bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceived Patient Safety Culture in Nursing Homes Associated With “Nursing Home Compare” Performance Indicators
Authors: Li Yue , Cen Xi , Cai Xueya , Temkin-Greener Helena
Published: June 2019

Background:

The safety and quality of care provided to nursing home residents is a significant concern. Little is known whether fostering patient safety culture helps improve the safety and quality of nursing home care.

Methods:

This study determined the associations of nursing home patient safety culture performance, as reported by administrators, directors of nursing, and unit leaders in a large national sample of free-standing nursing homes, with several “Nursing Home Compare” performance indicators. We conducted the survey in 2017 using the Agency for Healthcare Research and Quality Survey on Patient Safety Culture for nursing homes to collect data on 12 core domains of safety culture scores. Survey data were linked to other nursing home files for multivariable regression analyses.

Results:

Overall, 818 of the 2254 sampled nursing homes had at least 1 completed survey returned for a response rate of 36%. After adjustment for nursing home, market, and state covariates, every 10 percentage points increase in overall positive response rate for safety culture was associated with 0.56 fewer health care deficiencies (P=0.001), 0.74 fewer substantiated complaints (P=0.004), reduced fines by $2285.20 (P=0.059), and 20% increased odds of being designated as 4-star or 5-star (vs. 1 to 3 star) facilities (odds ratio roughly=1.20, P<0.05).

Conclusions:

Efforts to improve nursing home performance in patient safety culture have the potential to improve broad safety and quality of care measures encapsulated in the Nursing Home Compare publication.
Evaluation of a Novel Educational Tool in Adolescents With Inflammatory Bowel Disease
Authors: Vaz Karla K.H. , Carmody Julia K. , Zhang Yue , Denson Lee A. , Hommel Kevin A.
Published: June 2019

Objectives:

Among adolescents with inflammatory bowel disease (IBD), nonadherence rates are 50 to 88% across medications. Improving education in adults with IBD has been shown to improve coping and adherence to treatment in adults with IBD. Therapeutic patient education (TPE) has been used in patients with chronic diseases to train patients in skills to support treatment adaptation and condition management. This study tested the feasibility and preliminary efficacy of a novel TPE intervention in adolescents with IBD.

Methods:

In this pilot, mixed‐methods study, we evaluated the feasibility and preliminary efficacy of TPE with the IBD Pocket Guide on medication adherence, IBD knowledge, and transition readiness in adolescents ages 11 to 18 years. Medication adherence was monitored using a MedMinder Pill Dispensing system. Participants who were <90% adherent during a 4‐week pre‐intervention monitoring period were randomized to either a usual care group or an educational intervention (EI) group. Participants were followed for an additional 4 weeks after intervention.

Results:

Trends were found in the EI group indicating improved medication adherence and IBD knowledge compared with the usual care group, though differences between groups did not reach statistical significance. Qualitative data showed that participants perceived that they had improved knowledge after the educational intervention.

Conclusions:

Therapeutic patient education may be beneficial for improving patient medication adherence and IBD knowledge. Future directions include testing the effects of the intervention with a larger sample.
Methotrexate Polyglutamate Values in Children and Adolescents With Acute Lymphoblastic Leukemia During Maintenance Therapy
Authors: Kandikonda Pooja , Bostrom Bruce
Published: June 2019

Inadequate adherence to maintenance therapy is a major cause of relapse in patients with acute lymphoblastic leukemia (ALL). Therapeutic monitoring of mercaptopurine (thiopurine) red cell metabolites to assess adherence has been available for many years. Recently a clinical laboratory improvement amendments of 1988-approved test for methotrexate with three polyglutamate residues (MTXPG3) measured in peripheral blood red cells was approved. MTXPG3 is the primary intracellular metabolite of methotrexate, and like thiopurine metabolites, is retained for the life of the red cell giving an estimate of drug exposure over time. Normative values for MTXPG3 are available for adults and children with rheumatoid arthritis on methotrexate monotherapy, which are not applicable for patients with ALL on maintenance. Older literature on the MTXPG3 fraction in children with ALL is limited. We examined the MTXPG3 levels from 123 samples in 76 patients with ALL on maintenance oral methotrexate and mercaptopurine that were collected for clinical care. Male individuals had significantly higher MTXPG3 levels than female individuals which was unrelated to absolute neutrophil count, age, serum creatinine, and average doses of methotrexate or mercaptopurine. The MTXPG3 5th, 10th, 90th, and 95th percentile values are 0, 8.4, 53, and 64, respectively with a median of 24.7 nmol/L. The low 5th percentile MTXPG3 reflects 6 samples from 3 patients, age 16 to 21 years that were considered poorly adherent before collecting the specimen. As with red cell thiopurine (mercaptopurine) metabolites, MTXPG3 normative values may provide useful information to monitor for poor patient adherence or methotrexate toxicity during maintenance chemotherapy in ALL.
Pediatric Stroke: A Single-Center Experience
Authors: Söbü Elif , Özdemir Nihal , Uysal Serap , Buyru Nur , Celkan Tiraje
Published: June 2019

