bluuebunny/crossref_metadata_2025 huggingface dataset:
Open Office Space: The Wave of the Future for Academic Health Centers?
Authors: Barnes Janice , Wineman Jean , Adler Nancy
Published: September 2019

Facing space constraints similar to those experienced by many urban campuses, the University of California, San Francisco (UCSF) looked to innovative office workplace design to curb growing facilities expenditures. Mission Hall, a new office building primarily for desktop and clinical researchers and staff, was designed as an activity-based workplace (ABW), a type of open-space design. ABW was simultaneously being proposed as the template for future UCSF desktop research workspaces. ABWs can be less costly to construct than other designs, and their mix of shared and open workspaces is intended to improve efficiency and interaction. Evaluations of ABWs in corporate settings have yielded mixed results. Examples of ABW buildings for faculty in academic health centers (AHCs) are rare.

The Mission Hall experience provided a unique opportunity to understand the impact of an ABW design on faculty satisfaction, work effectiveness, well-being, and engagement. In a 2016 survey of faculty, 1 year after occupancy, respondents reported adverse changes in all 4 areas. The most common complaints involved noise exposure and lack of visual and auditory privacy. In response to these issues, faculty reported working at home or elsewhere more frequently, making collaboration more difficult. In 2018, UCSF retrofitted the building to create some private offices and adjusted its overall program to balance private office and open workspaces in future projects.

Lessons drawn from this experience can inform workplace solutions at other AHCs. Most critical are the needs to assess functional requirements of work and align design, change management, and technologies to support those requirements.
Bleeding Assessment Scale in Critically Ill Children (BASIC): Physician-Driven Diagnostic Criteria for Bleeding Severity
Authors: Nellis Marianne E. , Tucci Marisa , Lacroix Jacques , Spinella Philip C. , Haque Kelly D. , Stock Arabela , Steiner Marie E. , Faustino E. Vincent S. , Zantek Nicole D. , Davis Peter J. , Stanworth Simon J. , Cholette Jill M. , Parker Robert I. , Demaret Pierre , Kneyber Martin C. J. , Russell Robert T. , Stricker Paul A. , Vogel Adam M. , Willems Ariane , Josephson Cassandra D. , Luban Naomi L. C. , Loftis Laura L. , Leteurtre Stéphane , Stocker Christian F. , Goobie Susan M. , Karam Oliver
Published: September 2019

Objective:

Although bleeding frequently occurs in critical illness, no published definition to date describes the severity of bleeding accurately in critically ill children. We sought to develop diagnostic criteria for bleeding severity in critically ill children.

Design:

Delphi consensus process of multidisciplinary experts in bleeding/hemostasis in critically ill children, followed by prospective cohort study to test internal validity.

Setting:

PICU.

Patients:

Children at risk of bleeding in PICUs.

Interventions:

None.

Measurements and Main Results:

Twenty-four physicians worldwide (10 on a steering committee and 14 on an expert committee) from disciplines related to bleeding participated in development of a definition for clinically relevant bleeding. A provisional definition was created from 35 descriptors of bleeding. Using a modified online Delphi process and conference calls, the final definition resulted after seven rounds of voting. The Bleeding Assessment Scale in Critically Ill Children definition categorizes bleeding into severe, moderate, and minimal, using organ dysfunction, proportional changes in vital signs, anemia, and quantifiable bleeding. The criteria do not include treatments such as red cell transfusion or surgical interventions performed in response to the bleed. The definition was prospectively applied to 40 critically ill children with 46 distinct bleeding episodes. The kappa statistic between the two observers was 0.74 (95% CI, 0.57–0.91) representing substantial inter-rater reliability.

Conclusions:

The Bleeding Assessment Scale in Critically Ill Children definition of clinically relevant bleeding severity is the first physician-driven definition applicable for bleeding in critically ill children derived via international expert consensus. The Bleeding Assessment Scale in Critically Ill Children definition includes clear criteria for bleeding severity in critically ill children. We anticipate that it will facilitate clinical communication among pediatric intensivists pertaining to bleeding and serve in the design of future epidemiologic studies if it is validated with patient outcomes.
Severe Acute Kidney Injury Due to Nivolumab/Ipilimumab-induced Granulomatosis and Fibrinoid Vascular Necrosis
Authors: Person Fermin , Chahoud-Schriefer Tuhama , Fehrle Wilfrid , Janneck Matthias , Huber Tobias B. , Wiech Thorsten
Published: September 2019

Immune-checkpoint inhibitors have revolutionized the treatment of cancers in recent years. Four drugs have obtained FDA approval in a variety of cancer types. Immune-related adverse events are common and occur in up to 60% of treated patients. Common manifestations of immune-related adverse events include rash, colitis, hepatitis, and hypophysitis. Most cases are mild to moderate in grade; however, severe manifestations with lethal outcomes have been described. Acute kidney injury is reported as a rare complication. In this case report, we present a patient with metastatic melanoma undergoing combined immune-checkpoint inhibitor therapy and displaying multiple immune-related adverse events. Despite receiving systemic steroid therapy for extrarenal immune-related adverse events, the patient developed acute progressive kidney injury requiring renal replacement therapy. Findings on renal biopsy included granulomatous interstitial nephritis, vasculitis, and thrombotic microangiopathy–like lesions. This case indicates that, although severe acute kidney injury is a rare complication of immune-checkpoint inhibitors, fulminant cases do occur and can be resistant to therapeutic intervention.
Dermatomyositis in a patient undergoing nivolumab therapy for metastatic melanoma: a case report and review of the literature
Authors: Kosche Cory , Stout Molly , Sosman Jeffrey , Lukas Rimas V. , Choi Jennifer N.
Published: September 2019

