bluuebunny/crossref_metadata_2025 huggingface dataset:
Gait characteristics of post-stroke hemiparetic patients with different walking speeds
Authors: Wang Yiji , Mukaino Masahiko , Ohtsuka Kei , Otaka Yohei , Tanikawa Hiroki , Matsuda Fumihiro , Tsuchiyama Kazuhiro , Yamada Junya , Saitoh Eiichi
Published: December 2019

Hemiparesis resulting from stroke presents characteristic spatiotemporal gait patterns. This study aimed to clarify the spatiotemporal gait characteristics of hemiparetic patients by comparing them with height-, speed-, and age-matched controls while walking at various speeds. The data on spatiotemporal gait parameters of stroke patients and that of matched controls were extracted from a hospital gait analysis database. In total, 130 pairs of data were selected for analysis. Patients and controls were compared for spatiotemporal gait parameters and the raw value (RSI) and absolute value (ASI) of symmetry index and coefficient of variation (CV) of these parameters. Stroke patients presented with prolonged nonparetic stance (patients vs. controls: 1.01 ± 0.41 vs. 0.83 ± 0.25) and paretic swing time (0.45 ± 0.12 vs. 0.39 ± 0.07), shortened nonparetic swing phase (0.35 ± 0.07 vs. 0.39 ± 0.07), and prolonged paretic and nonparetic double stance phases [0.27 ± 0.13 (paretic)/0.27 ± 0.17 (nonparetic) vs. 0.22 ± 0.10]. These changes are especially seen in low-gait speed groups (<3.4 km/h). High RSIs of stance and swing times were also observed (–9.62 ± 10.32 vs. –0.79 ± 2.93, 24.24 ± 25.75 vs. 1.76 ± 6.43, respectively). High ASIs and CVs were more generally observed, including the groups with gait speed of ≥3.5 km/h. ASI increase of the swing phase (25.79 ± 22.69 vs. 4.83 ± 4.88) and CV of the step length [7.7 ± 4.9 (paretic)/7.6 ± 5.0 (nonparetic) vs. 5.3 ± 3.0] were observed in all gait speed groups. Our data suggest that abnormalities in the spatiotemporal parameters of hemiparetic gait should be interpreted in relation to gait speed. ASIs and CVs could be highly sensitive indices for detecting gait abnormalities.
On the Continuity Between Autistic and Schizoid Personality Disorder Trait Burden
Authors: Cook Michal Lauren , Zhang Yi , Constantino John N.
Published: December 2019

Although widely conceived as distinct conditions, higher-functioning autism spectrum disorder (ASD) and schizoid personality disorder (schizoid PD) share similar clinical symptomatology. This study explored the relationship between the two disorders by collecting extensively validated measures of autistic trait burden (Social Responsive Scale, Second Edition) and schizoid PD affectation (Diagnostic Interview for Genetic Studies) from clinically ascertained verbal males with and without autism ages 12 to 25 years (N = 72) via parent, teacher, and self-report. Although only a small minority of adolescents with ASD met full diagnostic criteria for schizoid PD, participants with ASD endorsed a continuous distribution of schizoid PD traits that reflected a pronounced pathological shift in comparison with those in the control group, with one half of ASD males experiencing three or more Diagnostic and Statistical Manual of Mental Disorders, 4th Edition schizoid PD criterion items “often” or “almost always.” Results suggest significant amplification of schizoid PD trait burden in adolescents with ASD. ASD-specific interventions should be considered for patients with schizoid PD with premorbid histories of ASD.
Strategies to Teach the National Council of State Boards of Nursing Clinical Judgment Model
Authors: Hensel Desirée , Billings Diane M.
Published: December 2019

BACKGROUND

There is a growing concern that novice nurses who achieve licensure do not have the clinical judgment to practice safely. The National Council of State Boards of Nursing (NCSBN) began the Next Generation NCLEX (NGN) project to find methods to better assess entry-level competency. The NGN project is based on an integrative clinical judgment model (CJM) with 6 well-defined cognitive steps.

PROBLEM

Teaching and assessing clinical judgment skills using the NCSBN-CJM will take faculty planning and commitment.

APPROACH

Clinical scenarios can be used to teach clinical judgment. Using prompts, instructors can deliberately lead students through the steps of recognizing cues, analyzing cues, prioritizing hypothesis, generating solutions, taking action, and evaluating outcomes.

CONCLUSION

Committing to integrating a CJM throughout the curriculum, using realistic clinical scenarios, and having students work through all the steps of a selected model are important ways educators can help students prepare for safe clinical practice.
Development of a Medication Safety Science Curriculum for Nursing Students
Authors: Davis Melissa , Coviello Jessica
Published: December 2019

BACKGROUND

Medication errors, now thought to be 4 times greater than previous estimates, harm patients, families, health care institutions, and nurses themselves, who are second victims of their mistakes.

PROBLEM

Current nursing education may lack coherent medication safety frameworks other than the classic Five Rights construct.