The aim of this study was to evaluate the clinical characteristics, risk factors, treatment, and outcomes of pediatric stroke cases. A total of 118 patients diagnosed with arterial ischemic stroke (AIS), hemorrhagic stroke, and sinovenous thrombosis (SVT) between January 2000 and December 2011 were included. Neonatal cases were excluded. Demographic and clinical findings were retrospectively examined from medical records. We identified 118 patients with stroke. The age of the patients ranged from 1 to 215 months (17.92 y), with a mean age of 5.19±5.25 years. AIS accounted for the majority of cases (n=69, 58.5%), and the major etiology was cardiac disease (17%). Hemorrhagic stroke accounted for 19.5% (n=23) of the cases, and late hemorrhagic disease of the newborn was the major etiology (43%, n=10). SVT accounted for 22% (n=26) of the cases, and the major etiology was otitis media-mastoiditis (27%, n=7). Hemiplegia and headache were the most frequent symptoms for AIS and SVT, respectively. Stroke is rare in children compared with adults; however, it is detected more frequently with better imaging techniques and increased awareness. We found that children with AIS presented more commonly with hemiplegia and children with SVT with headache and strabismus. We did not find an association between thrombophilia and stroke.
Development and Validation of the Warfarin-Aspirin Bleeding Assessment Tool (WA-BAT) in Children
Authors: Attard Chantal , Huang Joanna , Newall Fiona , Monagle Paul , d’Udekem Yves , Ignjatovic Vera
Published: June 2019

Bleeding assessment tools (BATs) aim to screen and estimate bleeding risk in patients with inherited bleeding disorders. However, the use of BAT as a standardized measure for comparing bleeding in patients on long-term thromboprophylaxis has not yet been validated. We developed a self-administrable BAT to assess bleeding in patients undergoing long-term thromboprophylaxis with aspirin or warfarin. Eligible participants were invited to complete the warfarin-aspirin -BAT (WA-BAT) online. The WA-BAT was readministered a number of weeks later to determine intrarater reliability. The WA-BAT showed substantial intrarater reliability and assesses major and minor bleeding associated with long-term warfarin or aspirin use.
The Management of Pediatric Oncology Inpatients With Oral Mucositis
Authors: Hurrell Lloyd , Burgoyne Laura , Logan Richard , Revesz Tamas , Gue Sam
Published: June 2019

The purpose of the study was to investigate the management of chemotherapy-induced oral mucositis (OM) in pediatric patients. A total of 68 separate episodes of OM were assessed in 47 children who had received chemotherapy. The severity of the child’s OM was assessed using 2 scales, and relevant clinical information was collected. The mean onset time of OM was 8.4 days (±4.0), with a median duration of 7.0 days (4.0, 10.5), with median admission of 7.0 days (4.5, 13.5). The overall adherence to an oral health protocol was 59%, which decreased with more severe OM. A third of patients used chlorhexidine mouthwash only, which was used in preference in cases of severe OM. Almost all patients had some systemic analgesia administered, with a significant increase in patient-controlled analgesia/nurse-controlled analgesia and intravenous ketamine in severe cases. Various types of prophylaxis/treatment of secondary infections and supportive care were associated with the severity of OM. The management of OM in children is important to limit its burden. An oral care protocol was recommended. Chlorhexidine mouthwash can maintain some form of oral care when brushing becomes too uncomfortable in severe OM. Pain management is important for the management of OM, and its intensity increases with increasing severity of OM.
Bone Marrow Failure in Fanconi Anemia: Clinical and Genetic Spectrum in a Cohort of 20 Pediatric Patients
Authors: Kelaidi Charikleia , Makis Alexandros , Petrikkos Loizos , Antoniadi Kondilia , Selenti Nikoletta , Tzotzola Vasiliki , Ioannidou Eleni-Dikaia , Tsitsikas Konstantinos , Kitra Vassiliki , Kalpini-Mavrou Ariadni , Fryssira Helen , Polychronopoulou Sophia
Published: June 2019

Prognostic refinement in Fanconi anemia (FA) is needed, especially when considering allogeneic hematopoietic stem cell transplantation (HCT). We studied 20 children with FA and bone marrow failure from a single center. According to Hôpital Saint-Louis risk classification for FA, patients were classified in stage A (no or mild cytopenia/dysplasia), B (single non–high-risk cytogenetic abnormality), C (severe cytopenia and/or significant dysplasia and/or high-risk cytogenetic abnormality), and D (myelodysplastic syndrome with excess of blasts/acute myeloid leukemia) in 4, 2, 13, and 0 cases, respectively. Nine patients received androgens +/− steroids, with a response rate of 30%, and 11 patients underwent HCT. Ten-year cumulative incidence (CI) of myelodysplastic syndrome/acute myeloid leukemia and overall survival (OS) were 21.9% and 45.3%, respectively, in the entire cohort, whereas cumulative incidence of transplantation-related mortality and OS were 27% and 63%, respectively, in patients who underwent HCT. Patients with significant dysplasia at diagnosis (stages C and D) had significantly shorter OS post-HCT as compared with patients without dysplasia. All patients in stages C and D at diagnosis or during evolution died from their disease. HCT in recent years was associated with more favorable outcomes. Larger cohorts could validate homogenous reporting of risk and help decision-making, particularly for HCT.
Does Depressive-Type Schizophrenia Exist? How Do We Prove It?
Authors: Huang Jianjie , Zhuo Chuanjun , Song Xueqin , Li Yachen , Jing Rixing , Tian Hongjun , Wang Lina , Mao Fuqiang , Li Shen , Jiang Ronghuan , Chen Suling
Published: June 2019