Checkpoint inhibitor immunotherapy is a transformative treatment for advanced malignancies, but can be associated with numerous immune-related adverse events (irAEs). The majority of irAEs include those that closely resemble known cutaneous and neurocutaneous autoimmune or autoinflammatory diseases, such as scleroderma, psoriasis, and dermatomyositis. We present the case of a 63-year-old man with metastatic melanoma undergoing treatment with nivolumab who developed significant motor weakness, paresthesias of both hands, swollen fingers, and a pruritic rash over the face, chest, and upper back after two cycles. Creatine kinase was elevated. Electromyography revealed a myopathic pattern, muscle biopsy of the deltoid revealed an inflammatory myopathy, and skin biopsy showed interface dermatitis. There were no detectable autoantibodies except positive antinuclear antibody. He was diagnosed with immunotherapy-induced dermatomyositis, nivolumab was held, and he was treated with oral prednisone and intravenous immunoglobulin with overall improvement in myopathic and cutaneous symptoms. Dermatomyositis is an inflammatory myopathy with a characteristic dermatologic presentation that can occur spontaneously, as a paraneoplastic phenomenon, or as a drug reaction. This is the second known case of nivolumab-induced dermatomyositis. A review of the literature revealed seven total cases of immunotherapy-induced dermatomyositis. Functionally disabling autoimmune adverse effects of this severity would frequently persuade providers to discontinue immunotherapy in patients with metastatic disease.
Maternal Anxiety, Parenting Stress, and Preschoolers' Behavior Problems: The Role of Child Self-Regulation
Authors: Tsotsi Stella , Broekman Birit F.P. , Sim Lit Wee , Shek Lynette P. , Tan Kok Hian , Chong Yap Seng , Qiu Anqi , Chen Helen Y. , Meaney Michael J. , Rifkin-Graboi Anne
Published: September 2019

Objective:

Maternal anxiety is a well-known risk factor for early childhood behavior problems. In this study, we explore (1) whether parenting stress mediates this relation and also (2) whether child factors, namely self-regulation, modify the influence of maternal well-being on child externalizing and internalizing problems at 4 years of age.

Method:

Mothers taking part in the Growing Up in Singapore Towards Healthy Outcomes cohort completed the Spielberger State-Trait Anxiety Inventory when their children were 24 months of age. At 42 months of age, children performed a self-regulation task (n = 391), and mothers completed the Parenting Stress Index. When children were 48 months old, both parents completed the Child Behavior Checklist.

Results:

As predicted, parenting stress mediated the relation between maternal trait anxiety and child externalizing and internalizing problems. This mediating effect was further moderated by child self-regulation. The indirect effect of maternal trait anxiety through parenting stress on child externalizing problems was stronger among children with low self-regulation.

Conclusion:

Parenting stress is an additional pathway connecting maternal trait anxiety and children's externalizing and internalizing behavior problems. The risk for child externalizing problems conveyed by elevated maternal trait anxiety and parenting stress may be buffered by better self-regulation in 4-year-olds. These results suggest that interventions that include decreasing parenting stress and enhancing child self-regulation may be important to limiting the transgenerational impact of maternal trait anxiety.
Meeting FNP students' and faculty clinical needs: Two perspectives
Authors: Nicoteri Jo Ann L.
Published: September 2019

Appropriate clinical practice sites with skilled preceptors are the backbone of family nurse practitioner (FNP) students' education. Faculty are also in need of practice sites to stay abreast of current clinical practice and maintain clinical hours for certification. The purpose of this article is to relate the process of developing a practice model to meet the needs of the FNP student and faculty. Academia and student life professionals collaborated to use an existing student health center on campus as an education site with an FNP nursing faculty member as a preceptor. This qualitative descriptive study presents reflections of the experience from the student perspective. Three main themes were identified: independence, confidence, and trust. Lessons learned from the faculty perspective are also reviewed. Benefits of the project ultimately outweighed barriers. The interdepartmental precepted practice experience completed its fourth successful year and maintains support through the university's student life division. The model may provide strategies, particularly for FNP programs and faculty in smaller universities, to increase and diversify clinical experiences and provide a faculty practice site.
Epidemiology of carbapenem-resistant Gram-negative infections globally
Authors: Brink Adrian J.
Published: September 2019

Purpose of review

The spread of carbapenem-resistant Gram-negative bacteria (GNB) with changes in institutional epidemiology continues to evolve worldwide. The purpose of this review is to evaluate new data with regard to the epidemiology, mechanisms of resistance and the impact of carbapenem resistance on mortality.

