bluuebunny/crossref_metadata_2025 huggingface dataset:
PIEZO2: A Novel Molecule Involved in the Development of AIS
Authors: Wu Zhichong , Wang Yuwen , Xia Chao , Feng Zhenhua , Qiu Yong , Cheng Jack Chun-Yiu , Xu Leilei , Zhu Zezhang
Published: September 2019

Study Design.

A case–control study.

Objective.

This study aimed to investigate the potential role of PIEZO2 gene in the development of AIS.

Summary of Background Data.

Mutations of PIEZO2 gene have been reported to be associated with progressive scoliosis and impaired proprioception. Previous studies showed that patients with AIS may have impaired proprioception. However, there is lack of knowledge concerning the mechanism underlying the proprioception of AIS patients and the role of PIEZO2 gene in the etiology of AIS.

Methods.

Proprioception tests were performed in both AIS patients and age-matched healthy controls. Based on the falling risk scores, AIS patients were divided into impaired proprioception group and unimpaired proprioception group. Paraspinal muscle was collected from 34 AIS patients during surgery. The tissue expression of PIEZO2 was compared between the impaired group and the unimpaired group. In addition, the average number of muscle fibers in the muscle spindle was compared between the two groups.

Results.

Proprioception test showed that patients had significantly higher falling index (41.7 ± 16.5 vs. 11.3 ± 8.3, P = 0.004). In addition, the expression of PIEZO2 gene was remarkably decreased in the impaired group (0.51 ± 0.24 vs. 1.00 ± 0.33, P = 0.04). The average number of muscle fibers in the muscle spindle was significantly decreased in AIS patients of the impaired group than those of the unimpaired group (2.2 ± 1.3 vs. 3.5 ± 2.1, P = 0.04). PIEZO2 expression level was remarkably correlated with the average number of muscle fibers in the muscle spindle (r = 0.352, P = 0.04).

Conclusion.

Proprioception is remarkably impaired in patients with AIS. Abnormal expression of PIEZO2 may play a role in AIS via altered proprioception and number of muscle fibers in the muscle spindles. Further investigation is warranted to illustrate the mechanism regulating PIEZO2 expression in AIS.

Level of Evidence: 4
Early Self-directed Home Exercise Program After Anterior Cervical Discectomy and Fusion
Authors: Coronado Rogelio A. , Devin Clinton J. , Pennings Jacquelyn S. , Vanston Susan W. , Fenster Dana E. , Hills Jeffrey M. , Aaronson Oran S. , Schwarz Jacob P. , Stephens Byron F. , Archer Kristin R.
Published: September 2019

Study Design.

Pilot randomized controlled trial.

Objective.

To examine the acceptability and preliminary safety and outcome effects of an early self-directed home exercise program (HEP) performed within the first 6 weeks after anterior cervical discectomy and fusion (ACDF).

Summary of Background Data.

Little is known regarding optimal postoperative management after ACDF.

Methods.

Thirty patients (mean ± standard deviation, age = 50.6 ± 11.0 years, 16 women) undergoing ACDF were randomized to receive an early HEP (n = 15) or usual care (n = 15). The early HEP was a 6-week self-directed program with weekly supportive telephone calls to reduce pain and improve activity. Treatment acceptability was assessed after the intervention period (6 weeks after surgery). Safety (adverse events, radiographic fusion, revision surgery) was determined at routine postoperative visits. Disability (Neck Disability Index), pain intensity (Numeric Rating Scale for neck and arm pain), physical and mental health (SF-12), and opioid use were assessed preoperatively, and at 6 weeks and 6 and 12 months after surgery by an evaluator blinded to group assignment.

Results.

Participants reported high levels of acceptability and no serious adverse events with the early HEP. No difference in fusion rate was observed between groups (P > 0.05) and no participants underwent revision surgery. The early self-directed HEP group reported lower 6-week neck pain than the usual care group (F = 3.3, P = 0.04, r
2 = 0.3, mean difference = −1.7 [−3.4; −0.05]) and lower proportion of individuals (13% vs. 47%) using opioids at 12 months (P = 0.05). No other between-group outcome differences were observed (P > 0.05).

Conclusion.

An early self-directed HEP program was acceptable to patients and has the potential to be safely administered to patients immediately after ACDF. Benefits were noted for short-term neck pain and long-term opioid utilization. However, larger trials are needed to confirm safety with standardized and long-term radiograph assessment and treatment efficacy.

Level of Evidence: 2
Increasing Access to Autism Spectrum Disorder Diagnostic Consultation in Rural and Underserved Communities: Streamlined Evaluation Within Primary Care
Authors: Hine Jeffrey F. , Allin Jessica , Allman Angela , Black Michelle , Browning Brooke , Ramsey Bobbie , Swanson Amy , Warren Zachary E. , Zawoyski Andrea , Allen William
Published: September 2019

Objective:

Preliminary feasibility and clinical utility research has demonstrated that implementation of a streamlined diagnostic model embedded within primary care (PC) clinics promotes early identification of young children with autism spectrum disorder (ASD). Use of this model results in dramatically reduced waits for diagnostic consultation, high levels of family/provider satisfaction, and reductions in referrals to overtaxed tertiary diagnostic centers. The current study extends this work by providing data before/after implementation of a streamlined model across a diverse range of PC clinics that provide health care to rural and underserved communities.