Depressive symptoms can occur at any point in the duration of schizophrenia. However, we are unable to predict if or when depression will occur in schizophrenic patients. Simultaneously, the standard treatment of depression in schizophrenic patients is the combination of antidepressants and antipsychotics, which has been minimally effective for most patients. Based on several studies, we hypothesized the existence of depressive-type schizophrenia and reviewed the substantial evidence supporting the hypothesis of depressive-type schizophrenia. Simultaneously, we propose technical methods to explore the neuropathology of depressive-type schizophrenia in order to identify the disease during its early stages and to predict how patients will respond to the standard treatment strategies. We believe that the new classification of depressive-type schizophrenia will differentiate it from other forms of depression. In return, this will aid in the discovery of new therapeutic strategies for combatting this disease.
Religious Belief at the Level of the Brain
Authors: Gaw Albert C.
Published: June 2019

This article summarizes key functional magnetic resonance imaging studies that correlate the neural substrate of religious belief and the influence of culture. I searched and updated PubMed (http://www.ncbi.nlm.nih.gov/pubmed) publications until March 2018 on religious belief and related topics. Belief, whether religious or nonreligious, is associated with greater signal in the ventromedial prefrontal cortex (vMPFC), a brain region important for self-representation, emotional associations, reward, and goal-driven behavior. However, religious belief, compared with nonreligious belief, registers greater signal in the precuneus, anterior insula, ventral striatum, anterior cingulate cortex, and posterior medial cortex—areas associated with governance of emotion, self-representation, and cognitive conflict. In contrast, nonreligious belief registers more signal in the left hemisphere memory networks (Harris et al. PLoS One 2009;4:e0007272). Moreover, cultural studies revealed self-judgment tasks in nonbelievers involved more the vMPFC, whereas Christians had significantly increased activation in the dorsomedial prefrontal cortex (Han et al. Soc Neurosci 2008;3:1–15). Consequently, the Christian belief of “surrendering to Christ” seemed to weaken neural coding of stimulus self-relatedness but enhanced neural activity underlying evaluative processes of self-referential stimuli. The findings suggest a transformation of the semantic autobiographical self to Christ's conceptual self.
Activation of Hypoxia-Inducible Factor-1α Via Succinate Dehydrogenase Pathway During Acute Lung Injury Induced by Trauma/Hemorrhagic Shock
Authors: Li Mengya , Li Guifeng , Yu Buwei , Luo Yan , Li Qifang
Published: June 2019

Hypoxia-inducible factor (HIF)-1α is a transcription factor that is critical for tissue adaptation to hypoxia and inflammation. Previous studies had indicated that normoxic activation of HIF-1α in cancer involves inhibition or mutation of the metabolic enzyme succinate dehydrogenase (SDH). We have found that local inhibition of HIF-1α ameliorates acute lung injury (ALI) induced by trauma/hemorrhagic shock (T/HS) in rats. In this study, we found pulmonary activation of HIF-1α and inhibition of SDH during THS-induced ALI in rats and transcriptional activation of HIF-1α during ALI induced by T/HS lymph via SDH pathway in vitro. Furthermore, pharmacologic inhibition of HIF-1α attenuates lung inflammation and pulmonary edema during ALI by T/HS. Activation of HIF-1α is detrimental to ALI induced by T/HS. Thus, our data suggest that HIF-1α activation by T/HS is necessary for T/HS-induced lung injury and a critical role for SDH in the initiation of acute inflammatory response after ALI. Nevertheless, this is a preclinical work and several limitations impede translation of the findings to patients, such as uncontrolled bleeding and simultaneous treatment, and prolonged course of clinical shock on the outcome of the work, which needs to be addressed in future.
The Effect of an Intervention to Increase Fruit and Vegetable Intake on Skin Carotenoid Scores
Authors: Chauncey Katherine , DeCanio Brian , Larumbe Eneko , Reed Debra B.
Published: June 2019

Our study aimed to increase consumption of fruits and vegetables (F/V) in a group of healthy adults and to measure skin carotenoid levels. Thirty-three medical students were asked to increase their F/V intake to 4 to 6 cups per day during an 8-week intervention period. Students were given a list of F/V high in antioxidants and a $50 gift card every 2 weeks to purchase the food items. Fruits and vegetables intake and skin carotenoid levels were measured using resonance Raman spectroscopy. All students were successful in increasing F/V intake and skin carotenoid levels. However, students with lower baseline skin carotenoid levels may not be so effective in maintaining higher levels.
Skeletal Muscle Mass Ratio as an Index for Sarcopenia in Patients With Type 2 Diabetes
Authors: Shimizu Ryo , Tando Yusuke , Yokoyama Asami , Yanagimachi Miyuki
Published: June 2019

We aimed to establish an indicator for sarcopenia and glycemic control by comparing 3 muscle indices and investigating nutrients used for treating type 2 diabetes mellitus and sarcopenia. Physical and body composition measurements, biochemical test results, and dietary surveys of 26 type 2 diabetes mellitus patients were performed in 2015 and after 1 year. Grip strength values were measured. Skeletal muscle mass ratio positively correlated with grip strength in obese women. Skeletal muscle mass ratio correlated with glycated hemoglobin (HbA1c), animal protein, and vitamin D intake levels. Skeletal muscle mass ratio may be a useful index of type 2 diabetes mellitus treatment in sarcopenic obese patients.
The Measurement of Donor-Specific Cell-Free DNA Identifies Recipients With Biopsy-Proven Acute Rejection Requiring Treatment After Liver Transplantation
Authors: Goh Su Kah , Do Hongdo , Testro Adam , Pavlovic Julie , Vago Angela , Lokan Julie , Jones Robert M. , Christophi Christopher , Dobrovic Alexander , Muralidharan Vijayaragavan
Published: June 2019

Background.

