bluuebunny/crossref_metadata_2025 huggingface dataset:
Poisson Probability of Failing to Meet Minimum Case Volumes in Pediatric Surgery Fellowships
Authors: Lucas Donald J. , Huang Eunice Y. , Gosain Ankush
Published: August 2019

Introduction:

With the expansion of pediatric surgery fellowships from 2008 to 2018, there is concern for the dilution of training experience, especially for rare index cases. The Accreditation Council for Graduate Medical Education (ACGME) established required minimum case numbers by case type, but this is a program requirement rather than an individual trainee requirement. The American Board of Surgery (ABS) is considering instituting minimum case requirements across 5 broad categories for individuals to be board-eligible in pediatric surgery.

Methods:

The ACGME National Data Report summary case logs were obtained for graduating fellows in pediatric surgery from 2008 to 2018. Median case volumes were compared to minimum ACGME case numbers and proposed ABS individual requirements. Using Poisson distributions, probabilities of individual fellows failing to meet minimum case numbers were calculated.

Results:

The average annual probability that a median program would fail to meet minimum ACGME case numbers in at least 1 category was estimated at 16.6%. Using the proposed ABS system, the probability of failure was estimated at 44.1%. No temporal trend was found in the annual probability of failure in either the ACGME or the proposed ABS system.

Conclusions:

There is significant risk of a fellow failing to meet case minimums in the ACGME system and the proposed ABS system. This probability is increased for the half of programs below median. If the ABS institutes case minimums as a requirement for certification in pediatric surgery, the current training paradigm may be impacted at some programs.
X-shaped Breast Lift to Improve Surgical Ergonomics in Bilateral Axillo-Breast Approach Thyroidectomy
Authors: Tsai Chung-Yu , Liu Shiuh-Inn , Chen I-Shu , Liang Tsung-Jung
Published: August 2019

Background:

Endoscopic thyroidectomy through the bilateral axillo-breast approach (BABA) is a good option for patients who have been advised thyroid resection but are concerned about the cosmetic results. This technique uses the breast tissue as a pivot to facilitate maneuvering of the surgical instruments. However, it is difficult to use this technique in patients with small breasts or having a flat chest.

Materials and Methods:

The authors developed an “X-shaped breast lift” method using fabric adhesive tape, to push up and augment the breast tissue to facilitate the thyroid dissection procedure. Changes before and after the breast lift were quantified by measuring the angle of breast tilt and the distance between relevant anatomic landmarks.

Results:

Fifteen consecutive patients underwent this procedure before undergoing BABA thyroidectomy. The mean breast tilt angle increased from 3.2 to 9.8 degrees, which is a >3-fold increase (+6.6 degree, 206%). The mean distance between the cricoid cartilage and nipple was reduced by 1.9 cm (−8%), and the mean distance between the axillary incision and nipple increased by 1.1 cm (9%). No skin trauma or ulceration was observed.

Conclusions:

X-shaped breast lift is easy to perform, and it significantly improves the thyroid dissection process with no significant adverse effects. It can be used for all cases of BABA thyroidectomy.
Postcolonoscopy Appendicitis: A Review of 57 Cases
Authors: Hamid Hytham K.S. , Ahmed Amjed Y. , Simmons Joshua R.
Published: August 2019

The purpose of this study is to review the cases of postcolonoscopy appendicitis (PCA) reported in the literature. A comprehensive search using PubMed, EMBASE, Scopus, and Google Scholar identified 57 cases. The median age at presentations of PCA was 55 years. PCAs typically occurred during the first 24 hours after colonoscopy, and the majority developed after diagnostic colonoscopy. Clinical presentations were similar to those with common acute appendicitis, though with a high perforation rate. Most patients were correctly diagnosed using ultrasound or computed tomography scan. Treatment included open appendicectomy, laparoscopic appendicectomy or cecotomy, radiologic drainage of the abscess, nonoperative treatment with antibiotics. In addition to barotrauma, fecalith impaction into the appendiceal lumen, direct trauma to the appendiceal orifice, and underlying ulcerative colitis, a pre-existing subclinical disease of the appendix seems to play an important role in the pathogenesis. For PCA, timely diagnosis and management are crucial to attain a satisfactory outcome.
Use of ShotSpotter detection technology decreases prehospital time for patients sustaining gunshot wounds
Authors: Goldenberg Anna , Rattigan Deviney , Dalton Michael , Gaughan John P. , Thomson J. Scott , Remick Kyle , Butts Christopher , Hazelton Joshua P.
Published: August 2019

BACKGROUND

Shorter prehospital time in patients sustaining penetrating trauma has been shown to be associated with improved survival. Literature has also demonstrated that police transport (vs. Emergency Medical Services [EMS]) shortens transport times to a trauma center. The purpose of this study was to determine if ShotSpotter, which triangulates the location of gunshots and alerts police, expedited dispatch and transport of injured victims to the trauma center.