Recent findings

The rapid expansion of acquired carbapenem resistance is increasingly propagated by mobile genetic elements such as epidemic plasmids that transfer carbapenemase genes within and between GNB. The risk of acquisition of carbapenem-resistant Acinetobacter baumannii increases four-fold with carbapenem exposure and new meta-analyses have confirmed excess mortality associated with carbapenem-resistant Pseudomonas aeruginosa. Carbapenemase-producing Klebsiella pneumoniae, the most commonly encountered carbapenemase-producing Enterobacterales (CPE) and a major cause of high-mortality hospital-related infections, represents the most rapidly growing global threat. Carbapenem use in patients colonized with such genotypes, leads to an increase in CPE abundance in the gastrointestinal tract, which in turn increases the risk of blood-stream infections four-fold.

High-resistance rates in carbapenem-resistant GNB in many countries will inevitably complicate treatment of serious infections in vulnerable patient groups and should accelerate global attempts to overcome the impediments we face with regard to effective antimicrobial stewardship and infection prevention and control programs.
Death rattle: reassuring harbinger of imminent death or a perfect example of inadequacies in evidence-based practice
Authors: Watts Tessa , Willis Derek , Noble Simon , Johnston Bridget
Published: September 2019

Purpose of review

Death is the inevitable consequence of life. Although clinicians are unlikely to accurately pinpoint when death is likely to occur in the people they care for, the death in a person with a diagnosis of malignant and nonmalignant tends to involve a period of predictable progressive clinical and functional deterioration. During this time, it is common for death rattle to occur. Due to its presentation, death rattle can cause stress and distress to caregivers. This often prompts clinicians to consider medical interventions that are not only ineffective in treating the problem but may also do harm.

Recent findings

There is a dearth of research related to the management of death rattle.

The article discusses the existing evidence in the management of death rattle, considerations for clinicians in the absence of reliable evidence and suggests areas for future research.
Autonomic dysfunction following mild traumatic brain injury
Authors: Callaway Cali C.M. , Kosofsky Barry E.
Published: September 2019

Purpose of review

Between 1.6 and 3.6 million concussions, or mild traumatic brain injuries (mTBI), occur each year, nearly half of which go unreported and untreated. Despite the high incidence, practitioners currently lack both objective gold-standard diagnostic tools and evidence-based treatments to enable optimal care of concussed individuals.

Recent findings

This article aims to review recent research on the topic, emphasizing the role of the autonomic nervous system (ANS) in concussion. Current data suggests that ANS dysfunction is often evident following mTBI and accounts for many of the symptoms commonly seen in concussed patients. This link suggests several objective biomarkers that could be used to diagnose and monitor recovery following mTBI. Contrary to conventional wisdom, symptoms and biomarkers of ANS function improve when individuals are exposed to a program of graded exercise as treatment within the first week following concussion.

ANS dysfunction contributes to concussion symptomatology, an effect likely mediated through diffuse axonal injury, including brainstem structures and pathways mediating normal cerebrovascular autoregulation. Exercise, which enhances ANS function, is a well tolerated and effective method of treatment for both acute concussion patients and those suffering from postconcussion syndrome (PCS). The relationship between the ANS, exercise, and concussion creates an opportunity for the identification of objective biomarkers that can facilitate the diagnosis and treatment of mTBI.
Stable genetic integration of a red fluorescent protein in a virulent Group A Streptococcus strain
Authors: Liang Zhong , Carothers Katelyn , Holmes Adam , Donahue Deborah , Lee Shaun W. , Castellino Francis J. , Ploplis Victoria A.
Published: September 2019

There are several advantages, both in vitro and in vivo, in utilizing bacteria that express a fluorescent protein. Such a protein can be transiently incorporated into the bacteria or integrated within the bacterial genome. The most widely utilized fluorescent protein is green fluorescent protein (GFP), but limitations exist on its use. Additional fluorescent proteins have been designed that have many advantages over GFP and technologies for their incorporation into bacteria have been optimized. In the current study, we report the successful integration and expression of a stable fluorescent reporter, mCherry (red fluorescent protein, RFP), into the genome of a human pathogen, Group A

Streptococcus pyogenes

(GAS) isolate AP53(S-). RFP was targeted at the atg codon of the fcR pseudogene that is present in the mga regulon of AP53(S-). Transcription of critical bacterial genes was not functionally altered by the genomic integration of mCherry. Host virulence both in vitro (keratinocyte infection and cytotoxicity) and in vivo (skin infection) was maintained in AP53(S-)-RFP. Additionally, survival of mice infected with either AP53(S-) or AP53(S-)-RFP was similar, demonstrating that overall pathogenicity of the AP53(S-) strain was not altered by the expression of mCherry. These studies demonstrate the feasibility of integrating a fluorescent reporter into the bacterial genome of a naturally virulent isolate of Group A

S. pyogenes

for comparative experimental studies.
Estimates of the global burden of Japanese Encephalitis and the impact of vaccination from 2000-2015
Authors: Quan Tran Minh , Thao Tran Thi Nhu , Duy Nguyen Manh , Nhat Tran Minh , Clapham Hannah E.
Published: September 2019