Assessment of donor-specific cell-free DNA (dscfDNA) in the recipient is emerging as a noninvasive biomarker of organ rejection after transplantation. We previously developed a digital polymerase chain reaction (PCR)-based approach that readily measures dscfDNA within clinically relevant turnaround times. Using this approach, we characterized the dynamics and evaluated the clinical utility of dscfDNA after liver transplantation (LT).

Methods.

Deletion/insertion polymorphisms were used to distinguish donor-specific DNA from recipient-specific DNA. Posttransplant dscfDNA was measured in the plasma of the recipients. In the longitudinal cohort, dscfDNA was serially measured at days 3, 7, 14, 28, and 42 in 20 recipients. In the cross-sectional cohort, dscfDNA was measured in 4 clinically stable recipients (>1-y posttransplant) and 16 recipients (>1-mo posttransplant) who were undergoing liver biopsies.

Results.

Recipients who underwent LT without complications demonstrated an exponential decline in dscfDNA. Median levels at days 3, 7, 14, 28, and 42 were 1936, 1015, 247, 90, and 66 copies/mL, respectively. dscfDNA was higher in recipients with treated biopsy-proven acute rejection (tBPAR) when compared to those without. The area under the receiver operator characteristic curve of dscfDNA was higher than that of routine liver function tests for tBPAR (dscfDNA: 98.8% with 95% confidence interval, 95.8%-100%; alanine aminotransferase: 85.7%; alkaline phosphatase: 66.4%; gamma-glutamyl transferase: 80.1%; and bilirubin: 35.4%).

Conclusions.

dscfDNA as measured by probe-free droplet digital PCR methodology was reflective of organ health after LT. Our findings demonstrate the potential utility of dscfDNA as a diagnostic tool of tBPAR.
Complement Markers in Blood and Urine: No Diagnostic Value in Late Silent Antibody-Mediated Rejection
Authors: Mező Blanka , Heilos Andreas , Böhmig Georg A. , Eskandary Farsad , Wahrmann Markus , Bond Gregor , Kozakowski Nicolas , Halloran Philip F. , Rusai Krisztina , Prohászka Zoltán
Published: June 2019

Background.

Antibody-mediated rejection (AMR) is a major cause of kidney allograft failure. Its molecular mechanisms are multifaceted and may include a role of complement activation via the classical pathway. Here, we investigated whether noninvasive complement monitoring adds predictive power to the diagnosis of AMR in the setting of donor-specific antibody (DSA) positivity.

Methods.

In this cross-sectional study, 741 kidney transplant recipients with stable graft function ≥180 days posttransplantation were screened for the presence of human leukocyte antigen (HLA) alloantibodies. Eighty-three of 111 DSA-positive recipients underwent protocol biopsies and were tested for blood and urinary levels of complement proteins (C1q, C4, C3) and activation products (C4d, C3a, C5a, C5b-9).

Results.

Forty-seven recipients were diagnosed with AMR, and 21 were C4d-positive. While biopsy-confirmed AMR (and C4d) associated with DSA-binding strength (IgG mean fluorescence intensity of the immunodominant DSA versus AMR; area under the receiver operating characteristic curve: 0.76), tested complement markers did not have any predictive value for rejection (area under the receiver operating characteristic curve: 0.49–0.56). There were, however, tight correlations between complement activation products in urine and protein/creatinine ratio (ρ = 0.44–0.64; P < 0.001). Analysis of death-censored graft survival over a median of 60 months revealed no independent associations with levels of complement markers in blood or urine.

Conclusions.

Complement patterns in blood and urine failed to identify AMR in late biopsies and may have no relevant diagnostic value in this particular context.
Insights into human genetic variation and population history from 929 diverse genomes
Authors: Bergström Anders , McCarthy Shane A. , Hui Ruoyun , Almarri Mohamed A. , Ayub Qasim , Danecek Petr , Chen Yuan , Felkel Sabine , Hallast Pille , Kamm Jack , Blanché Hélène , Deleuze Jean-François , Cann Howard , Mallick Swapan , Reich David , Sandhu Manjinder S. , Skoglund Pontus , Scally Aylwyn , Xue Yali , Durbin Richard , Tyler-Smith Chris
Published: June 2019

Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented private genetic variation in southern and central Africa and in Oceania and the Americas, but an absence of fixed, private variants between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the last 10,000 years, a potentially major population growth episode after the peopling of the Americas, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations. We also demonstrate benefits to the study of population relationships of genome sequences over ascertained array genotypes. These genome sequences are freely available as a resource with no access or analysis restrictions.
Laws of diversity and variation in microbial communities
Authors: Grilli Jacopo
Published: June 2019