APPROACH

This project piloted an educational intervention with senior associate degree nursing students based on high-reliability organization (HRO) safety principles.

OUTCOMES

Subjects evaluated the HRO safety concepts learning experience positively and improved pretest to posttest scores by 74%.

CONCLUSIONS

This study demonstrates subjects' ready acceptance and comprehension of HRO safety theory as applied to medication safety, an alternative to the Five Rights construct.
KRAS-mutated Uterine Endometrioid Carcinoma With Extensive Surface Changes Resulting in Striking Morphologic Mimicry of an Ovarian Serous Borderline Tumor
Authors: Kir Gozde , Olgun Zeynep C. , Gunel Humeyra , Ozen Filiz , McCluggage W. Glenn
Published: December 2019

Surface epithelial changes involving endometrioid carcinomas of the uterine corpus mimicking papillary syncytial metaplasia or cervical microglandular hyperplasia are relatively common. There have been rare reports of surface epithelial changes in endometrioid carcinomas mimicking ovarian serous borderline tumor or low-grade serous carcinoma. We report an endometrioid carcinoma of the uterine corpus with striking morphologic mimicking of an ovarian serous borderline tumor with only a minimal amount of conventional endometrioid carcinoma. The tumor was diffusely positive for estrogen receptor, negative for WT1, and showed wild-type immunoreactivity with p53. Targeted sequencing revealed a KRAS mutation (G12V/D/A), but no BRAF mutation. This close mimicry of a serous borderline tumor by a uterine endometrioid carcinoma has not been emphasized in the literature and this case is unique because the features involved almost the entire neoplasm. In reporting this case, we review surface changes in endometrioid carcinomas of the uterine corpus.
Posttraumatic Augmentation Rhinoplasty Using an Osseocartilaginous Cantilever Graft
Authors: Park Seong Hyuk , Kang Byungkwon , Chung Jee H. , Eun Seokchan
Published: December 2019

Background

Augmentation rhinoplasty in Asians may be effectively accomplished with alloplastic materials. However, certain circumstances such as nasal bone fractures mandate the use of autologous grafts. The purpose of this study was to describe and evaluate the results of modified osseocartilaginous rib cantilever grafting for aesthetic and reconstructive rhinoplasty in patients with acute nasal bone fractures.

Methods

Forty-three patients with nasal bone fracture underwent surgical reconstruction with an autogenous rib graft. Anatomic reconstruction and dorsal augmentation were performed using 1 piece of a carved osseocartilaginous rib graft each for the bony and cartilaginous parts of the nose. The average time to surgery was 6.5 days, and patient's subjective satisfaction was scored.

Results

“Excellent” or “good” cosmetic outcomes were reported by 37 patients (86%). There were 3 cases of secondary revision. Donor-site morbidity was not an issue in any patient.

Conclusions

Anatomic reconstruction of the nasal dorsum and refining the nasal tip using an osseocartilaginous rib graft with the cantilever technique are effective in acute nasal trauma patients who wish to enhance their nasal profile in the primary treatment setting.
Strategy for Optimizing Airway Volume With Genioglossal Advancement Using Cutting Guide in the Treatment of Obstructive Sleep Apnea
Authors: Hadad Henrique , Mendes Bruno Coelho , Lima Valthierre Nunes de , Ferraz Flávio Wellington da Silva , Souza Francisley Ávila , Magro Filho Osvaldo
Published: December 2019

The genioglossus advancement muscle is a technique used to treat obstructive sleep apnea and depends on the precise location of the muscle insertion into the geniotubercle. The aim of this article was to present a case report about a 38-year-old male patient with obstructive sleep apnea even after undergoing uvulopalatopharyngoplasty and mentoplasty. A maxillo-mandibular advancement and genioglossus was proposed, for this a virtual planning of the surgical guide was done using a specialized software. The great advantage is to reduce the osteotomy by focusing precisely on the insertion of the muscle. The cutting guide facilitated the surgical procedure in all aspects and brought safety.
Classification of Obviously Asymmetric Palpebral Fissures and Correction Based on Double Eyelid Surgery of the Primary Type
Authors: Zhao Feng , Yang Xiaoliang , Li Weifeng , Shi Yunxia
Published: December 2019