Methods:

The streamlined assessment involved record/history review, diagnostic interview, standard rating scales, and an interactive screening tool. Eighty children between the ages of 19 and 47 months were seen across 5 different clinics. Data were collected through chart review.

Results:

Implementation of streamlined model resulted in a significant decrease in latency to diagnostic conclusion from a mean of 144.7 to 49.9 days. Children were likely to experience a greater reduction in wait times if they were a PC patient versus a non-PC patient.

Conclusion:

Results show significant reduction in wait times for ASD diagnostic decisions across both PC and non-PC patients. By reducing waits and identifying concerns more efficiently, we may increase the ability of families to access early intervention and support services.
Transversus Abdominis Plane Block in Laparoscopic Colorectal Surgery: A Systematic Review
Authors: Wu Robert C. , Jensen Christine C. , Douaiher Jeffrey , Madoff Robert D. , Kwaan Mary R.
Published: September 2019

BACKGROUND:

Multimodal analgesia is important for postoperative recovery in laparoscopic colorectal surgery. Multiple randomized controlled trials have investigated the use of transversus abdominis plane local anesthetic infiltration as a method of decreasing postoperative pain and opioid consumption, with variable results.

OBJECTIVE:

This study aimed to examine the overall effect of transversus abdominis plane block in postoperative pain, opioid use, and speed of recovery in laparoscopic colorectal surgery.

DATA SOURCES:

A literature search was done with PubMed, EMBASE, Web of Knowledge, and Cochrane Library. Only randomized controlled trials were selected for review.

INTERVENTIONS:

Transversus abdominis plane local anesthetic infiltration versus no intervention, saline, or other techniques in laparoscopic colorectal surgeries was investigated.

MAIN OUTCOME MEASURES:

The primary outcome measured was postoperative pain on day 1, at rest or with activity. The secondary outcomes measured were postoperative pain beyond day 1, consumptions of opioid, and length of hospital stay.

RESULTS:

Eight clinical trials including 649 patients between 2013 and 2018 were included. Resting pain scores within 2 hours (standardized mean difference, –0.53; p = 0.01), 4 hours (standardized mean difference, –0.42; p = 0.004), and 6 hours (standardized mean difference, –0.47; p = 0.03) showed statistically significant reduction. Six studies including 413 patients demonstrated lower cumulative opioid consumption within 24 hours after surgery (standardized mean difference, –0.82; p = 0.01). Five studies including 357 patients did not show a significant difference in length of stay (standardized mean difference, –0.04; p = 0.82).

LIMITATIONS:

Local anesthetic used in block varied in type and quantity across different studies. There were heterogeneities in pain score measurements and opioid consumption. Patient populations may be different among studies.

CONCLUSIONS:

Transversus abdominis block can lead to a lower pain score at rest within the first 6 hours and reduce opioid consumption within the first 24 hours. See Video Abstract at http://links.lww.com/DCR/A997.
BaiJiu Increases Nitric Oxide Bioactivity of Chinese Herbs Used to Treat Coronary Artery Disease Through the NO3 −–NO2 −–NO Pathway
Authors: Tang Yaoping , Liu Ying , Yin Bangqiao , Guo Yuhong , Liu Yuan , Zhao Yangyang , Wang Ying , Cao Yingying , Feng Jiaoqun , Leng Jing , Huang Congxin
Published: September 2019

BaiJiu (BJ) is a type of Chinese rice wine combined with the traditional Chinese herbs GuaLou (GL) and XieBai (XB), which have been used to treat and prevent coronary artery disease for nearly 2000 years in China. However, the mechanisms behind the compatibility of the components of this compound (GLXBBJ) have not been deeply investigated. In this study, the compatibility of the GLXBBJ compounds with nitric oxide (NO) bioactivity was evaluated in herbs, cells, and isolated aortic rings. Nitrate (NO3
−) and nitrite (NO2
−) concentrations were quantified by the Griess method. Nitric oxide (NO) was quantified by a multifunctional enzyme marker using a fluorescent probe. Qualitative analysis of l-arginine-endothelial NO synthase (eNOS) was performed by Western blotting. The tension of aortic rings was measured by multimyograph system. The ability of BJ to reduce NO3
− to NO2
− and NO2
− to NO was strongest under hypoxic conditions and was not affected by temperature. BJ-containing serum significantly decreased the NO3
− content and increased the NO2
− content in hypoxic cells. Combining BJ with GL, XB, or GLXB resulted in stronger vasodilation effects. These results demonstrate that BJ effectively reduces NO3
−/NO2
−, although only a small amount of NO3
− is present. Once combined with GL, XB, or GLXB, which are rich in NO3
−/NO2
−, robust NO bioactivity was generated through the NO3
−–NO2
−–NO pathway. Therefore, this study supports the potential of using traditional Chinese herbs for promoting medical innovation and for future drug development.
Development and Psychometric Characteristics of the TBI-QOL Communication Item Bank
Authors: Cohen Matthew L. , Kisala Pamela A. , Boulton Aaron J. , Carlozzi Noelle E. , Cook Christine V. , Tulsky David S.
Published: September 2019

Objective:

To develop an item response theory (IRT)-based patient-reported outcome measure of functional communication for adults with traumatic brain injury (TBI).