How coexistence of many species is maintained is a fundamental and unanswered question in ecology. Coexistence is a puzzle because we lack a quantitative understanding of the variation in species presence and abundance. Whether variation in ecological communities is driven by deterministic or random processes is one of the most controversial issues in ecology. Here, we study the variation of species presence and abundance in microbial communities from a macroecological standpoint. We identify three novel, fundamental, and universal macroecological laws that characterize the fluctuation of species abundance across communities and over time. These three laws — in addition to predicting the presence and absence of species, diversity and other commonly studied macroecological patterns — allow to test mechanistic models and general theories aiming at describing the fundamental processes shaping microbial community composition and dynamics. We show that a mathematical model based on environmental stochasticity quantitatively predicts the three macroecological laws, as well as non-stationary properties of community dynamics.
Cue-reactivity and approach bias to social alcohol cues and their association with drinking in a social setting in young adults
Authors: Groefsema Martine M. , Mies Gabry W. , Cousijn Janna , Engels Rutger C.M.E. , Sescousse Guillaume , Luijten Maartje
Published: June 2019

Alcohol is mainly consumed in social settings, in which people often adapt their drinking behavior to that of others, also called imitation of drinking. Yet, it remains unclear what drives this drinking in a social setting. In this study, we expected to see stronger brain and behavioral responses to social compared to non-social alcohol cues, that would be associated with actual drinking in a social setting. The sample consisted of 153 beer-drinking males, aged 18-25 years. Brain responses to social alcohol cues were measured during an alcohol cue exposure task in the scanner. Behavioral responses to social alcohol cues were measured using a stimulus-response compatibility task, providing an index of approach bias towards these cues. Drinking in a social setting was measured in a Bar-Lab setting. Specific brain responses to social alcohol cues were observed in the bilateral superior temporal sulcus and the left inferior parietal lobe. There was no approach bias towards social alcohol cues specifically, however, we did find an approach bias towards alcohol (versus soda) cues in general. Brain responses and approach bias towards social alcohol cues were unrelated and not associated with drinking, measured in the Bar-Lab. Thus, we found no support for a relation between drinking in a social setting on the one hand, and brain cue-reactivity or behavioral approach biases to social alcohol cues on the other hand. This suggests that, in contrast to our hypothesis, drinking in a social setting may not be driven by brain or behavioral responses to social alcohol cues.
Reflexive gaze following in common marmoset monkeys
Authors: Spadacenta Silvia , Dicke Peter W. , Thier Peter
Published: June 2019

The ability to extract the direction of the other’s gaze allows us to shift our attention to an object of interest to the other and to establish joint attention. By mapping one’s own expectations, desires and intentions on the object of joint attention, humans develop a Theory of (the other’s) Mind (TOM), a functional sequence possibly disrupted in autism. Although old world monkeys probably do not possess a TOM, they follow the other’s gaze and they establish joint attention. Gaze following of both humans and old world monkeys fulfills Fodor’s criteria of a domain specific function and is orchestrated by very similar cortical architectures, strongly suggesting homology. Also new world monkeys, a primate suborder that split from the old world monkey line about 35 million years ago, have complex social structures. One member of this group, the common marmoset (Callithrix jacchus), has received increasing interest as a potential model in studies of normal and disturbed human social cognition. Marmosets are known to follow human head-gaze. However, the question is if they use gaze following to establish joint attention with conspecifics. Here we show that this is indeed the case. In a free choice task, head-restrained marmosets prefer objects gazed at by a conspecific and, moreover, they exhibit considerably shorter choice reaction times for the same objects. These findings support the assumption of an evolutionary old domain specific faculty shared within the primate order and they underline the potential value of marmosets in studies of normal and disturbed joint attention.

HIGHLIGHTS

Common marmosets follow the head gaze of conspecifics in order to establish joint attention.

Brief exposures to head gaze are sufficient to reallocate an animal’s attention.

The tendency to follow the other’s gaze competes with the attractional binding of the conspecific’s face
Prism adaptation modulates connectivity of the intraparietal sulcus with multiple brain networks
Authors: Schintu Selene , Freedberg Michael , Gotts Stephen J. , Cunningham Catherine A. , Alam Zaynah M. , Shomstein Sarah , Wassermann Eric M.
Published: June 2019

Prism adaptation (PA) alters spatial cognition according to the direction of visual displacement by temporarily modifying sensorimotor mapping. Right-shifting prisms (right PA) improve neglect of left space in patients, possibly by decreasing activity in the left hemisphere and increasing it in the right. Left PA shifts attention to the right in healthy individuals by an opposite mechanism. However, functional imaging studies of PA are inconsistent, perhaps because of differing activation tasks. We measured resting-state functional connectivity (RSFC) in healthy individuals before and after PA. Right, vs. left, PA decreased RSFC in the navigation network defined by the right posterior parietal cortices (PPCs), hippocampus, and cerebellum. Right PA, relative to baseline, increased RSFC between regions within both PPCs and between the PPCs and the right middle frontal gyrus, whereas left PA decreased RSFC between these regions. These results show that right PA modulates connectivity within the right-hemisphere navigation network and shifts attention leftward by increasing connectivity in the right frontoparietal network and left PA produces essentially opposite effects, consistent with the interhemispheric competition model. These finding explain the action of PA on intact cognition and will help optimize interventions in neglect patients.
Two pathways for thiosulfate oxidation in the alphaproteobacterial chemolithotrophParacoccus thiocyanatusSST
Authors: Rameez Moidu Jameela , Pyne Prosenjit , Mandal Subhrangshu , Chatterjee Sumit , Alam Masrure , Bhattacharya Sabyasachi , Mondal Nibendu , Sarkar Jagannath , Ghosh Wriddhiman
Published: June 2019