Bilateral palpebral fissures (PF) are rarely symmetrical. Palpebral plastic surgery is common in the Chinese population. This study aimed to assess the classification of obviously asymmetric palpebral fissures (OAPF). In addition, double eyelid surgery-based correction for the primary subtype was examined. Various clinical signs and etiologies were examined, and OAPF were classified into 3 subtypes: primary, secondary, and aging. For the secondary and aging subtypes, curative surgeries target the relevant underlying conditions. Patients with the primary subtype underwent corrective surgery based on double eyelid operation. After 8 to 12 months of follow-up, the corrective effects of different surgeries were evaluated in patients (n = 48) with primary OAPF. Satisfying look was obtained in all 48 cases, with smooth double eyelid lines and shapes, and no overt asymmetry between the 2 eyes. Thirteen patients developed hypophasis after levator plication, which was resolved within 1 month. Preoperative and postoperative PF were significantly different (1.48 ± 0.24 versus 0.19 ± 0.09 mm; P < 0.05). Overall, patients with OAPF can be classified into the primary, secondary, and aging subtypes. The 48 cases with the primary subtype showed a satisfying look after double eyelid surgery-based correction.
Efficacy of Hand and Foot Massage in Anxiety and Pain Management Following Laparoscopic Cholecystectomy: A Controlled Randomized Study
Authors: Sözen Kezban Koraş , Karabulut Neziha
Published: December 2019

This study was planned and performed to evaluate the effect of foot and hand massage on pain and anxiety management, which is one of the nonpharmacological pain relief methods in patients who undergo laparoscopic cholecystectomy. The present study was designed and conducted in the randomized controlled manner to determine the impacts of foot and hand massage on postoperative pain and anxiety scores of patients who receive laparoscopic cholecystectomy. The universe of the study consisted of the patients who received laparoscopic cholecystectomy between April 2018 and January 2019. The study was completed with 196 patients as 63 patients in the foot massage group, 65 patients in the hand massage group, and 68 patients in the control group. To collect the data, the “Descriptive Characteristics Form,” “Visual Analog Scale,” and “State-Trait Anxiety Inventory” were used. The pain intensity of patients in the foot massage group and hand massage group were less than in the control group at 90 and 150 minutes after intervention (P<0.05). A significant reduction was determined in the need for analgesics for the patients in the foot massage group and hand massage group compared with the control group (P<0.05). A significant positive relationship was found between pain intensity and state anxiety levels in patients of the foot massage group and hand massage group. Foot and hand massage are influential in decreasing pain and anxiety levels after surgeries for patients who undergo laparoscopic cholecystectomy.
A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis
Authors: Bond Jonathan , Krzywon Aleksandra , Lhermitte Ludovic , Roumier Christophe , Roggy Anne , Belhocine Mohamed , Kheirallah Alexander Kaden , Villarese Patrick , Hypolite Guillaume , Garnache-Ottou Francine , Castaigne Sylvie , Boissel Nicolas , Asnafi Vahid , Preudhomme Claude , Dombret Hervé , Laurenti Elisa , Macintyre Elizabeth
Published: December 2019

Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains heavily based on phenotypic resemblance to normal hematopoietic precursors. This framework can provide diagnostic challenges for immunophenotypically heterogeneous immature leukemias, and ignores recent advances in understanding of developmental multipotency of diverse normal hematopoietic progenitor populations that are identified by transcriptional signatures. We performed transcriptional analyses of a large series of acute myeloid and lymphoid leukemias and detected significant overlap in gene expression between cases in different diagnostic categories. Bioinformatic classification of leukemias along a continuum of hematopoietic differentiation identified leukemias at the myeloid/T-lymphoid interface, which shared gene expression programs with a series of multi or oligopotent hematopoietic progenitor populations, including the most immature CD34+CD1a-CD7- subset of early thymic precursors. Within these interface acute leukemias (IALs), transcriptional resemblance to early lymphoid progenitor populations and biphenotypic leukemias was more evident in cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses revealed that expression of IAL transcriptional programs significantly correlated with poor outcome in independent AML patient cohorts. Our results suggest that traditional binary approaches to acute leukemia categorization are reductive, and that identification of IALs could allow better treatment allocation and evaluation of therapeutic options.
Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing
Authors: Srivastava Aayushi , Giangiobbe Sara , Kumar Abhishek , Dymerska Dagmara , Behnisch Wolfgang , Witzens-Harig Mathias , Lubinski Jan , Hemminki Kari , Försti Asta , Bandapalli Obul Reddy
Published: December 2019

Hodgkin lymphoma (HL) is a lymphoproliferative malignancy of B-cell origin that accounts for 10% of all lymphomas. Despite evidence suggesting strong familial clustering of HL, there is no clear understanding of the contribution of genes predisposing to HL. In this study, whole genome sequencing (WGS) was performed on 7 affected and 9 unaffected family members from three HL-prone families and variants were prioritized using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). WGS identified a total of 98564, 170550 and 113654 variants which were reduced by pedigree-based filtering to 18158, 465 and 26465 in families I, II and III, respectively. In addition to variants affecting amino acid sequences, variants in promoters, enhancers, transcription factors binding sites and microRNA seed sequences were identified from upstream, downstream, 5’ and 3’ untranslated regions. A panel of 565 cancer predisposing and other cancer-related genes and of 2383 high-risk HL genes were also screened in these families to aid further prioritization. Pathway analysis of segregating genes with CADD (Combined Annotation Dependent Depletion Tool) scores > 20 was performed using Ingenuity Pathway Analysis software which implicated several candidate genes in pathways involved in B-cell activation and proliferation and in the network of “Cancer, Hematological disease and Immunological Disease”. We used the FCVPPv2 for further in silico analysis and prioritized 45 coding and 79 non-coding variants from the three families. Further literature-based analysis allowed us to constrict this list to one rare germline variant each in families I and II and two in family III. Functional studies were conducted on the candidate from family I in a previous study, resulting in the identification and functional validation of a novel heterozygous missense variant in the tumor suppressor gene DICER1 as potential HL predisposition factor. We aim to identify the individual genes responsible for predisposition in the remaining two families and will functionally validate these in further studies.
Development of a Mixture Model (SMM) Allowing for Smoothing Functions of Trajectories
Authors: Ding Ming , Chavarro Jorge E. , Fitzmaurice Garrett M.
Published: December 2019