Setting:

Five medical centers that were TBI Model Systems sites.

Participants:

A total of 569 adults with TBI (28% complicated-mild; 13% moderate; and 58% severe).

Design:

Grounded theory-based qualitative item development, large-scale item calibration testing, confirmatory factor analyses, psychometric analyses with graded response model IRT.

Main Measure:

Traumatic Brain Injury-Quality of Life (TBI-QOL) Communication Item Bank, version 1.0.

Results:

From an initial pool of 48 items, 31 items were retained in the final instrument based on adequate fit to a unidimensional model and absence of bias across several demographic and clinical subgroupings. The TBI-QOL Communication Item Bank demonstrated excellent score precision (reliability ≥ 0.95) across a wide range of communication impairment levels, particularly for individuals with more severe difficulties. The TBI-QOL Communication Item Bank is available as a full item bank, fixed-length short form, and as a computerized adaptive test.

Conclusions:

The TBI-QOL Communication Item Bank permits precise measurement of patient-reported functional communication after TBI. Future development will validate the instrument against performance-based, clinician-reported, and surrogate-reported assessments.
An Exploratory Study on the Use of Event-Related Potentials as an Objective Measure of Auditory Processing and Therapy Effect in Patients With Tinnitus: A Transcranial Direct Current Stimulation Study
Authors: Jacquemin Laure , Mertens Griet , Van de Heyning Paul , Vanderveken Olivier M. , Topsakal Vedat , De Hertogh Willem , Michiels Sarah , Beyers Jolien , Moyaert Julie , Van Rompaey Vincent , Gilles Annick
Published: September 2019

Objective:

Treatment effect in tinnitus research is commonly evaluated by use of self-report questionnaires. As this is a solely subjective assessment method, the need for an objective measurement is paramount to genuinely evaluate the effects of therapeutic interventions. The current study explores the value of event-related potentials (ERPs) in the evaluation of high-definition transcranial direct current stimulation (HD-tDCS) for tinnitus treatment.

Study Design:

Prospective exploratory study.

Setting:

Tertiary referral center.

Patients:

Twenty-two chronic tinnitus patients.

Intervention:

HD-tDCS.

Main Outcome Measures:

ERPs.

Results:

The results show a significant shortening of the N1, P2, N2, and P3 latencies after HD-tDCS treatment. Moreover, the increased amplitude of the P2 and N2 peaks result in more salient and clear peaks, with the amplitude of N2 being significant larger after HD-tDCS. However, the ERP changes are not significantly correlated with the change in tinnitus functional index (TFI) total score.

Conclusions:

The current study was the first to explore ERPs as objective measure in a study with HD-tDCS in tinnitus patients. Adding ERPs to the outcome measures in tinnitus research may lead to a better understanding of the therapeutic effect in the future. The results showed a shortening of ERP latencies and an increased N2 amplitude, possibly reflecting more effective sound processing with higher recruitment of synchronized neurons in the auditory cortex. Future studies should elaborate on these results, by collecting control data and adding a sham group, to provide a better insight in the underlying mechanism of the ERP changes after tinnitus treatment.
Glucocorticoid for Hearing Preservation After Cochlear Implantation: A Systemic Review and Meta-analysis of Animal Studies
Authors: Shaul Chanan , Venkatagiri Padmavathi K. , Lo Jonathon , Eastwood Hayden T. , Bester Christofer W. , Briggs Robert J. S. , O’Leary Stephen J.
Published: September 2019

Objectives:

To conduct systematic review and meta-analyses of preclinical studies describing the efficacy of glucocorticoids administered via different routes for hearing preservation after cochlear implantation.

Data Sources:

A literature search was performed in PubMed to identify peer-reviewed articles published before December 31, 2017, with no language restrictions. Search components were “Cochlear implant,” “Glucocorticoids,” and “Hearing preservation.” The results were specified for animal studies.

Study Selection:

Original studies in which glucocorticoids were administered before or during cochlear implantation in animal models and hearing threshold shifts were measured using auditory brainstem response.

Data Extraction:

Quality of included studies was assessed using the SYstematic Review Centre for Laboratory animal Experimentation protocol. Threshold Shift reduction between the “study” and “control” groups at 1-month postimplantation was the parameter used to evaluate hearing preservation.

Data Synthesis:

The random-effects models were used to combine the results of selected studies. Separate meta-analyses were performed for drug-eluting electrodes, systemic, and local administration.