Chemolithotrophic bacteria oxidize various sulfur species for energy and electrons, thereby operationalizing biogeochemical sulfur cycles in nature. The best-studied pathway of bacterial sulfur-chemolithotrophy, involving direct oxidation of thiosulfate to sulfate (without any free intermediate) by the SoxXAYZBCD multienzyme system, is apparently the exclusive mechanism of thiosulfate oxidation in facultatively chemolithotrophic alphaproteobacteria. Here we explore the molecular mechanisms of sulfur oxidation in the thiosulfate- and tetrathionate-oxidizing alphaproteobacteriumParacoccus thiocyanatusSST, and compare them with the prototypical Sox process characterized inParacoccus pantotrophus. Our results revealed the unique case where, an alphaproteobacterium has Sox as its secondary pathway of thiosulfate oxidation, converting ∼10% of the thiosulfate supplied whilst 90% of the substrate is oxidized via a Tetrathionate-Intermediate pathway. Knock-out mutation, followed by the study of sulfur oxidation kinetics, showed that thiosulfate-to-tetrathionate conversion, in SST, is catalyzed by a thiosulfate dehydrogenase (TsdA) homolog that has far-higher substrate-affinity than the Sox system of this bacterium, which, remarkably, is also less efficient than theP. pantotrophusSox.soxB-deletion in SST abolished sulfate-formation from thiosulfate/tetrathionate while thiosulfate-to-tetrathionate conversion remained unperturbed. Physiological studies revealed the involvement of glutathione in SST tetrathionate oxidation. However, zero impact of the knock-out of a thiol dehydrotransferase (thdT) homolog, together with no production of sulfite as an intermediate, indicated that tetrathionate oxidation in SST is mechanistically novel, and distinct from its betaproteobacterial counterpart mediated by glutathione, ThdT, SoxBCD and sulfite:acceptor oxidoreductase. All the present findings collectively highlight extensive functional diversification of sulfur-oxidizing enzymes across phylogenetically close, as well as distant, bacteria.
Actomyosin regulation by Eph receptor signaling couples boundary cell formation to border sharpness
Authors: Cayuso Jordi , Xu Qiling , Addison Megan , Wilkinson David G.
Published: June 2019

The segregation of cells with distinct regional identity underlies formation of a sharp border, which in some tissues serves to organise a boundary signaling centre. It is unclear whether or how border sharpness is coordinated with induction of boundary-specific gene expression. We show that forward signaling of EphA4 is required for border sharpening and induction of boundary cells in the zebrafish hindbrain, which we find both require kinase-dependent signaling, with a lesser input of PDZ domain-dependent signaling. We find that boundary-specific gene expression is regulated by myosin II phosphorylation, which increases actomyosin contraction downstream of EphA4 signaling. Myosin phosphorylation leads to nuclear translocation of Taz, which together with Tead1a is required for boundary marker expression. Since actomyosin contraction maintains sharp borders, there is direct coupling of border sharpness to boundary cell induction that ensures correct organisation of signaling centres.
Using a barcoded AAV capsid library to select for novel clinically relevant gene therapy vectors
Authors: Pekrun Katja , De Alencastro Gustavo , Luo Qing-Jun , Liu Jun , Kim Youngjin , Nygaard Sean , Galivo Feorillo , Zhang Feijie , Song Ren , Tiffany Matthew R. , Xu Jianpeng , Hebrok Matthias , Grompe Markus , Kay Mark A.
Published: June 2019

While gene transfer using recombinant adeno-associated viral (rAAV) vectors have shown success in some clinical trials, there remain many tissues that are not well transduced. Because of the recent success in reprogramming islet derived cells into functional β-cells in animal models, we constructed two highly complex barcoded replication competent capsid shuffled libraries and selected for high transducing variants on primary human islets. We describe a chimeric capsid (AAV-KP1) that penetrated and transduced primary human islet cells and human embryonic stem cell derived β-cells with up to 10-fold higher efficiency compared to previously studied best in class AAV vectors. Remarkably, this chimeric capsid was also able to transduce both mouse and human hepatocytes at very high levels in a humanized-chimeric mouse model, thus providing a versatile vector which has the potential to be used in both preclinical testing and human clinical trials for both liver-based diseases and diabetes.
Restoring ancestral phenotypes by reduction of plasticity is a general pattern in gene expression during adaptation to different stressors in Tribolium castaneum
Authors: Koch Eva L. , Guillaume Frédéric
Published: June 2019

Plasticity and evolution are two processes individuals to respond to environmental change, but how both are related and impact each other is still controversial. We studied plastic and evolutionary responses in gene expression of Tribolium castaneum after exposure to new environments that differed from ancestral conditions in temperature, humidity or both. Using experimental evolution with ten replicated lines per condition, we were able to demonstrate adaptation after 20 generations. We measured gene expression in each condition in adapted selection lines and control lines to infer evolutionary and plastic changes. We found more evidence for changes in mean expression (shift in the intercept of reaction norms) in adapted lines than for changes in plasticity (shifts in slopes). Plasticity was mainly preserved and was responsible for a large part of the phenotypic divergence in expression between ancestral and new conditions. However, we found that genes with the largest evolutionary changes in expression also evolved reduced plasticity and often showed expression levels closer to the ancestral stage. Results obtained in the three different conditions were similar suggesting that restoration of ancestral expression levels during adaptation is a general evolutionary pattern. We increased the sample size in the most stressful condition and were then able to detect a positive correlation between proportion of genes with reversion of the ancestral plastic response and mean fitness per selection line.
Exogenous Protein as an Environmental Stimuli of Biofilm Formation in Select Bacterial Strains
Authors: Ye Donna , Bapu Lekha , Cavalcante Mariane Mota , Kato Jesse , Sneideman Maggie Lauria , Scribner Kim , Loch Thomas , Marsh Terence L.
Published: June 2019