In the health and social sciences, two types of mixture model have been widely used by researchers to identify heterogeneous trajectories of participants within a population: latent class growth analysis (LCGA) and the growth mixture model (GMM). Both methods parametrically model trajectories of individuals, and capture latent trajectory classes, by using an expectation-maximization (E-M) algorithm. However, parametric modeling of trajectories using polynomial functions or monotonic spline functions results in limited flexibility for modelling trajectories; as a result, group membership may not be classified accurately due to model misspecification. In this paper, we propose a mixture model (SMM) allowing for smoothing functions of trajectories using a modified E-M algorithm. In the E step, participants are reassigned to only one group for which the estimated trajectory is the most similar to the observed one; in the M step, trajectories are fitted using generalized additive mixed models (GAMM) with smoothing functions of time. This modified E-M algorithm is straightforward to implement using the recently released “gamm4” macro in R. The SMM can incorporate time-varying covariates and be applied to longitudinal data with normal, Bernoulli, and Poisson distributions. Simulation results show favorable performance of the SMM in terms of classification of group membership. The proposed method is illustrated by its application to body mass index data of individuals followed from adolescence to young adulthood and the relationship with incidence of cardiometabolic disease.
Evaluation and classification of severity for 176 genes on an expanded carrier screening panel
Authors: Arjunan Aishwarya , Bellerose Holly , Torres Raul , Ben-Shachar Rotem , Hoffman Jodi D. , Angle Brad , Slotnick Robert Nathan , Simpson Brittany N. , Lewis Andrea M. , Magoulas Pilar L. , Bontempo Kelly , Schulze Jeanine , Tarpinian Jennifer , Bucher Jessica A , Dineen Richard , Goetsch Allison , Lazarin Gabriel A. , Taber Katherine Johansen
Published: December 2019

Background

Severity is an important factor for inclusion of diseases on expanded carrier screening (ECS) panels. Here, we applied a validated algorithm that objectively classifies diseases into severity categories to 176 genes on a clinically available ECS panel. We then mapped disease traits from the algorithm to severity-related criteria cited by the American College of Obstetricians and Gynecologists (ACOG).

Methods

Eight genetic counselors (GCs), followed by four medical geneticists (MDs), applied the algorithm to subsets of the 176 genes. MDs and GCs then determined which disease traits met ACOG severity criteria.

Results

Upon initial GC and MD review, 107/176 genes (61%) and 133/176 genes (76%), respectively, had concordant classifications, with consensus reached for all genes. Final severity classifications were 68 (39%) profound, 71 (40%) severe, 36 (20%) moderate, and one (1%) mild. The vast majority of genes (170 out of 176) met at least one of ACOG’s four severity criteria.

Conclusion

This study classified the severity of a large set of Mendelian genes by collaborative clinical expert application of an algorithm. Further, it clarified and operationalized difficult to interpret ACOG severity criteria via mapping of disease traits, thereby promoting consistency of ACOG criteria interpretation across laboratories.

What’s already known about this topic?

Disease severity is an important consideration for disease inclusion on expanded carrier screening panels.

An algorithm that objectively classifies diseases into severity categories has been published and validated.

What does this study add?

176 genes were classified into severity categories.

The algorithm was used to bring clarity to American College of Obstetricians and Gynecologist’s (ACOG’s) severity criteria that are not easily interpretable.

170 of 176 genes met at least one of ACOG’s severity criteria.