METHODS

All shootings which occurred in Camden, NJ, from 2010 to 2018 were reviewed. Demographic, geographic, response time, transport time, and field intervention data were collected from medical and police records. We compared shootings where the ShotSpotter was activated versus shootings where ShotSpotter was not activated. Incidents, which did not occur in Camden or where complete data were not available, were excluded as were patients not transported by police or EMS.

RESULTS

There were 627 shootings during the study period which met inclusion criteria with 190 (30%) activating the ShotSpotter system. Victims involved in shootings with ShotSpotter activation were more severely injured, more likely to be transported by police, less likely to undergo trauma bay resuscitative measures, and more likely to receive blood products. Mortality, when adjusted for distance, Trauma, and Injury Severity Score, Injury Severity Score, and shock index, was not significantly different between ShotSpotter and non-ShotSpotter incidents. ShotSpotter activation significantly reduced both the response time as well as transport time for both police and EMS (all p < 0.05).

CONCLUSION

The activation of the ShotSpotter technology increased the likelihood of police transport of gunshot victims. Furthermore, the use of this technology resulted in shorter response times as well as transport times for both police and EMS. This technology may be beneficial in enhancing the care of victims of penetrating trauma.

LEVEL OF EVIDENCE

Therapeutic/Care management, level III.
Propranolol attenuates cognitive, learning, and memory deficits in a murine model of traumatic brain injury
Authors: Zeeshan Muhammad , Hamidi Mohammad , O'Keeffe Terence , Bae Esther H. , Hanna Kamil , Friese Randall S. , Kulvatunyou Narong , Zakaria El Rasheid , Gries Lynn , Tang Andrew , Joseph Bellal
Published: August 2019

BACKGROUND

β-blockers have been shown to improve survival after traumatic brain injury (TBI); however, the impact of continuous dosage of β-blockers on cognitive function has not been elucidated. We hypothesized that a daily dose of propranolol can improve memory, learning, and cognitive function following TBI.

STUDY DESIGN

Twenty male C57BL mice were subjected to a cortical-controlled moderate TBI. Two hours after TBI, animals were randomly allocated to either the β-blocker group (n = 10) or the placebo group (n = 10). Mice in the β-blocker group received intraperitoneal 4 mg/kg propranolol every 24 hours for 7 days while the placebo group received 4 mg/kg normal saline. Baseline novel object recognition and classic maze tests were done prior to TBI and then daily from Day 1 through 7 after TBI. Animals were sacrificed on Day 7. Serum biomarkers were measured using ELISA and brain sections were analyzed using western blot and hematoxylin and eosin staining.

RESULTS

Both the β-blocker and placebo groups had lower recognition index scores compared with the baseline following TBI. β-blocker mice had significantly higher novel object recognition scores compared with placebo mice 2 days after TBI. The β-blocker group required less time to complete the maze-test compared to placebo group after Day 4. There was no difference regarding the serum levels of IL-1β, IL-6, and TNF-α. The β-blocker group had lower levels of UCHL-1 and higher levels of Hsp-70 in brain lysate. Hematoxylin and eosin staining revealed that more neurons in the hippocampal-CA1 area underwent apoptosis in the placebo group compared with the β-blocker group.

CONCLUSION

Postinjury propranolol administration results in improved memory, learning and cognitive functions in a murine model of moderate TBI. Propranolol increases the expression of antiapoptotic protein (Hsp-70) and decreases cell death in the hippocampal-CA1 area compared with the placebo.
The utility of magnetic resonance imaging in pediatric trauma patients suspected of having cervical spine injuries
Authors: Derderian S. Christopher , Greenan Krista , Mirsky David M. , Stence Nicholas V. , Graber Sarah , Hankinson Todd C. , Hubbell Noah , Alexander Allyson , O'Neill Brent R. , Wilkinson C. Corbett , Handler Michael H.
Published: August 2019

BACKGROUND

Pediatric cervical spine injuries (CSI) are rare but potentially devastating sequelae of blunt trauma. Existing protocols to evaluate children at risk for CSI frequently incorporate computed topography (CT) and magnetic resonance imaging (MRI); however, the clinical value of performing both remains unclear.