Conclusions:

Administering either systemic or topical glucocorticosteroids had a significant effect on preserving low and high-frequency hearing. Topical administration was equally effective across a range of concentration levels and provided maximal hearing preservation when applied 120 minutes before implantation. The effect of systemic treatment was achieved with high doses, equivalent to 26 mg of dexamethasone per day in humans. No significant effect was found with the use of drug-eluting electrodes and more studies are needed to characterise the utility and efficacy of this administration method.
Integrated model for end-stage liver disease maybe superior to some other model for end-stage liver disease-based systems in addition to Child-Turcotte-Pugh and albumin-bilirubin scores in patients with hepatitis B virus-related liver cirrhosis and spontaneous bacterial peritonitis
Authors: Chen Pin-Cheng , Chen Bo-Huan , Huang Chien-Hao , Jeng Wen-Juei , Hsieh Yi-Chung , Teng Wei , Chen Yi-Cheng , Ho Yu-Pin , Sheen I-Shyan , Lin Chun-Yen
Published: September 2019

Objectives

For mortality prediction of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis, no direct comparisons have been made among the eight models, Child-Turcotte-Pugh (CTP) score, model for end-stage liver disease (MELD), MELD-Na, integrated MELD (iMELD) score, MELD to sodium (MESO) index, modification of the MELD scoring system (Refit MELD), Refit MELD-Na and Albumin-Bilirubin (ALBI) score.

Materials and methods

Between January 2005 and July 2017, 314 patients who met the criteria for liver cirrhosis with the first episode of SBP were enrolled in this retrospective study. Clinical and laboratory data were obtained at diagnosis. Patients were followed up until February 2018 or death.

Results

Patients were predominantly middle-aged male. Hepatitis B virus (HBV) infection accounted for the majority of the etiologies (41.7%) with 33.6% of the patients received antivirals. The in-hospital mortality rate was 39.8%. The cumulative 3-month and 6-month mortality rates were 51.6 and 60.2%, respectively. For patients with HBV related, not hepatitis C virus or alcohol related, liver cirrhosis, iMELD had the highest area under receiver operating characteristic curve (AUC) and was significantly superior to MELD, MESO, and Refit MELD in addition to CTP and ALBI scores in predicting 3-month and 6-month mortality.

Conclusion

For patients with HBV-related liver cirrhosis and SBP, iMELD had the highest AUC among these eight models and was significantly superior to MELD, MESO, and Refit MELD in addition to CTP and ALBI scores in predicting 3-month and 6-month mortalities.
Fostering Civility in Learning Conversations
Authors: Clark Cynthia M. , Fey Mary K.
Published: September 2019

Background

Civility, psychological safety, and effective stress management are essential for meaningful learning conversations.

Problem

Incivility triggers fear and humiliation, impairs clinical judgment and learning, reduces psychological safety, and increases cognitive load. These factors converge to make learners less likely to incorporate feedback, speak up when there is a problem, and discuss practice errors and patient safety issues.

Approach

The authors combined the Basic Assumption and the PAAIL (Preview, Advocacy1, Advocacy2, Inquiry, and Listen) conversational strategy to help surface (rather than obscure) both educators' and learners' thinking. The synergy of these 2 strategies allows educators to identify individual learning needs and develop the learners' clinical judgment skills. This process improves learning by reducing incivility and cognitive load, improving psychological safety, and strengthening clinical judgment skills.

Conclusion

This conversational strategy can minimize stress and anxiety in learners and optimize learning.
Quality Improvement Project to Evaluate Discharge Prescriptions in Children With Cystic Fibrosis
Authors: Merino Sanjuán Matilde , Chorro-Mari Veronica , Nwokoro Chinedu , Christiansen Nanna , Pao Caroline , Gomez-Pastrana Duran David , Climente Marti Monica
Published: September 2019

Introduction:

Cystic Fibrosis (CF) requires multiple pharmaceutical treatments, elevating the risk of medication errors (ME), which may compromise patient safety. This study aimed to improve the quality of discharge prescriptions (DPs) using indicators following admissions for IV antibiotics in pediatric CF patients.

Methods:

This project involved a longitudinal observational retrospective descriptive study followed by a longitudinal quasi-experimental prospective phase between January 2013 and December 2016 in CF patients admitted to a London Children’s Hospital. The CF pharmacist reviewed DPs. Six rights of medication administration were defined (6R): dose, drug, frequency, duration of treatment, pharmaceutical form, and route of administration. We classified ME according to 6R, including subtype of error: committed/omitted. We calculated quality indicators by dividing the number of each correct parameter defined by 6R by number of DPs. Retrospective results were used prospectively to describe and implement improvement strategies and safety actions.

Results:

The retrospective study phase included 42 CF children (100 hospital admissions and 1,343 drugs). The prospective phase included thirty-five children (55 admissions and 822 drugs). The total number of ME identified was 148 (78 committed; 70 omitted) in retrospective phase and 135 (19 committed; 116 omitted) in prospective phase. Quality indicators for drug and dose showed significant improvement after implementing safety strategies. The global quality indicator increased from 22% (retrospective) to 41.82% (prospective), but we did not achieve the previously defined quality standard value (50%).