Data Availability Statement

The data that support the findings of this study have been completely reported in this manuscript and shared in the Figures and Supplementary Material.
Confidence in perceptual decision-making is preserved in schizophrenia
Authors: Faivre Nathan , Roger Matthieu , Pereira Michael , de Gardelle Vincent , Vergnaud Jean-Christophe , Passerieux Christine , Roux Paul
Published: December 2019

Metacognition is the set of reflexive processes allowing humans to evaluate the accuracy of their mental operations. Deficits in synthetic metacognition have been described in schizophrenia using mostly narrative assessment and linked to several key symptoms. Here, we assessed metacognitive performance by asking individuals with schizophrenia or schizoaffective disorder (N=20) and matched healthy participants (N = 21) to perform a visual discrimination task and subsequently report confidence in their performance. Metacognitive performance was defined as the adequacy between visual discrimination performance and confidence. Bayesian analyses revealed equivalent metacognitive performance in the two groups despite a weaker association between confidence and trajectory tracking during task execution among patients. These results were reproduced using a bounded evidence accumulation model which showed similar decisional processes in the two groups. The inability to accurately attune confidence to perceptual decisions in schizophrenia remains to be experimentally demonstrated, along with the way such impairments may underpin functional deficits.
Gut Health, Nutrient intake and Well-being in Community-Dwelling Older Adults
Authors: Fart F. , Tingö L. , Engelheart S. , Lindqvist C. M. , Brummer R. J. , Kihlgren A. , Schoultz I.
Published: December 2019

Background

A majority of community-dwelling older people will in the near future be in need of increased health care. By investigating the relationship between gut health, well-being and nutrient intake we aim to recognize areas through which health might be promoted.

Methods

A cross-sectional observational study was performed enrolling 229 older adults (≥65 years). Validated questionnaires were used to assess gut health, nutrient intake and well-being.

Results

65% of the participant experienced gastrointestinal symptoms. Gastrointestinal symptoms significantly correlated to anxiety, stress and decreased quality of life. Dyspepsia correlated to a lower energy percentage of protein. An intake below the nutritional recommendations was found for protein, fibre, fat (monounsaturated/polyunsaturated), while an intake above the recommendations was found for saturated fats and alcohol

Discussion

A majority of the community-dwelling older adults experienced gastrointestinal symptoms and had an imbalanced macronutrient intake. Gut health, diet and well-being all represents important areas for future intervention studies.
Theta rhythm supports hippocampus-dependent integrative encoding in schematic memory networks
Authors: Nicolás Berta , Sala-Padró Jacint , Cucurell David , Santurino Mila , Falip Mercè , Fuentemilla Lluís
Published: December 2019

Integrating new information into existing schematic structures of knowledge is the basis of learning in our everyday life activity as it enables structured representation of information and goal-directed behaviour in an ever-changing environment. However, how schematic mnemonic structures aid the integration of novel elements remains poorly understood. Here, we showed that the ability to integrate novel picture information into learn structures of picture associations that overlap by the same picture scene (associative network) or by the conceptually related scene information (schematic network) is hippocampus-dependent, as patients with lesions at the medial temporal lobe (including the hippocampus) were impaired in inferring novel relations between elements within these mnemonic networks but not in retrieving individual pictures in a subsequent memory test. In addition, we observed more persistent and widespread scalp electroencephalographic (EEG) theta oscillatory pattern (3-6Hz) while healthy participants encoded novel pictures related to schematic memory networks, suggesting that theta may reflect distances between elements within a representational network space. Finally, we found high similarity values for neural activity patterns elicited by novel and related events only within associative networks, thereby suggesting that neural reactivation may promote the integration of new information into existing memory networks only when direct associations within the network link their elements. These findings have important implications for our understanding of the neural mechanisms that support the development and organization of structures of knowledge.
Habitat loss in the restricted range of the endemic Ghanaian cichlidLimbochromis robertsi
Authors: Lamboj A. , Lucanus O. , Osei Darko P. , Arroyo-Mora J.P , Kalacska M
Published: December 2019

Remote sensing, through satellite image analysis has become an integral and invaluable tool to inform biodiversity conservation and monitoring of habitat degradation and restoration over time. Despite the disproportionately high levels of biodiversity loss in freshwater ecosystems worldwide, ichthyofauna are commonly overlooked in favor of other keystone species. Freshwater fish, as indicators of overall aquatic ecosystem health can also be indicators of larger scale problems within an ecosystem. If endemic and specialized fishes are at risk, the forest and landscape around their habitat is also undergoing change. As a case study demonstrating the utility of multi-temporal, multi-resolution satellite imagery, we examined deforestation and forest fragmentation around the Atewa Forest Reserve, south eastern Ghana. Within small creeks,Limbochromis robertsi, a unique freshwater cichlid with an extremely limited distribution range can be found. Historically, the land cover in the area has undergone substantial deforestation for agriculture and artisanal small-scale mining, primarily for gold. We found deforestation accelerated along with increased forest fragmentation in the 2014 – 2017 period with the majority of the forest loss along the river and creek banks due to small-scale mining operations and increased agriculture. Field visits indicate a decrease in the total population by approximately 90% from the early 1990s to 2018. We illustrate the benefits of determining landscape metrics from local scale remote sensing studies as proxies to assess the decline of endemic species with restricted ranges, whose habitat characteristics and the subsequent pressures they face require detailed analysis at fine temporal and spatial scales not captured by global or continental scale datasets.
Therapeutic Targeting of 15-PGDH in Murine Idiopathic Pulmonary Fibrosis
Authors: Smith Julianne N.P. , Witkin Matthew D. , Jogasuria Alvin P. , Christo Kelsey F. , Raffay Thomas M. , Markowitz Sanford D. , Desai Amar B.
Published: December 2019

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Therapeutic strategies for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts TGFβ signaling and suppresses myofibroblast differentiation, however practical strategies to raise tissue PGE2 during IPF have been limited. We previously described the discovery of a small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced IPF. Long-term PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine IPF, and may have clinical utility to treat human disease.