METHODS

Single-center retrospective review of pediatric trauma patients who underwent both CT and MRI of the cervical spine between 2001 and 2015. Based on radiographic findings, CT and MRI results were grouped into one of three categories: no injury, stable injury, or unstable injury. Radiographic instability was defined by disruption of two or more contiguous spinal columns while radiographic stability was defined by any other acute cervical spine abnormality on imaging. Clinical instability was defined by the need for surgical intervention (halo or spinal fusion), with the remaining patients, including children discharged in a cervical collar, considered clinically stable.

RESULTS

In total, 221 children met inclusion criteria, with a median age of 9 (interquartile range, 3–14). The Glasgow Coma Scale (GCS) score of the cohort was 9 (interquartile range, 4–15). Thirty-three (14.9%) children had clinically unstable injuries, requiring surgical intervention. Among the 160 (72.4%) children with no injury on CT, MRI identified no injury in 84 (52.5%) cases, a stable injury in 76 (47.5%) cases, and an unstable injury in none. Among the 21 children with stable injuries on CT, MRI findings were concordant in 17 (81.0%) cases. In four (19.0%) cases, a spinal column injury was identified on CT and appeared to be stable, but later deemed unstable on MRI. Forty (18.1%) patients had an unstable injury on CT with 100% MRI concordance.

CONCLUSION

In pediatric trauma patients suspected of having a CSI, a normal cervical spine CT is sufficient to rule out a clinically significant CSI as no child with a normal cervical CT was found to be radiographically or clinically unstable.

LEVEL OF EVIDENCE

Diagnostic Test, level III.
Sport and Exercise in Improving Outcomes After Solid Organ Transplantation: Overview From a UK Meeting
Authors: Neuberger James , Armstrong Matthew J. , Fisher James , Mark Patrick , Schmidtke Kelly , Sharif Adnan , Vlaev Ivo
Published: August 2019

Outcomes after solid organ transplantation continue to improve, but premature loss of life remains a major concern, with death from cerebrovascular disease and cardiovascular disease accounting for around 20% late deaths. There are multiple contributory factors including preexisting, and the posttransplant development of, cardiometabolic conditions (such as hypertension, diabetes mellitus, hyperlipidemia, and obesity). There is accumulating evidence that the regular engagement in exercise is an important factor affecting outcomes before, during, and after transplantation; yet most waitlist candidates and recipients have reduced levels of physical activity. The mechanisms whereby physical activity is associated with better outcomes and a reduction in risk factors for cardiovascular disease are incompletely understood. Attempts to increase physical activity in the transplant population, as in the general population, have had limited success. Use of concepts from Nudge theory provides an evidence-based approach that may help increase physical activity and so reduce premature mortality. Both National and International Transplant Games provide a vehicle for increasing physical activity in this population and may also help to reduce premature death by providing a forum for mutual support for recipients and their families as well as an excellent forum for highlighting the success and impact of organ donation.
Ulnar Neuropathy at Elbow in Patients With Type 2 Diabetes Mellitus
Authors: Gündüz Ayşegül , Candan Fatma , Asan Furkan , Uslu Ferda , Uzun Nurten , Karaali-Savrun Feray , E. Kızıltan Meral
Published: August 2019

Purpose:

In diabetes mellitus (DM), upper extremity entrapment neuropathies are suggested to be a component of polyneuropathy (PNP). Our aim is to examine the presence of ulnar neuropathy at the elbow (UNE) and its relation to other findings including PNP in symptomatic and asymptomatic type-2 DM patients who were admitted for routine examinations.

Methods:

The study included all cases referred for electromyography because of type-2 DM between November 2017 and May 2018. Demographic and clinical characteristics were recorded. Routine electromyography examinations in all cases included the following: bilateral motor conduction of the median, ulnar, peroneal, and tibial nerves and sensory conduction of the median, ulnar, and sural nerves. For ulnar nerve examination, stimuli were given at the wrist, below the elbow, and above the elbow. Electrophysiological findings were evaluated according to the American Association of Neuromuscular and Electrodiagnostic Medicine criteria.