Conclusions:

A retrospective review of DP by a CF Pharmacist identified failures in DP quality. Implementing improvement strategies improved prescribing. Integrating pharmacist within multidisciplinary team improves DP reducing errors.
Ten Years of Kidney Paired Donation at Mayo Clinic: The Benefits of Incorporating ABO/HLA Compatible Pairs
Authors: Basu Arpita , Prieto Mikel , Kosberg Catherine , Mai Martin L. , Khamash Hasan A. , Jadlowiec Caroline C. , Issa Naim S. , Dean Patrick G. , Lorenz Elizabeth C. , Stegall Mark D. , Schinstock Carrie A.
Published: September 2019

Background.

We examined the 10-year experience of Mayo Clinic's kidney paired donation (KPD).We aimed to determine the benefits for the recipients of enrolled ABO/HLA compatible pairs and determine the factors associated with prolonged KPD waiting time.

Methods.

We performed a retrospective study of 332 kidney transplants facilitated by the Mayo 3-site KPD program from September 2007 to June 2018.

Results.

The median (interquartile range) time from KPD entry to transplantation was 89 days (42-187 days). The factors independently associated with receiving a transplant >3 months after KPD entry included recipient blood type O and calculated panel reactive antibodies ≥98%. Fifty-four ABO/HLA compatible pairs participated in KPD for the following reasons: cytomegalovirus mismatch (18.5% [10/54]), Epstein-Barr virus (EBV) mismatch (EBV) (9.3% [5/54]), age/size mismatch (51.9% [28/54]), or altruistic reasons (20.3% [11/54]). Cytomegalovirus and EBV mismatch were avoided in 90% (9/10) and 100% (5/5) of cases. Recipients who entered KPD for age/size mismatch and altruistic reasons received kidneys from donors with lower Living Kidney Donor Profile Index scores than their actual donor (median [interquartile range] 31.5 [12.3-47]; P < 0.001 and 26 (-1 to 46); P = 0.01 points lower, respectively). Median time to transplant from KPD entry for compatible pair recipients was 70 days (41-163 days), and 44.4% (24/54) of these transplants were preemptive. All chains/swaps incorporating compatible pairs included ABO/HLA incompatible pairs.

Conclusions.

KPD should be considered for all living donor/recipient pairs because the recipients of these pairs can derive personal benefit from KPD while increasing the donor pool for difficult to match pairs.
Serotonergic modulation of walking inDrosophila
Authors: Howard Clare E. , Chen Chin-Lin , Tabachnik Tanya , Hormigo Rick , Ramdya Pavan , Mann Richard S.
Published: September 2019

To navigate complex environments, animals must generate highly robust, yet flexible, locomotor behaviors. For example, walking speed must be tailored to the needs of a particular environment: Not only must animals choose the correct speed and gait, they must also rapidly adapt to changing conditions, and respond to sudden and surprising new stimuli. Neuromodulators, particularly the small biogenic amine neurotransmitters, allow motor circuits to rapidly alter their output by changing their functional connectivity. Here we show that the serotonergic system in the vinegar fly,Drosophilamelanogaster, can modulate walking speed in a variety of contexts and in response to sudden changes in the environment. These multifaceted roles of serotonin in locomotion are differentially mediated by a family of serotonergic receptors with distinct activities and expression patterns.
DirectMS1: MS/MS-free identification of 1000 proteins of cellular proteomes in 5 minutes
Authors: Ivanov Mark V. , Bubis Julia A. , Gorshkov Vladimir , Tarasova Irina A. , Levitsky Lev I. , Lobas Anna A. , Solovyeva Elizaveta M. , Pridatchenko Marina L. , Kjeldsen Frank , Gorshkov Mikhail V.
Published: September 2019

Proteome characterization relies heavily on tandem mass spectrometry (MS/MS) and is thus associated with instrumentation complexity, lengthy analysis time, and limited duty-cycle. It was always tempting to implement approaches which do not require MS/MS, yet, they were constantly failing in achieving meaningful depth of quantitative proteome coverage within short experimental times, which is particular important for clinical or biomarker discovery applications. Here, we report on the first successful attempt to develop a truly MS/MS-free and label-free method for bottom-up proteomics. We demonstrate identification of 1000 protein groups for a standard HeLa cell line digest using 5-minute LC gradients. The amount of loaded sample was varied in a range from 1 ng to 500 ng, and the method demonstrated 10-fold higher sensitivity compared with the standard MS/MS-based approach. Due to significantly higher sequence coverage obtained by the developed method, it outperforms all popular MS/MS-based label-free quantitation approaches.
Causal adaptation to visual input dynamics governs the development of complex cells in V1
Authors: Matteucci Giulio , Zoccolan Davide
Published: September 2019