Article summary

In IPF, lung epithelial injury leads to local inflammation and fibrosis, which impairs pulmonary function. Inhibition of 15-PGDH using a well-tolerated small molecule attenuates inflammation and prevents pulmonary fibrosis and dysfunction in a mouse model of bleomycin-induced IPF.
Modulating brain networks with transcranial magnetic stimulation over the primary motor cortex: a concurrent TMS/fMRI study
Authors: Jung JeYoung , Bungert Andreas , Bowtell Richard , Jackson Stephen R.
Published: December 2019

Stimulating the primary motor cortex (M1) using transcranial magnetic stimulation (TMS) causes unique multisensory experience such as the targeted muscle activity, afferent/reafferent sensory feedback, tactile sensation over the scalp and ‘click’ sound. Although the human M1 has been intensively investigated using TMS, the experience of the M1 stimulation has not been elucidated at the whole brain. Here, using concurrent TMS/fMRI, we investigated the acute effect of the M1 stimulation of functional brain networks during task and at rest. A short 1Hz train of TMS pulses applied to individuals’ hand area in the M1 during motor execution or at rest. Employing the independent component analysis (ICA), we showed the M1 stimulation decreased the motor networks activity when the networks were engaged in the task and increased the deactivation of networks when the networks were not involved in the ongoing task. The M1 stimulation induced the activation in the key networks involved in bodily self-consciousness (BSC) including the insular and rolandic operculum systems regardless of states. The degree of activation in these networks was highest at rest compared to during task, showing the state-dependent TMS effect. Furthermore, we demonstrated that the M1 stimulation modulated other domain general networks such as the default mode network and attention network and the inter-network connectivity between these networks. Our results showed that the M1 stimulation induced the widespread changes in the brain at the targeted system as well as non-motor, remote brain networks, specifically related to the BSC. Our findings shed light on understanding the neural mechanism of the complex and multisensory experience of the M1 stimulation.
The hippocampus and dorso-lateral striatum link distinct types of memories through time and space, respectively
Authors: Ferbinteanu Janina
Published: December 2019

Several decades of research have established that different kinds of memories result from the activity of discrete neural networks. Studying how these networks process information in experiments that target specific types of mnemonic representations has provided deep insights into memory architecture and its neural underpinnings. However, in natural settings reality confronts organisms with problems that are not neatly compartmentalized. Thus, a critical problem in memory research that still needs to be addressed is how distinct types of memories are ultimately integrated. Here we demonstrate how two memory networks, the hippocampus and dorso-lateral striatum, may accomplish such a goal. The hippocampus supports memory for facts and events, collectively known as declarative memory and often studied as spatial memory in rodents. The dorso-lateral striatum (putamen in primates) provides the basis for habits which are assessed in stimulus-response types of tasks. Expanding previous findings, the current work revealed that the hippocampus and dorso-lateral striatum use time and space in distinct and largely complementary ways to link spatial and habitual representations. Specifically, the hippocampus supported both types of memories when they were formed in temporal juxtaposition even if the learning took place in different environments. In contrast, the lateral striatum supported both types of memories if they were formed in the same environment even if at temporally distinct points. These results reveal for the first time that by using fundamental aspects of experience in specific ways, the hippocampus and dorso-lateral striatum can transcend their attributed roles in information storage.

SIGNIFICANCE STATEMENT

The current paradigm in memory research postulates that different types of memories reflected in separate types of behavioural strategies result from activity in distinct neural circuits. However, recent data have shown that when rats concurrently acquired in the same environment hippocampal-dependent spatial navigation and striatal-dependent approach of a visual cue, each of the two types of memories became dependent on both the hippocampus and dorso-lateral striatum. The current work reveals that the hippocampus and dorso-lateral striatum utilize distinct and complementary principles to integrate different types of memories in time and space: the hippocampus links memories formed in temporal proximity, while the lateral striatum links memories formed in the same space.
Stochastic challenges to interrupting helminth transmission
Authors: Hardwick Robert J. , Werkman Marleen , Truscott James E. , Anderson Roy M.
Published: December 2019