Japanese encephalitis (JE) is a mosquito-borne disease, known for its high death and disability rate among symptomatic cases. Many effective vaccines are available for JE, and the use of a recently developed and inexpensive vaccine has been increasing over the recent years particularly with Gavi support. Estimates of the local burden and the past impact of vaccination are therefore increasingly needed, but difficult due to the limitations of JE surveillance. In this study, we implemented a mathematical modelling method combined with age-stratifed case data which can overcome some of these limitations. We estimate in 2015 JE infections caused 100,308 cases (95%CI: 61,720 - 157,522) and 25,125 deaths (95%CI: 14,550 - 46,031), and that between 2000 and 2015 307,774 JE cases (95%CI: 167,442- 509,583) were averted due to vaccination. Our results highlight areas that could have the greatest benefit from starting vaccination or from scaling up existing programs and will be of use to support local and international policymakers in making vaccine allocation decisions.
Anticipatory Control of Momentum for Bipedal Walking on Uneven Terrain
Authors: Darici Osman , Temeltas Hakan , Kuo Arthur D.
Published: September 2019

Humans and other walking bipeds often encounter and compensate for uneven terrain. They might, for example, regulate the body’s momentum when stepping on stones to cross a stream. We examined what to do and how far to look, as a simple optimal control problem, where forward momentum is controlled to compensate for a step change in terrain height, and steady gait regained with no loss of time relative to nominal walking. We modeled planar, human-like walking with pendulum-like legs, and found the most economical control to be quite stereotypical. It starts by gaining momentum several footfalls ahead of an upward step, in anticipation of the momentum lost atop that step, and then ends with another speed-up to regain momentum thereafter. A similar pattern can be scaled to a variety of conditions, including both upward or downward steps, yet allow for considerably reduced overall energy and peak power demands, compared to compensation without anticipation. We define a “persistence time” metric from the transient decay response after a disturbance, to describe how momentum is retained between steps, and how far ahead a disturbance should be planned for. Anticipatory control of momentum can help to economically negotiate uneven terrain.
Mutation ofCFAP57causes primary ciliary dyskinesia by disrupting the asymmetric targeting of a subset of ciliary inner dynein arms
Authors: Bustamante-Marin Ximena M. , Horani Amjad , Stoyanova Mihaela , Charng Wu-Lin , Bottier Mathieu , Sears Patrick R. , Daniels Leigh Anne , Bowen Hailey , Conrad Donald F. , Knowles Michael R. , Ostrowski Lawrence E. , Zariwala Maimoona A. , Dutcher Susan K.
Published: September 2019

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis, and is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious TEM structural phenotype for pathogenic variants using whole exome capture and next generation sequencing. The population sampling probability (PSAP) algorithm identified one subject with a homozygous nonsense variant [(c.1762C>T) p.(Arg588*) exon 11] in the uncharacterizedCFAP57gene. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Analysis of cells from the PCD patient shows a loss of CFAP57, reduced beat frequency, and an alteration in the ciliary waveform. Knockdown ofCFAP57in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is conserved in organisms that assemble motile cilia, andCFAP57is allelic with theBOP2gene identified previously inChlamydomonas. Two independent, insertionalfap57 Chlamydomonasmutant strains show reduced swimming velocity and altered waveforms. Tandem mass spectroscopy showed that CFAP57 is missing, and the “g” inner dyneins (DHC7 and DHC3) and the “d” inner dynein (DHC2) are reduced. Our data demonstrate that the FAP57 protein is required for the asymmetric assembly of inner dyneins on only a subset of the microtubule doublets, and this asymmetry is essential for the generation of an effective axonemal waveform. Together, our data identifies mutations inCFAP57as a cause of PCD with a specific defect in the inner dynein arm assembly process.

Significance

Motile cilia are found throughout eukaryotic organisms and performs essential functions. Primary ciliary dyskinesia (PCD) is a rare disease that affects the function of motile cilia. By applying a novel population sampling probability algorithm (PSAP) that uses large population sequencing databases and pathogenicity prediction algorithms, we identified a variant in an uncharacterized gene,CFAP57. This is the first reported example of PCD caused by a mutation that affects only a subset of the inner dynein arms, which are needed to generate the waveform. CFAP57 identifies an address for specific dynein arms. These findings demonstrate the effectiveness of the PSAP algorithm, expand our understanding of the positioning of dynein arms, and identify mutations inCFAP57as a cause of PCD.
Non-invasive stimulation of vagal afferents reduces gastric frequency
Authors: Teckentrup Vanessa , Neubert Sandra , Santiago João C. P. , Hallschmid Manfred , Walter Martin , Kroemer Nils B.
Published: September 2019

Metabolic feedback between the gut and the brain relayed via the vagus nerve contributes to energy homeostasis. We investigated in healthy adults whether non-invasive stimulation of vagal afferents impacts energy homeostasis via efferent effects on metabolism or digestion. In a randomized crossover design, we applied transcutaneous auricular vagus nerve stimulation (taVNS) while recording efferent metabolic effects using simultaneous electrogastrography (EGG) and indirect calorimetry. We found that taVNS reduced gastric myoelectric frequency (p =.008), but did not alter resting energy expenditure. We conclude that stimulating vagal afferents induces gastric slowing via vagal efferents without acutely affecting net energy expenditure at rest. Collectively, this highlights the potential of taVNS to modulate digestion by activating the dorsal vagal complex. Thus, taVNS-induced changes in gastric frequency are an important peripheral marker of brain stimulation effects.
Neuroinflammation and EIF2 signaling persist in an HiPSC tri-culture model of HIV infection despite antiretroviral treatment
Authors: Ryan Sean K. , Gonzalez Michael V. , Garifallou James P. , Bennett Frederick C. , Williams Kimberly S. , Hakonarson Hakon , Anderson Stewart A. , Jordan-Sciutto Kelly L.
Published: September 2019