Visual perception relies on cortical representations of visual objects that remain relatively stable with respect to the variation in object appearance typically encountered during natural vision (e.g., because of position changes). Such stability, known as transformation tolerance, is built incrementally along the ventral stream (the cortical hierarchy devoted to shape processing), but early evidence of position tolerance is already found in primary visual cortex (V1) for complex cells1. To date, it remains unknown what mechanisms drive the development of this class of neurons, as well as the emergence of tolerance across the ventral stream. Leading theories suggest that tolerance is learned, in an unsupervised manner, either from the temporal continuity of natural visual experience2–10 or from the spatial statistics of natural scenes11,12. However, neither learning principle has been empirically proven to be at work in the postnatal developing cortex. Here we show that passive exposure to temporally continuous visual inputs during early postnatal life is essential for normal development of complex cells in rat V1. This was causally demonstrated by rearing newborn rats with frame-scrambled versions of natural movies, resulting in temporally unstructured visual input, but with unaltered, natural spatial statistics. This led to a strong reduction of the fraction of complex cells, which also displayed an abnormally fast response dynamics and a reduced ability to support stable decoding of stimulus orientation over time. Conversely, our manipulation did not prevent the development of simple cells, which showed orientation tuning and multi-lobed, Gabor-like receptive fields as sharp as those found in rats reared with temporally continuous natural movies. Overall, these findings causally implicate unsupervised temporal learning in the postnatal development of transformation tolerance but not of shape tuning, in agreement with theories that place the latter under the control of unsupervised adaptation to spatial, rather than temporal, image statistics13–16.
A small family business: synergistic and additive effects of the queen and the brood on worker reproduction in a primitively eusocial bee
Authors: Orlova Margarita , Starkey Jesse , Amsalem Etya
Published: September 2019

The mechanisms that maintain reproductive division of labor in social insects are still incompletely understood. Most studies focus on the relationship between adults, overlooking another important stakeholder in the game – the juvenile offspring. Recent studies from various social species show that not only the queen, but also the brood regulates reproductive division of labor between females, but how the two coordinate to maintain reproductive monopoly remained unexplored.

Our study aims at disentangling the roles of the brood and the queen in regulating worker reproduction in primitively eusocial bees. We examined the effects induced by the brood and queen, separately and together, on the behavioral, physiological and brain gene expression of Bombus impatiens workers. We found that young larvae induce a releaser effect in workers, decreasing egg laying and aggressive behaviors, while the queen induces both releaser and primer effects, modifying worker aggressive and egg laying behavior and reproductive physiology. The expression of reproduction- and aggression-related genes was altered in the presence of both queen and brood, but the effect was stronger or the same in the presence of the queen.

We identified two types of interactions between the queen and the brood in regulating worker reproduction: (1) synergistic interactions regulating worker physiology, where the combined effect of the queen and the brood was greater than each of them separately; (2) additive interactions regulating worker behavior, where the combined effects of the queen and the brood are the gross sum of their separated effects. In these interactions the brood acted in a manner similar to the queen but to a much smaller extent and improved the quality of the effect induced by the queen. Our results suggest that the queen and the brood of primitively eusocial bees coordinate synergistically, additively, and sometimes even redundantly to regulate worker behavior and reproduction, and the interaction between them exists in multiple regulatory levels.
Field manipulation of competition among hybrids reveals dynamic and highly stable features of a complex fitness landscape driving adaptive radiation
Authors: Martin Christopher H. , Gould Katelyn
Published: September 2019

The effect of the environment on fitness in natural populations is a fundamental question in evolutionary biology. However, experimental manipulations of environment and phenotype are rare. Thus, the relative importance of the competitive environment versus intrinsic organismal performance in shaping the location, height, and fluidity of fitness peaks and valleys remains largely unknown. We experimentally tested the effect of competitive environment on the fitness landscape driving the evolution of novelty in a sympatric adaptive radiation of a generalist and two trophic specialist pupfishes, a scale-eater and molluscivore, endemic to San Salvador Island, Bahamas. We manipulated phenotypes, by generating 2,611 F4/F5 lab-reared hybrids, and competitive environment, by altering frequencies of rare phenotypes between high- and low-frequency field enclosures, then tracked hybrid survival in two natural lake populations on San Salvador. We found no evidence of frequency-dependent effects on survival fitness landscapes, indicating robustness to the competitive environment. Although survival surfaces favored alternate phenotypes between lakes, joint fitness estimation across lake environments supported multiple fitness peaks for generalist and molluscivore phenotypes and a large fitness valley isolating the most divergent scale-eater phenotype, strikingly similar to a previous independent field experiment. The consistency of this complex fitness landscape across competitive environments, multivariate trait axes, and spatiotemporal heterogeneity provides surprising evidence of stasis in major features of fitness landscapes despite substantial environmental variance, possibly due to absolute biomechanical constraints on diverse prey capture strategies within this radiation. These results challenge competitive speciation theory and highlight the interplay between organism and environment underlying static and dynamic features of the adaptive landscape.
Deep learning for brains?: Different linear and nonlinear scaling in UK Biobank brain images vs. machine-learning datasets
Authors: Schulz Marc-Andre , Yeo B.T. Thomas , Vogelstein Joshua T. , Mourao-Miranada Janaina , Kather Jakob N. , Kording Konrad , Richards Blake , Bzdok Danilo
Published: September 2019