Results:

Eighty-two patients with type-2 DM and 144 upper extremities were included in the study. Of the 82 patients who participated in the study, 3 had findings suggesting ulnar neuropathy, and electrophysiology confirmed UNE in only one. Electrophysiological studies showed UNE in 36 patients. Other diagnoses identified by electrophysiology were carpal tunnel syndrome and PNP. Ulnar neuropathy at the elbow was more commonly associated with PNP compared with carpal tunnel syndrome. Gender and PNP were independent risk factors for the development of UNE.

Conclusions:

Although the majority of diabetic patients were asymptomatic for the UNE, approximately one third of all patients with DM were found to have UNE. Ulnar neuropathy at the elbow is closely related with PNP.
Growth and remodelling of living tissues: perspectives, challenges and opportunities
Authors: Ambrosi Davide , Ben Amar Martine , Cyron Christian J. , DeSimone Antonio , Goriely Alain , Humphrey Jay D. , Kuhl Ellen
Published: August 2019

One of the most remarkable differences between classical engineering materials and living matter is the ability of the latter to grow and remodel in response to diverse stimuli. The mechanical behaviour of living matter is governed not only by an elastic or viscoelastic response to loading on short time scales up to several minutes, but also by often crucial growth and remodelling responses on time scales from hours to months. Phenomena of growth and remodelling play important roles, for example during morphogenesis in early life as well as in homeostasis and pathogenesis in adult tissues, which often adapt to changes in their chemo-mechanical environment as a result of ageing, diseases, injury or surgical intervention. Mechano-regulated growth and remodelling are observed in various soft tissues, ranging from tendons and arteries to the eye and brain, but also in bone, lower organisms and plants. Understanding and predicting growth and remodelling of living systems is one of the most important challenges in biomechanics and mechanobiology. This article reviews the current state of growth and remodelling as it applies primarily to soft tissues, and provides a perspective on critical challenges and future directions.
A general model of hormesis in biological systems and its application to pest management
Authors: Tang Sanyi , Liang Juhua , Xiang Changcheng , Xiao Yanni , Wang Xia , Wu Jianhong , Li Guoping , Cheke Robert A.
Published: August 2019

Hormesis, a phenomenon whereby exposure to high levels of stressors is inhibitory but low (mild, sublethal and subtoxic) doses are stimulatory, challenges decision-making in the management of cancer, neurodegenerative diseases, nutrition and ecotoxicology. In the latter, increasing amounts of a pesticide may lead to upsurges rather than declines of pests, ecological paradoxes that are difficult to predict. Using a novel re-formulation of the Ricker population equation, we show how interactions between intervention strengths and dose timings, dose–response functions and intrinsic factors can model such paradoxes and hormesis. A model with three critical parameters revealed hormetic biphasic dose and dose timing responses, either in a J-shape or an inverted U-shape, yielding a homeostatic change or a catastrophic shift and hormetic effects in many parameter regions. Such effects were enhanced by repeated pulses of low-level stimulations within one generation at different dose timings, thereby reducing threshold levels, maximum responses and inhibition. The model provides insights into the complex dynamics of such systems and a methodology for improved experimental design and analysis, with wide-reaching implications for understanding hormetic effects in ecology and in medical and veterinary treatment decision-making. We hypothesized that the dynamics of a discrete generation pest control system can be determined by various three-parameter spaces, some of which reveal the conditions for occurrence of hormesis, and confirmed this by fitting our model to both hormetic data from the literature and to a non-hormetic dataset on pesticidal control of mirid bugs in cotton.
Atypical somatic symptoms in adults with prolonged recovery from mild traumatic brain injury
Authors: Stubbs Jacob L. , Green Katherine E. , Silverberg Noah D. , Howard Andrew , Dhariwal Amrit , Brubacher Jeffrey R. , Garraway Naisan , Heran Manraj K. S. , Sekhon Mypinder S. , Aquino Angela , Purcell Victoria , Hutchison James S. , Torres Ivan J. , Panenka William J.
Published: August 2019