HIV-Associated Neurocognitive Disorders (HAND) affect over half of HIV-infected individuals worldwide, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive. We developed a human-induced pluripotent stem cell (HiPSC) based model; whereby, we independently differentiate HiPSCs into neurons, astrocytes, and microglia and systematically combine to generate a tri-culture with or without HIV-infection and ART. scRNAseq analysis on tri-cultures including HIV-infected microglia revealed inflammatory signatures in the microglia and EIF2 signaling in all three cell types. Remarkably, EFZ alone induced a similar response to infection. Treatment with the antiretroviral compound Efavirenz (EFZ) mostly resolved these signatures; However, EFZ increased RhoGDI and CD40 signaling in the HIV-infected microglia. This activation was associated with a persistent increase in TNFa expression. This work establishes a tri-culture that recapitulates key features of HIV infection in the CNS and provides a new model to examine the effects of HIV infection and its treatment with antiretrovirals.
Revealing the Temporal Dynamics in Non-invasive Electrophysiological recordings with Topography-based Analyses
Authors: Wang Xuefei , Zhu Hao , Tian Xing
Published: September 2019

The fine temporal resolution of electroencephalography (EEG) makes it one of the most widely used non-invasive electrophysiological recording methods in cognitive neuroscience research. One of the common ways to explore the neural dynamics is to create event-related potentials (ERPs) by averaging trials, followed by the examination of the response magnitude at peak latencies. However, a complete profile of neural dynamics, including temporal indices of onset time, offset time, duration, and processing speed, is needed to investigate cognitive neural mechanisms. Based on the multivariate topographic analysis, we developed an analytical framework that included two methods to explore neural dynamics in ERPs. The first method separates continuous ERP waveforms into distinct components based on their topographic patterns. Crucial temporal indices such as the peak latency, onset and offset times can be automatically identified and indices about processing speed such as duration, rise, and fall speed can be derived. The second method scrutinizes the temporal dynamics of identified components by reducing the temporal variance among trials. The response peaks of signal trials are identified based on a target topographic template, and temporal-variance-free ERPs are obtained after aligning individual trials. This method quantifies the temporal variance as a new measure of cognitive noise, as well as increases both the accuracy of temporal dynamics estimation and the signal-to-noise ratio (SNR) of the ERP responses. The validity and reliability of these methods were tested with simulation as well as empirical datasets from an attention study and a semantic priming (N400) study. Together, we offer an analytical framework in a data-driven, bias-free manner to investigate neural dynamics in non-invasive scalp recordings. These methods are implemented in the Python-based open-source package TTT (Topography-based Temporal-analysis Toolbox).
Habitual foot strike pattern does not affect simulated Triceps Surae muscle metabolic energy consumption during running
Authors: Swinnen Wannes , Hoogkamer Wouter , De Groote Friedl , Vanwanseele Benedicte
Published: September 2019

Foot strike pattern affects ankle joint work and Triceps Surae muscle-tendon dynamics during running. Whether these changes in muscle-tendon dynamics also affect Triceps Surae muscle energy consumption is still unknown. In addition, as the Triceps Surae muscle accounts for a substantial amount of the whole body metabolic energy consumption, changes in Triceps Surae energy consumption may affect whole body metabolic energy consumption. However, direct measurements of muscle metabolic energy consumption during dynamic movements is hard. Model-based approaches can be used to estimate individual muscle and whole body metabolic energy consumption based on Hill type muscle models. In this study, we use an integrated experimental and dynamic optimization approach to compute muscle states (muscle forces, lengths, velocities, excitations and activations) of 10 habitual mid-/forefoot striking and 9 habitual rearfoot striking runners while running at 10 and 14 km/h. The Achilles tendon stiffness of the musculoskeletal model was adapted to fit experimental ultrasound data of the Gastrocnemius medialis muscle during ground contact. Next, we calculated Triceps Surae muscle and whole body metabolic energy consumption using four different metabolic energy models provided in literature. Neither Triceps Surae metabolic energy consumption (p > 0.35), nor whole body metabolic energy consumption (p > 0.14) was different between foot strike patterns, regardless of the energy model used or running speed tested. Our results provide new evidence that mid-/forefoot and rearfoot strike pattern are metabolically equivalent.
Behavioural relevance of spontaneous, transient brain network interactions in fMRI
Authors: Vidaurre D. , Llera A. , Smith S.M. , Woolrich M.W.
Published: September 2019