In recent years, deep learning has unlocked unprecedented success in various domains, especially in image, text, and speech processing. These breakthroughs may hold promise for neuroscience and especially for brain-imaging investigators who start to analyze thousands of participants. However, deep learning is only beneficial if the data have nonlinear relationships and if they are exploitable at currently available sample sizes. We systematically profiled the performance of deep models, kernel models, and linear models as a function of sample size on UK Biobank brain images against established machine learning references. On MNIST and Zalando Fashion, prediction accuracy consistently improved when escalating from linear models to shallow-nonlinear models, and further improved when switching to deep-nonlinear models. The more observations were available for model training, the greater the performance gain we saw. In contrast, using structural or functional brain scans, simple linear models performed on par with more complex, highly parameterized models in age/sex prediction across increasing sample sizes. In fact, linear models kept improving as the sample size approached ∼10,000 participants. Our results indicate that the increase in performance of linear models with additional data does not saturate at the limit of current feasibility. Yet, nonlinearities of common brain scans remain largely inaccessible to both kernel and deep learning methods at any examined scale.
A novel fully automated MRI-based deep-learning method for classification of IDH mutation status in brain gliomas
Authors: Bangalore Yogananda Chandan Ganesh , Shah Bhavya R , Vejdani-Jahromi Maryam , Nalawade Sahil S , Murugesan Gowtham K , Yu Frank F , Pinho Marco C , Wagner Benjamin C , Mickey Bruce , Patel Toral R , Fei Baowei , Madhuranthakam Ananth J , Maldjian Joseph A
Published: September 2019

“The authors have withdrawn their manuscript because they have identified errors in their analysis. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.”
Tracking infection dynamics at single-cell level reveals highly resolved expression programs of a large virus infecting algal blooms
Authors: Ku Chuan , Sheyn Uri , Sebé-Pedrós Arnau , Ben-Dor Shifra , Schatz Daniella , Tanay Amos , Rosenwasser Shilo , Vardi Assaf
Published: September 2019

Nucleocytoplasmic large DNA viruses have the largest genomes among all viruses and infect diverse eukaryotes across various ecosystems, but their expression regulation and infection strategies are not well understood. We profiled single-cell transcriptomes of the worldwide-distributed microalga Emiliania huxleyi and its specific coccolithovirus responsible for massive bloom demise. Heterogeneity in viral transcript levels detected among single cells was used to reconstruct the viral transcriptional trajectory and to map cells along a continuum of infection states. This enabled identification of novel viral genetic programs, which are composed of five kinetic classes with distinct promoter elements. The infection substantially changed the host transcriptome, causing rapid shutdown of protein-encoding nuclear transcripts at the onset of infection, while the plastid and mitochondrial transcriptomes persisted to mid- and late stages, respectively. Single-cell transcriptomics thereby opens the way for tracking host-pathogen infection dynamics at high resolution within microbial communities in the marine environment.
The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection
Authors: Giraud-Gatineau Alexandre , Coya Juan Manuel , Maure Alexandra , Biton Anne , Thomson Michael , Bernard Elliott M. , Gutierrez Maximiliano G. , Larrouy-Maumus Gérald , Brosch Roland , Gicquel Brigitte , Tailleux Ludovic
Published: September 2019

Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed macrophages into potent bactericidal phagocytes. We found that 1,495 genes were differentially expressed in M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of genes involved in metabolism, lysosome biogenesis and activation. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including nitric oxide production, phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB (TFEB), involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections.
Parallel evolution of tobramycin resistance across species and environments
Authors: Scribner Michelle R. , Santos-Lopez Alfonso , Marshall Christopher W. , Deitrick Christopher , Cooper Vaughn S.
Published: September 2019

An important problem in evolution is identifying the genetic basis of how different species adapt to similar environments. Understanding how various bacterial pathogens evolve in response to antimicrobial treatment is a pressing example of this problem, where discovery of molecular parallelism could lead to clinically useful predictions. Evolution experiments with pathogens in environments containing antibiotics combined with periodic whole population genome sequencing can be used to characterize the evolutionary dynamics of the pathways to antimicrobial resistance. We separately propagated two clinically relevant Gram-negative pathogens,Pseudomonas aeruginosaandAcinetobacter baumannii, in increasing concentrations of tobramycin in two different environments each: planktonic and biofilm. Independent of the pathogen, populations adapted to tobramycin selection by parallel evolution of mutations infusA1, encoding elongation factor G, andptsP, encoding phosphoenolpyruvate phosphotransferase. As neither gene is a direct target of this aminoglycoside, both are relatively novel and underreported causes of resistance. Additionally, both species acquired antibiotic-associated mutations that were more prevalent in the biofilm lifestyle than planktonic, in electron transport chain components inA. baumanniiand LPS biosynthesis enzymes inP. aeruginosapopulations. Using existing databases, we discovered bothfusA1andptsPmutations to be prevalent in antibiotic resistant clinical isolates. Additionally, we report site-specific parallelism offusA1mutations that extend across several bacterial phyla. This study suggests that strong selective pressures such as antibiotic treatment may result in high levels of predictability in molecular targets of evolution despite differences between organisms’ genetic background and environment.
The cell division factor ZapB is required for bile resistance inSalmonella enterica
Authors: Hernández Sara B. , Fernández-Fernández Rocío , Puerta-Fernández Elena , Urdaneta Verónica , Casadesús Josep
Published: September 2019