Predicting the effect of different programmes designed to control both the morbidity induced by helminth infections and parasite transmission is greatly facilitated by the use of mathematical models of transmission and control impact. In such models, it is essential to account for the many sources of uncertainty — natural, or otherwise — to ensure robustness in prediction and to accurately depict variation around an expected outcome. In this paper, we investigate how well the standard deterministic models match the predictions made using individual-based stochastic simulations. We also explore how well concepts which derive from deterministic models, such as ‘breakpoints’ in transmission, apply in the stochastic world. Employing an individual-based stochastic model framework we also investigate how transmission and control are affected by the migration of infected people into a defined community. To give our study focus we consider the control of soil-transmitted helminths (STH) by mass drug administration (MDA), though our methodology is readily applicable to the other helminth species such as the schistosome parasites and the filarial worms. We show it is possible to theoretically define a ‘stochastic breakpoint’ where much noise surrounds the expected deterministic breakpoint. We also discuss the concept of the ‘interruption of transmission’ independent of the ‘breakpoint’ concept where analyses of model behaviour illustrate the current limitations of deterministic models to account for the ‘fade-out’ or transmission extinction behaviour in simulations. Our analysis of migration confirms a relationship between the critical infected human migration rate scale (i.e., order of magnitude) per unit of time and the death rate of infective stages that are released into the free-living environment. This relationship is shown to determine the likelihood that control activities aim at chemotherapeutic treatment of the human host will eliminate transmission. The development of a new stochastic simulation code for STH in the form of a publicly-available open-source python package which includes features to incorporate many population stratifications, different control interventions including mass drug administration (with defined frequency, coverage levels and compliance patterns) and inter-village human migration is also described.
Foraging behavior across paths that vary in risk cues and frequency of occurrence
Authors: Lessig Emily K. , Nonacs Peter
Published: December 2019

Cooperatively foraging species often adjust their search strategies in complex environments to efficiently find and exploit food sources. These strategies become more complicated when food and risk can be simultaneously present and when they differ in predictability. For example, there may be multiple paths to reach a foraging site that vary in risk. This study examines how colonies of Argentine ants (Linepithema humile) respond to such a situation where identical-length paths differ in how they present risk. The risk cues are either a live competitor (velvety tree ants,Liometopum occidentale(LO)) or formic acid (FA), a defensive chemical commonly associated with formicine ant species. Across four paths to food, the presence of cues also varied from always to never present. Although the non-risky path was used more often, in no case did colonies completely avoid the paths with risk. Overall, moreL. humileworkers explored paths associated with LO than with FA. This had a significant impact on foraging ability where LO colonies were faster at finding food than FA colonies. Further, L.humileworkers’ response to FA was similar over time while declined for LO, suggesting a ‘dear enemy’ habituation and reduction in aggression over time. Thus, it appears thatL. humileforagers categorize risk cues and will vary their responses in potentially effective ways.
Near-complete Lokiarchaeota genomes from complex environmental samples using long and short read metagenomic analyses
Authors: Caceres Eva F. , Lewis William H. , Homa Felix , Martin Tom , Schramm Andreas , Kjeldsen Kasper U. , Ettema Thijs J. G.
Published: December 2019

Asgard archaea is a recently proposed superphylum currently comprised of five recognised phyla: Lokiarchaeota, Thorarchaeota, Odinarchaeota, Heimdallarchaeota and Helarchaeota. Members of this group have been identified based on culture-independent approaches with several metagenome-assembled genomes (MAGs) reconstructed to date. However, most of these genomes consist of several relatively small contigs, and, until recently, no complete Asgard archaea genome is yet available. Large scale phylogenetic analyses suggest that Asgard archaea represent the closest archaeal relatives of eukaryotes. In addition, members of this superphylum encode proteins that were originally thought to be specific to eukaryotes, including components of the trafficking machinery, cytoskeleton and endosomal sorting complexes required for transport (ESCRT). Yet, these findings have been questioned on the basis that the genome sequences that underpin them were assembled from metagenomic data, and could have been subjected to contamination and other assembly artefacts. Even though several lines of evidence indicate that the previously reported findings were not affected by these issues, having access to high-quality and preferentially fully closed Asgard archaea genomes is needed to definitively close this debate. Current long-read sequencing technologies such as Oxford Nanopore allow the generation of long reads in a high-throughput manner making them suitable for their use in metagenomics. Although the use of long reads is still limited in this field, recent analyses have shown that it is feasible to obtain complete or near-complete genomes of abundant members of mock communities and metagenomes of various level of complexity. Here, we show that long read metagenomics can be successfully applied to obtain near-complete genomes of low-abundant members of complex communities from sediment samples. We were able to reconstruct six MAGs from different Lokiarchaeota lineages that show high completeness and low fragmentation, with one of them being a near-complete genome only consisting of three contigs. Our analyses confirm that the eukaryote-like features previously associated with Lokiarchaeota are not the result of contamination or assembly artefacts, and can indeed be found in the newly reconstructed genomes.
Characterization ofSETD1Ahaploinsufficiency in humans andDrosophiladefines a novel neurodevelopmental syndrome
Authors: Kummeling Joost , Stremmelaar Diante E , Raun Nicholas , Reijnders Margot RF , Willemsen Marjolein H , Ruiterkamp-Versteeg Martina , Schepens Marga , Man Calvin CO , Gilissen Christian , Cho Megan T , McWalter Kirsty , Sinnema Margje , Wheless James W , Simon Marleen EH , Genetti Casie A , Casey Alicia M , Terhal Paulien A , van der Smagt Jasper J , van Gassen Koen L , Joset Pascal , Bahr Angela , Steindl Katharina , Rauch Anita , Keller Elmar , Raas-Rothschild Annick , Koolen David A , Agrawal Pankaj B , Hoffman Trevor L , Powell-Hamilton Nina N , Thiffault Isabelle , Engleman Kendra , Zhou Dihong , Bodamer Olaf , Hoefele Julia , Riedhammer Korbinian M , Schwaibold Eva MC , Tasic Velibor , Schubert Dirk , Top Deniz , Pfundt Rolph , Higgs Martin R , Kramer Jamie M , Kleefstra Tjitske
Published: December 2019