How spontaneously fluctuating functional magnetic resonance imaging (fMRI) signals in different brain regions relate to behaviour has been an open question for decades. Correlations in these signals, known as functional connectivity, can be averaged over several minutes of data to provide a stable representation of the functional network architecture for an individual. However, associations between these stable features and behavioural traits have been shown to be dominated by individual differences in anatomy. Here, using kernel learning tools, we propose methods to assess and compare the relation between time-varying functional connectivity, time-averaged functional connectivity, structural brain data, and non-imaging subject behavioural traits. We applied these methods on Human Connectome Project resting-state fMRI data to show that time-varying fMRI functional connectivity, detected at time-scales of a few seconds, has associations with some behavioural traits that are not dominated by anatomy. Despite time-averaged functional connectivity accounting for the largest proportion of variability in the fMRI signal between individuals, we found that some aspects of intelligence could only be explained by time-varying functional connectivity. The finding that time-varying fMRI functional connectivity has a unique relationship to population behavioural variability suggests that it might reflect transient neuronal communication fluctuating around a stable neural architecture.

Significance statement

Complex cognition is dynamic and emerges from the interaction between multiple areas across the whole brain, i.e. from brain networks. Hence, the utility of functional MRI to investigate brain activity depends on how well it can capture time-varying network interactions. Here, we develop methods to predict behavioural traits of individuals from either time-varying functional connectivity, time-averaged functional connectivity, or structural brain data. We use these to show that the time-varying nature of functional brain networks in fMRI can be reliably measured and can explain aspects of behaviour not captured by structural data or time-averaged functional connectivity. These results provide important insights to the question of how the brain represents information and how these representations can be measured with fMRI.
Exploring the effect of Relative Language Distance on Bilingual Brain Structure – a cross-sectional VBM study
Authors: Ramanujan Keerthi
Published: September 2019

It is known that bilinguals’ perpetual need for language control influences their brain structure in significant ways. But bilinguals’ language control needs are themselves influenced by key dimensions of the bilingual experience – variation in the age of bilingualism-onset, relative language proficiency, exposure and immersion has indeed been shown to have differential effects on bilingual neurostructural profiles. An under-studied dimension of bilingualism that could also generate differing bilingual language control needs is the extent of similarity between bilinguals’ language pairs, referred to in the present study as Relative Language Distance (RLD). The goal of the present study was to explore whether the experience of managing “close” and “distant” languages has any impact at all on bilingual brain structure. To this end, exploratory morphometric analysis of grey matter volumes was carried out on three groups, all very similar in their bilingual profiles except for the factor of RLD – high-distance Cantonese-English (hd-CE), intermediate distance Hindi-English (id-HE) and low-distance Dutch-English (ld-DE) speakers. The results after controlling for contribution of other bilingual dimensions revealed significant bilateral putaminal volume differences between the groups that varied along the relative language distance gradient in the pattern of CE>HE>DE. This might be attributable to the differing articulatory control needs that variation in L1-L2 RLD generates. The present study reveals how the dimension of Relative Language Distance could impact bilingual brain structure.
Agrobacterium-mediated transient transformation of sorghum leaves for accelerating functional genomics and genome editing studies
Authors: Sharma Rita , Liang Yan , Lee Mi Yeon , Pidatala Venkataramana R. , Mortimer Jenny C. , Scheller Henrik V.
Published: September 2019

Objectives

Sorghum is one of the most recalcitrant species for transformation. Considering the time and effort required for stable transformation in sorghum, establishing a transient system to screen the efficiency and full functionality of vector constructs is highly desirable.

Results

Here, we report anAgrobacterium-mediated transient transformation assay with intact sorghum leaves using green fluorescent protein as marker. It also provides a good monocot alternative to tobacco and protoplast assays with a direct, native and more reliable system for testing single guide RNA (sgRNA) expression construct efficiency. Given the simplicity and ease of transformation, high reproducibility, and ability to test large constructs, this method can be widely adopted to speed up functional genomic and genome editing studies.
Swimming motility and chemotaxis control the spatial organization, persistence, and inflammatory activity of a model intestinal pathobiont
Authors: Wiles Travis J. , Schlomann Brandon H. , Wall Elena S. , Betancourt Reina , Parthasarathy Raghuveer , Guillemin Karen
Published: September 2019

Understanding the processes that spatially restrict resident gut bacteria and the mechanisms by which disease-causing pathobionts escape this control will open new avenues for microbiome-based therapies. Using live imaging and genetically engineered bacteria, we discovered that flagella-based swimming motility and chemotaxis enable a modelVibriopathobiont to govern its own spatial organization within the larval zebrafish gut and to persist in the face of the disruptive forces of intestinal flow. Bacterial mutants lacking motility traits became aggregated and lumenally confined, making them susceptible to periodic expulsion from the host. Consequently, non-motile and non-chemotactic mutants experienced large fluctuations in absolute abundance and impaired interbacterial competition. Further, we found that motile bacterial cells induce expression of the proinflammatory cytokine TNFα in gut-associated macrophages and the liver. Using inducible genetic switches, we demonstrate that swimming motility can be manipulated in situ to modulate the spatial organization, persistence, and inflammatory activity of gut bacteria.
Retinal horizontal cells use different synaptic sites for global feedforward and local feedback signaling
Authors: Behrens Christian , Zhang Yue , Yadav Shubhash Chandra , Haverkamp Silke , Irsen Stephan , Korympidou Maria M. , Schaedler Anna , Dedek Karin , Smith Robert G. , Euler Thomas , Berens Philipp , Schubert Timm
Published: September 2019

In the outer plexiform layer (OPL) of the mouse retina, two types of cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). This transmission is modulated by a single horizontal cell (HC) type, the only interneuron in the outer retina. Horizontal cells form feedback synapses with cones and feedforward synapses with CBCs. However, the exact computational role of HCs is still debated. Along with performing global signaling within their laterally coupled network, HCs also provide local, cone-specific feedback. Specifically, it has not been clear which synaptic structures HCs use to provide local feedback to cones and global forward signaling to CBCs.