A gene annotated asyiiUin the genome ofSalmonella entericaserovar Typhimurium encodes a protein homologous toE. coliZapB, a non-essential cell division factor involved in Z-ring assembly. ZapB−null mutants ofS. entericaare bile-sensitive. The ZapB protein is degraded in the presence of sodium deoxycholate (DOC), and degradation appears to involve the Lon protease. The amount ofzapBmRNA increases in the presence of a sublethal concentration of DOC. This increase is not caused by upregulation ofzapBtranscription but by increased stability ofzapBmRNA. DOC-induced increase of thezapBtranscript is suppressed by anhfqmutation, suggesting the involvement of a small regulatory RNA. We provide evidence that such sRNA is MicA. Increased stability ofzapBmRNA in the presence of DOC may counter degradation of bile-damaged ZapB, thus providing sufficient level of functional ZapB protein to permit Z-ring assembly in the presence of bile.

IMPORTANCE

Bile salts have bactericidal activity as a consequence of membrane disruption, protein denaturation and DNA damage. However, intestinal bacteria are resistant to bile. Envelope structures such as the lipopolysaccharide and the enterobacterial common antigen act as barriers that reduce intake of bile salts. Remodelling of the outer membrane and the peptidoglycan, activation of efflux pumps, and upregulation of stress responses also contribute to bile resistance. This study adds the cell division factor ZapB (and presumably the Z-ring) to the list of cellular functions involved in bile resistance.
Integration of brief light flashes varying in intensity and duration by the human circadian system
Authors: Joyce Daniel S. , Spitschan Manuel , Zeitzer Jamie M.
Published: September 2019

The melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are characterised by a delayed off-time following light offset. Here, we exploited this unusual physiologic property to characterise the exquisite sensitivity of the human circadian system to flashed light. In a 34-hour in-laboratory between-subjects design, we examined variable-intensity (3-9500 photopic lux; n=28 participants) full-field flashes at fixed duration (2 ms), and variable-duration (10μs-10 s) full-field flashes at fixed intensity (2000 photopic lux; n=31 participants) delivered using eye masks. We measured the circadian phase shift of the dim-light melatonin onset (DLMO) on the subsequent evening, acute melatonin suppression, objective alertness, and subjective sleepiness during the flash sequence. We find a clear dose-response relationship between flash intensity and the induced circadian phase shift, with an approximate increase of 10 minutes of phase delay for each ten-fold increase in photopic illuminance, but no parametric relationship between flash duration and induced circadian phase shift.
Motor output and control input in flapping flight: a compact model of the deforming wing kinematics of manoeuvring hoverflies
Authors: Nagesh Indira , Walker Simon M. , Taylor Graham K.
Published: September 2019

Insects are conventionally modelled as controlling flight by varying a few summary kinematic parameters that are defined on a per-wingbeat basis, such as the stroke amplitude, mean stroke angle, and mean wing pitch angle. Nevertheless, as insects have tens of flight muscles and vary their kinematics continuously, the true dimension of their control input subspace is likely to be much higher. Here we present a compact description of the deforming wing kinematics of 36 manoeuvring Eristalis hoverflies, applying functional principal components analysis to Fourier series fits of the wingtip position and wing twist measured over 26,541 wingbeats. This analysis offers a high degree of data reduction, in addition to insight into the natural kinematic couplings. We used statistical resampling techniques to verify that the principal components were repeatable features of the data, and analysed their coefficient vectors to provide insight into the form of these natural couplings. Conceptually, the dominant principal components provide a natural set of control input variables that span the control input subspace of this species, but they can also be thought of as output states of the flight motor. This functional description of the wing kinematics is appropriate to modelling insect flight as a form of limit cycle control.
Conditional KCa3.1-Transgene Induction in Murine Skin Produces Pruritic Eczematous Dermatitis With Severe Epidermal Hyperplasia and Hyperkeratosis
Authors: Lozano-Gerona Javier , Oliván-Viguera Aida , Delgado-Wicke Pablo , Singh Vikrant , Brown Brandon M. , Tapia-Casellas Elena , Pueyo Esther , Sofía Valero Marta , Garcia-Otín Ángel-Luis , Giraldo Pilar , Abarca-Lachen Edgar , Surra Joaquín C. , Osada Jesús , Hamilton Kirk L. , Raychaudhuri Siba P. , Marigil Miguel , Juarranz Ángeles , Wulff Heike , Miura Hiroto , Gilaberte Yolanda , Köhler Ralf
Published: September 2019

Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-β1 (60-fold), IL-23 (34-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-β1 (−88%), IL-23 (−77%), and IL-6 (−90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles pathological features of eczematous dermatitis and identifies KCa3.1 as a regulator of epidermal homeostasis and spongiosis, and as a potential therapeutic target.