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants ofSETD1Ainvolved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency ofSETD1Aby investigating 15 predominantly pediatric individuals who all havede novo SETD1Avariants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion ofSETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals withSETD1Avariants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that theDrosophila MelanogasterSETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominantde novoLoF variants inSETD1Aand further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.
Characterization of a novel type III CRISPR-Cas effector provides new insights into the allosteric activation and suppression of the Cas10 DNase
Authors: Lin Jinzhong , Feng Mingxia , Zhang Heping , She Qunxin
Published: December 2019

Antiviral defense by type III CRISPR-Cas systems relies on two distinct activities of their effectors: the RNA-activated DNA cleavage and synthesis of cyclic oligoadenylate. Both activities are featured as indiscriminate nucleic acid cleavage and subjected to the spatiotemporal regulation. To yield further insights into the involved mechanisms, we reconstituted LdCsm, a lactobacilli III-A system inEscherichia coli. Upon activation by target RNA, this immune system mediates robust DNA degradation but lacks the synthesis of cyclic oligoadenylates. Mutagenesis of the Csm3 and Cas10 conserved residues revealed that Csm3 and multiple structural domains in Cas10 function in the allosteric regulation to yield an active enzyme. Target RNAs carrying various truncations in the 3′ anti-tag were designed and tested for their influence on DNA binding and DNA cleavage of LdCsm. Three distinct ternary LdCsm complexes were identified. In particular, binding of target RNAs carrying a single nucleotide in the 3′ anti-tag to LdCsm yielded an active LdCsm DNase regardless whether the nucleotide shows a mismatch, as in the cognate target RNA (CTR), or a match in the noncognate target RNAs (NTR), to the 5’ tag of crRNA. In addition, further increasing the number of 3′ anti-tag in CTR facilitated the substrate binding and enhanced the substrate degradation whereas doing the same as in NTR gradually decreased the substrate binding and eventually shut off the DNA cleavage by the enzyme. Together, these results provide the mechanistic insights into the allosteric activation and repression of LdCsm enzymes.
Transcriptome profiling ofVariovorax paradoxusEPS under different growth conditions reveals regulatory and structural novelty in biofilm formation
Authors: Fredendall Richard J. , Stone Jenny L. , Pehl Michael J. , Orwin Paul M.
Published: December 2019

We used transcriptome analysis by paired-end strand specific RNA-seq to evaluate the specific changes in gene expression associated with the transition to static biofilm growth in the rhizosphere plant growth promoting bacteriumVariovorax paradoxusEPS. Triplicate biological samples of exponential growth, stationary phase, and static biofilm samples were examined. DESeq2 and Rockhopper were used to identify robust and widespread shifts in gene expression the transcriptomic signals specific to each growth phase. Weidentified 1711 protein coding genes (28%) using DESeq2 that had altered expression greater than 2-fold specifically in biofilms compared to exponential growth. Fewer genes were specifically differentially expressed in stationary phase culture (757, 12%). A small set of genes (103/6020) were differentially expressed in opposing fashions in biofilm and stationary phase, indicating potentially substantial shifts in phenotype. Gene Ontology analysis showed that the only class of genes specifically upregulated in biofilms were associated with nutrient transport, highlighting the importance of nutrient uptake in the biofilm. The biofilm specific genes did not overlap substantially with the loci identified by mutagenesis studies, although some were present in both sets. The most highly upregulated biofilm specific gene is predicted to be a part of the RNA degradosome, which indicates that RNA stability is used to regulate the biofilm phenotype. Two small putative proteins, Varpa_0407 and Varpa_3832, are highly expressed specifically in biofilms and are predicted to be secreted DNA binding proteins, that may stabilize extracellular DNA as a component of the biofilm matrix. An flp/tad type IV pilus locus (Varpa_5148-60) is strongly downregulated in specifically in biofilms, in contrast with results from other systems for these pili. Mutagenesis confirms that this locus is important in surface motility rather than biofilm formation. These experimental results suggest thatV. paradoxusEPS biofilms have substantial regulatory and structural novelty.