A screening of environmental conditions that would elicit robust biofilm in a collection ofSerratia marcescensisolated from soil revealed that exogenous milk protein increased biofilm productivity up to ten-fold. A select screening of fish pathogens, freshwater and human isolates identified several other species that responded similarly to exogenous protein. The optimal protein concentration was species specific;S. marcescensat 5% milk protein,Aeromonassp. at 2-3%,Flavobacterium columnareat 1% andPseudomonas aeruginosaat 0.1-0.4%. Media supplemented with milk protein also increased the cell counts in biofilm as well as the protein incorporated into the biofilm matrix. These data suggest that relatively high concentrations of exogenous protein may serve as an environmental trigger for biofilm formation, particularly for pathogenic bacteria exposed to relatively high concentrations of protein in bodily fluids and mucosal surfaces.
FMRFGene Expression in the Nervous System of the SquidDoryteuthis Pealei* Hatchling
Authors: Burbach J. Peter H. , Grant Philip , Senft Stephen , Kripke Lizzie , Hellemons Anita J.C.G.M. , Pant Harish C.
Published: June 2019

FMRFamide is a neuropeptide that is widely distributed in invertebrates and known to be involved in many physiological functions. Previously we noted marked differences in expression of thefmrfgene in the stellate ganglion ofDoryteuthis pealei*compared to the central nervous system. In this study we aimed to examen the brain systems ofDoryteuthis pealei*for the presence and distribution offmrf-expressing cells and fiber networks. Late squid embryos and hatchlings were examined by in situ hybridization and immunohistochemistry in whole mounts and tissue sections. All central lobes contained limited numbers of scattered neurons expressingfmrf, but the FMRFamide-containing fiber systems were abundant and extensive, mostly present in the neuropil of lobes. Main clusters of neurons were located in the magnocellular and chromatophore lobes of the posterior subesophageal mass (PSM), and in dorsal aspects of the basal lobe (BL). Dense FMRFamide-immunoreactive fibers were particularly seen in the optic lobe (OL), medial and posterior supraesophageal masses (MSM and SPM) often with a commissural organization. The data show that the central lobes ofDoryteuthis pealeihatchlings have a matured FMRFamide system organized in a limited number of centers, but with widely distributed efferents. This suggests that FMRFamide neurons are already functionally engaged in the late embryo. The localization indicates that control of chromatophores and fin movement are amongst these functions.
The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8+T cell activity and synergizes with immune check-point inhibitors
Authors: Puca Emanuele , Probst Philipp , Stringhini Marco , Murer Patrizia , Pellegrini Giovanni , Cazzamalli Samuele , Hutmacher Cornelia , Gouyou Baptiste , Wulhfard Sarah , Matasci Mattia , Villa Alessandra , Neri Dario
Published: June 2019

We describe the cloning and characterization of a novel fusion protein (termed L19-mIL12), consisting of murine interleukin-12 in single-chain format, sequentially fused to the L19 anti-body in tandem diabody format. The fusion protein bound avidly to the cognate antigen (the alternatively-spliced EDB domain of fibronectin), retained the activity of the parental cyto-kine and was able to selectively localize to murine tumorsin vivo, as shown by quantitative biodistribution analysis. L19-mIL12 exhibited a potent anti-tumor activity in immunocompetent mice bearing CT26 carcinomas and WEHI-164 sarcomas, which could be boosted by combination with check-point blockade, leading to durable cancer eradication. L19-mIL12 also inhibited tumor growth in mice with Lewis lung carcinoma (LLC), but in this case cancer cures could not be obtained, both in monotherapy and in combination. A microscopic analysis and a depletion experiment of tumor-infiltrating leukocytes illustrated the contribution of NK cells and CD8+T cells for the anti-cancer activity observed in both tumor models. Upon L19-mIL12 treatment, the density of regulatory T cells (Tregs) was strongly increased in LLC, but not in CT26 tumors. A FACS analysis also revealed that the majority of CD8+T cells in CT26 tumors were specific to the retroviral AH1 antigen.

