent research on empathy finds evidence for 2 different pathways that enable individuals to accurately infer other persons’ inner mental states: an automatic, indirect pathway that operates by having a mental state similar to the target’s and (correctly) assuming that this state is similar to the target’s, and a more controlled direct pathway that involves assessing the target’s mental state with no regard for one’s own. We present 3 daily diary studies (N = 53, 38 and 80 couples) examining the contribution of these pathways to empathic accuracy in daily assessments of romantic partners’ negative moods, and examine the effects of gender and relational conflict on these pathways. Our studies revealed that both pathways consistently contributed to accuracy. Additionally, partners demonstrated greater indirect accuracy on conflict (vs. nonconflict) days, and indirect accuracy was somewhat higher for women than for men on conflict days (with the opposite pattern on nonconflict days). More importantly, we found evidence for a novel third pathway, in which the perception of conflict itself led to (correct) higher estimation of negative affect and thus, to higher accuracy. This pathway figured more consistently for men than for women. In our discussion, we link the pathways obtained in these studies to the extant social neuroscientific literature on empathy systems, arguing that the indirect pathway involves the effects of experience sharing, while the direct and conflict-based pathways involve the mental state attributions (Zaki & Ochsner, 2011). These findings demonstrate the importance of examining various empathic pathways for the understanding of empathic processes.
A population-based study for 30-d hospital readmissions after acute ischemic stroke

Objective: To determine post-stroke 30-d readmission rate, its predictors, its impact on mortality and to identify potentially preventable causes of post-stroke 30-d readmission in a population-based study. Patients and methods: We identified all acute ischemic strokes (AIS) using the International Classification of Diseases 9th revision codes (433.x1, 434.xx and 436) via the Rochester Epidemiology Project (REP) between January 2007 and December 2011. Acute stroke care in Olmsted County is provided by two medical centers, Saint Marys Hospital and Olmsted Medical Center Hospital. All readmissions to these two hospitals were accounted for this study. Thirty-day readmission data was abstracted through manual chart review. The REP linkage database was used to identify the status (living/dead) of all patients at last follow up. Results: Forty-one (7.6%, 95% CI 5.7%–10.2%) of total 537 AIS patients were readmitted 30-d post-stroke. In a multivariable logistic regression model, discharge to nursing home following index stroke (OR: 0.29, 95% CI 0.08–0.84) was an independent negative predictor of unplanned 30-d readmission. In a subgroup of patients with dementia, being married at time of index stroke was found to be a negative predictor of readmission (OR: 0.10, 95% CI 0.005–0.58). Only 2.8% of the patients had potentially preventable readmissions. Hospital readmission had no significant impact on patient's short-term (three months) or long-term (one or two years) mortality (p > 0.05). Conclusion: Post-stroke 30-d readmission rate is low in AIS patients from Olmsted County. Further research is needed in regarding discharge checklists, protocols and stroke transitional programs to reduce potentially preventable readmissions.