Here, we reconstructed in a serial block-face electron microscopy volume the dendritic trees of five HCs as well as cone axon terminals and CBC dendrites to quantitatively analyze their connectivity. In addition to the fine HC dendritic tips invaginating cone axon terminals, we also identified “bulbs”, short segments of increased dendritic diameter on the primary dendrites of HCs. These bulbs are located well below the cone axon terminal base and make contact to other cells mostly identified as other HCs or CBCs. Using immunolabeling we show that HC bulbs express vesicular gamma-aminobutyric acid transporters and co-localize with GABA receptor γ2 subunits. Together, this suggests the existence of two synaptic strata in the mouse OPL, spatially separating cone-specific feedback and feedforward signaling to CBCs. A biophysics-based computational model of a HC dendritic branch supports the hypothesis that the spatial arrangement of synaptic contacts allows simultaneous local feedback and global feedforward signaling.
Type IV CRISPR-Cas systems are highly diverse and involved in competition between plasmids
Authors: Pinilla-Redondo Rafael , Mayo-Muñoz David , Russel Jakob , Garrett Roger A. , Randau Lennart , Sørensen Søren J. , Shah Shiraz A.
Published: September 2019

CRISPR-Cas systems provide prokaryotes with adaptive immune functions against viruses and other genetic parasites by leveraging small non-coding RNAs for nuclease-dependent degradation of their nucleic acid targets. In contrast to all other types of CRISPR-Cas systems, the mechanisms and biological roles of type IV systems have remained largely overlooked. Here, we describe a previously uncharted diversity of type IV gene cassettes, distributed across diverse prokaryotic genome backgrounds, and propose their classification into subtypes and variants. Congruent with recent findings, type IV modules were primarily found on plasmid-like elements. Remarkably, via a comprehensive analysis of their CRISPR spacer content, these systems were found to exhibit a strong bias towards the targeting of other plasmids. Our data indicate that the functions of type IV systems have diverged from those of other host-related CRISPR-Cas immune systems to adopt a yet unrecognised role in mediating conflicts between plasmids that compete to monopolize their hosts. Furthermore, we find evidence for cross-talk between certain type IV and type I CRISPR-Cas systems that co-exist intracellularly, thus providing an answer to the enigmatic absence of adaptation modules in these systems. Collectively, our results lead to the expansion and reclassification of type IV systems and provide novel insights into the biological function and evolution of these elusive systems.
Single-cell analysis of antiviral neuroinflammatory responses in the mouse dorsal raphe nucleus
Authors: Huang Kee Wui , Sabatini Bernardo L.
Published: September 2019

Neuroinflammatory processes have been implicated in neurodegenerative and psychiatric diseases, and limit the utility of viruses for gene delivery. Here we analyzed 60,212 single-cell RNA profiles to assess both global and cell type-specific transcriptional responses in the mouse dorsal raphe nucleus following axonal infection of neurons by rabies viruses. We identified several leukocyte populations, which infiltrate the brain, that are distinct from resident immune cells. Additionally, we uncovered transcriptionally distinct states of microglia along an activation trajectory that may serve different functions, ranging from surveillance to antigen presentation and cytokine secretion. Our study also provides a critical evaluation of the compatibility between rabies-mediated connectivity mapping and single-cell transcriptional profiling. These findings provide additional insights into the distinct contributions of various cell types in the antiviral response, and will serve as a resource for the design of strategies to circumvent immune responses to improve the efficacy of viral gene delivery.
TNF receptor associated factor 6 interacts with ALS-linked misfolded superoxide dismutase 1 and promotes aggregation
Authors: Semmler Sabrina , Gagné Myriam , Garg Pranav , Pickles Sarah , Baudouin Charlotte , Hamon-Keromen Emeline , Destroismaisons Laurie , Khalfallah Yousra , Chaineau Mathilde , Caron Elise , Bayne Andrew N. , Trempe Jean-François , Cashman Neil R. , Star Alexandra T. , Haqqani Arsalan S. , Durcan Thomas M. , Meiering Elizabeth M. , Robertson Janice , Grandvaux Nathalie , Plotkin Steven S. , McBride Heidi M. , Vande Velde Christine
Published: September 2019

Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons leading to paralysis. Mutations in the gene encoding superoxide dismutase1(SOD1) are the second most common cause of familial ALS, and considerable evidence suggests that these mutations result in an increase in toxicity due to protein misfolding. We previously demonstrated in the SOD1G93Arat model that misfolded SOD1 exists as distinct conformers and forms deposits on mitochondrial subpopulations. Here, using SOD1G93Arats and conformation-restricted antibodies specific for misfolded SOD1 (B8H10 and AMF7-63), we identified the interactomes of the mitochondrial pools of misfolded SOD1. This strategy identified binding proteins that uniquely interacted with either AMF7-63 or B8H10-reactive SOD1 conformers as well as with a high proportion of interactors common to both conformers. Of this latter set, we identified the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) as a SOD1 interactor and determined that exposure of the SOD1 functional loops facilitates this interaction. Of note, this conformational change was not universally fulfilled by all SOD1 variants and differentiated TRAF6-interacting from TRAF6 non-interacting SOD1 variants. Functionally, TRAF6 stimulated polyubiquitination and aggregation of the interacting SOD1 variants. TRAF6 E3 ubiquitin ligase activity was required for the former, but was dispensable for the latter, indicating that TRAF6-mediated polyubiquitination and aggregation of the SOD1 variants are independent events. We propose that the interaction between misfolded SOD1 and TRAF6 may be relevant to the etiology of ALS.
Simultaneous discovery of candidate imprinted genes and Imprinting Control Regions in the mouse genome
Authors: Bina Minou , Wyss Phillip
Published: September 2019

In mammals, parent-of-origin-specific gene expression is regulated by specific genomic DNA segments known as Imprinting Control Regions (ICRs) and germline Differentially Methylated Regions (gDMRs). In the mouse genome, the known ICRs/gDMRs often include clusters of a set of composite-DNA-elements known as ZFBS-morph overlaps. These elements consist of the ZFP57 binding site (ZFBS) overlapping a subset of the MLL1 morphemes. To improve detection of such clusters, we created density-plots. In genome-wide analyses, peaks in these plots pinpointed ∼90% of the known ICRs/gDMRs and located candidate ICRs within relatively long genomic DNA sections. In several cases, the candidate ICRs mapped to chromatin boundaries, to a subset of gene-transcripts, or to both. By viewing the plots at the UCSC genome browser, we could examine the candidate ICRs in the context of the genes in their vicinity. This strategy uncovered several potential imprinted genes with a broad range of physiologically important functions. Examples include: folliculogenesis; lineage commitment of murine embryonic stem cells; the development of the junctional zone of the placenta; left-right patterning of the body axis; the development of the neocortex, hippocampus, and cerebellum; postnatal vision; self-renewal of mouse spermatogonial stem cells; and histone-to-protamine replacement during spermatogenesis.
CpG-ODN 2007 protects zebrafish against Vibrio vulnificus-induced infection
Authors: Chen Hua , Zhang Lijuan , Li Suyi , Ke Ling , Lin Chentao , Chen Xu
Published: September 2019

Vibrio vulnificus (V. vulnificus) is an aquatic pathogen that can cause primary sepsis and soft tissue infection. CpG oligodeoxynucleotides (CpG-ODN) are a type of essential immunomodulators, which can trigger or enhance immune responses in mammals, fish, and humans. In this study, we evaluated the effect of CpG-ODN 2007 as a potential immunostimulant for zebrafish infected with V. vulnificus (FJ03-X2). Fish injected with the CpG-ODN 2007 showed lower mortality rate compared with the fish that did not receive treatment. The survival rates of CpG-ODN 2007-treated group and PBS-treated group were 85% and 57.9%, respectively. In addition, our in vitro results demonstrated that CpG-ODN 2007 can effectively reduce the toxicity of V. vulnificus (FJ03-X2) to zebrafish embryonic fibroblast (ZF4) cells. Furthermore, we assessed immune-related genes expression patterns in FJ03-X2 infected zebrafish or ZF4 cells with and without CpG-ODN 2007 treatment, such as TLRs and IL-1β. To sum up, our data indicated that CpG-ODN 2007 protects zebrafish against Vibrio vulnificus induced infection.
Generalized Multi-SNP Mediation Intersection-Union Test
Authors: Zhong Wujuan , Darville Toni , Zheng Xiaojing , Fine Jason , Li Yun
Published: September 2019

Summary

To elucidate the molecular mechanisms underlying genetic variants identified from genome-wide association studies (GWAS) for a variety of phenotypic traits encompassing binary, continuous, count, and survival outcomes, we propose a novel and flexible method to test for mediation that can simultaneously accommodate multiple genetic variants and different types of outcome variables. Specifically, we employ the intersection-union test approach combined with likelihood ratio test to detect mediation effect of multiple genetic variants via some mediator (for example, the expression of a neighboring gene) on outcome. We fit high-dimensional generalized linear mixed models under the mediation framework, separately under the null and alternative hypothesis. We leverage Laplace approximation to compute the marginal likelihood of outcome and use coordinate descent algorithm to estimate corresponding parameters. Our extensive simulations demonstrate the validity of our proposed method and substantial, up to 97%, power gains over alternative methods. Applications to real data for the study ofChlamydia trachomatisinfection further showcase advantages of our method. We believe our proposed method will be of value and general interest in this post-GWAS era to disentangle the potential causal mechanism from DNA to phenotype for new drug discovery and personalized medicine.