NOVELTY AND IMPACT STATEMENT

In this study, we describe the generation of a novel fusion protein consisting of murine inter-leukin-12 fused to the L19 antibody (specific to the EDB domain of fibronectin). L19-mIL12 revealed favourable tumor to organ ratios 24h after intravenous administration and it was able to cure 60% of CT26 tumor-bearing mice. From a clinical perspective, the rapid clearance from circulation should ease the administration to patients as infusions could be stopped upon onset of side-effects.
Endocytosis of very low-density lipoprotein particles: an unexpected mechanism for lipid acquisition by breast cancer cells
Authors: Lupien Leslie E. , Bloch Katarzyna , Dehairs Jonas , Feng William W. , Davis Wilson L. , Dennis Thea , Swinnen Johannes V. , Wells Wendy A. , Smits Nicole C. , Kuemmerle Nancy B. , Kinlaw William B.
Published: June 2019

We previously described the expression of CD36 and lipoprotein lipase (LPL) by breast cancer (BC) cells and tissues, and the growth-promoting effect of very low-density lipoprotein (VLDL) supplementation observed in BC cell lines only in the presence of LPL. We now describe the deployment of LPL by BC cells. Our data support a model in which LPL is bound to a heparin-like heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to rapidly internalize intact lipoproteins via receptor-mediated endocytosis. We further observe substantial alterations in gene expression programs related to pathways for lipid acquisition (synthesis vs. uptake) in response to each the availability of exogenous triglyceride in tissue culture media and LPL expression status. Current literature emphasizesde novofatty acid synthesis as the paramount mechanism for lipid acquisition by cancer cells. Our findings indicate that exogenous lipid uptake can serve as an important method of lipid acquisition for cancer cells, alongsidede novolipogenesis, and that the relative reliance on these two modes of lipid acquisition may vary among different BC cell lines and in response to nutrient availability. This concept has obvious implications for the development of therapies aimed at the lipid dependence of many different cancer types. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology.
Telomere length and oxidative stress variations in a murine model of Alzheimer’s disease progression
Authors: Martínez-González Katia , Islas-Hernández Azul , Martínez-Ezquerro José Darío , Bermúdez-Rattoni Federico , Garcia-delaTorre Paola
Published: June 2019

Alzheimer’s Disease (AD) is the most common cause of dementia and aging is its major risk factor. Changes in telomere length have been associated with aging and some degenerative diseases. Our aim was to explore some of the molecular changes caused by the progression of AD in a transgenic murine model (3xTg-AD; B6; 129-Psen1  Tg (APPSwe, tauP301L) 1Lfa). Telomere length was assessed by qPCR in both brain tissue and peripheral blood cells and compared between three age groups: 5, 9, and 13 months. In addition, a possible effect of oxidative stress on telomere length and AD progression was explored. Shorter telomeres were found in blood cells of older transgenic mice compared to younger and wild type mice but no changes in telomere length in the hippocampus. An increase in oxidative stress with age was found for all strains but no correlation was found between oxidative stress and shorter telomere length for transgenic mice. Telomere length and oxidative stress are affected by AD progression in the 3xTg-AD murine model. Changes in blood cells are more noticeable than changes in brain tissue, suggesting that systemic changes can be detected early in the disease in this murine model.
Evaluating species distribution models with discrimination accuracy is uninformative for many applications
Authors: Warren Dan L. , Matzke Nicholas J. , Iglesias Teresa L.
Published: June 2019

Aim

Species distribution models are used across evolution, ecology, conservation, and epidemiology to make critical decisions and study biological phenomena, often in cases where experimental approaches are intractable. Choices regarding optimal models, methods, and data are typically made based on discrimination accuracy: a model’s ability to predict subsets of species occurrence data that were withheld during model construction. However, empirical applications of these models often involve making biological inferences based on continuous estimates of relative habitat suitability as a function of environmental predictor variables. We term the reliability of these biological inferences “functional accuracy.” We explore the link between discrimination accuracy and functional accuracy.

Methods

Using a simulation approach we investigate whether models that make good predictions of species distributions correctly infer the underlying relationship between environmental predictors and the suitability of habitat.

Results

We demonstrate that discrimination accuracy is only informative when models are simple and similar in structure to the true niche, or when data partitioning is geographically structured. However, the utility of discrimination accuracy for selecting models with high functional accuracy was low in all cases.

Main conclusions

These results suggest that many empirical studies and decisions are based on criteria that are unrelated to models’ usefulness for their intended purpose. We argue that empirical modeling studies need to place significantly more emphasis on biological insight into the plausibility of models, and that the current approach of maximizing discrimination accuracy at the expense of other considerations is detrimental to both the empirical and methodological literature in this active field. Finally, we argue that future development of the field must include an increased emphasis on simulation; methodological studies based on ability to predict withheld occurrence data may be largely uninformative about best practices for applications where interpretation of models relies on estimating ecological processes, and will unduly penalize more biologically informative modeling approaches.
A molecularly defined insular cortex --> central amygdala circuit mediates conditioned overconsumption of food
Authors: Stern S.A. , Pomeranz L.E. , Azevedo E.P. , Doerig K.R. , Friedman J.M.
Published: June 2019

Feeding is a complex motivated behavior that is controlled not just by metabolic and homeostatic factors, but also by environmental factors such as emotion and the hedonic nature of the food itself. Yet, little is known about how brain regions involved in cognition and emotion might contribute to overeating, and therefore, obesity. We used a recently developed behavioral task in which learned contextual cues induce feeding even in sated mice to investigate the underlying neural mechanisms. Using viral tracing, molecular profiling and chemo/optogenetic techniques, we discovered that an insular cortex projection to the central amygdala is required for conditioned overconsumption but not homeostatic feeding. The projection neurons express nitric oxide synthase-1 and activation of this population suppresses satiety signals in the central amygdala. The data thus indicate that the insular cortex provides top down control of homeostatic circuits to promote overconsumption in response to learned cues.

One Sentence Summary

Nitric oxide synthase-1 neurons in the insular cortex promote overconsumption by projecting to the central amygdala to suppress a homeostatic satiety signal.