Somatization may contribute to persistent symptoms after mild traumatic brain injury (mTBI). In two independently-recruited study samples, we characterized the extent to which symptoms atypical of mTBI but typical for somatoform disorders (e.g., gastrointestinal upset, joint pain) were present in adult patients with prolonged recovery following mTBI. The first sample was cross-sectional and consisted of mTBI patients recruited from the community who reported ongoing symptoms attributable to a previous mTBI (n = 16) along with a healthy control group (n = 15). The second sample consisted of patients with mTBI prospectively recruited from a Level 1 trauma center who had either good recovery (GOSE = 8; n = 33) or poor recovery (GOSE < 8; n = 29). In all participants, we evaluated atypical somatic symptoms using the Patient Health Questionnaire-15 and typical post-concussion symptoms with the Rivermead Post-Concussion Symptom Questionnaire. Participants with poor recovery from mTBI had significantly higher ‘atypical’ somatic symptoms as compared to the healthy control group in Sample 1 (b = 4.308, p = 9.43E-5) and to mTBI patients with good recovery in Sample 2 (b = 3.287, p = 6.83E-04). As would be expected, participants with poor outcome in Sample 2 had a higher burden of typical rather than atypical symptoms (t(28) = 3.675, p = 9.97E-04, d = 0.94). However, participants with poor recovery still reported atypical somatic symptoms that were significantly higher (1.4 standard deviations, on average) than those with good recovery. Our results suggest that although ‘typical’ post-concussion symptoms predominate after mTBI, a broad range of somatic symptoms also frequently accompanies mTBI, and that somatization may represent an important, modifiable factor in mTBI recovery.
Caffeine boosts preparatory attention for reward-related stimulus information
Authors: van den Berg Berry , de Jong Marlon , Woldorff Marty G. , Lorist Monicque M.
Published: August 2019

Both the intake of caffeine-containing substances and the prospect of reward for performing a cognitive task have been associated with improved behavioral performance. To investigate the possible common and interactive influences of caffeine and reward-prospect on preparatory attention, we tested 24 participants during a 2-session experiment in which they performed a cued-reward color-word Stroop task. On each trial, participants were presented with a cue to inform them whether they had to prepare for presentation of a Stroop stimulus and whether they could receive a reward if they performed well on that trial. Prior to each session, participants received either coffee with caffeine (3 mg/kg bodyweight) or with placebo (3 mg/kg bodyweight lactose). In addition to behavioral measures, electroencephalography (EEG) measures of electrical brain activity were recorded. Results showed that both the intake of caffeine and the prospect of reward improved speed and accuracy, with the effects of caffeine and reward-prospect being additive on performance. Neurally, reward-prospect resulted in an enlarged contingent negative variation (CNV) and reduced posterior alpha power (indicating increased cortical activity), both hallmark neural markers for preparatory attention. Moreover, the CNV enhancement for reward-prospect trials was considerably more pronounced in the caffeine condition as compared to the placebo condition. These results thus suggest that caffeine intake boosts preparatory attention for task-relevant information, especially when performance on that task can lead to reward.
Motor improvement estimation and task adaptation for personalized robot-aided therapy: a feasibility study
Authors: Giang Christian , Pirondini Elvira , Kinany Nawal , Pierella Camilla , Panarese Alessandro , Coscia Martina , Miehlbradt Jenifer , Magnin Cécile , Nicolo Pierre , Guggisberg Adrian , Micera Silvestro
Published: August 2019

Background

In the past years, robotic systems have become increasingly popular in both upper and lower limb rehabilitation. Nevertheless, clinical studies have so far not been able to confirm superior efficacy of robotic therapy over conventional methods. The personalization of robot-aided therapy according to the patients’ individual motor deficits has been suggested as a pivotal step to improve the clinical outcome of such approaches.

Methods

Here, we present a model-based approach to personalize robot-aided rehabilitation therapy within training sessions. The proposed method combines the information from different motor performance measures recorded from the robot to continuously estimate patients’ motor improvement for a series of point-to-point reaching movements in different directions and comprises a personalization routine to automatically adapt the rehabilitation training. We engineered our approach using an upper limb exoskeleton and tested it with seventeen healthy subjects, who underwent a motor-adaptation paradigm, and two subacute stroke patients, exhibiting different degrees of motor impairment, who participated in a pilot test.

Results

The experiments illustrated the model’s capability to differentiate distinct motor improvement progressions among subjects and subtasks. The model suggested personalized training schedules based on motor improvement estimations for each movement in different directions. Patients’ motor performances were retained when training movements were reintroduced at a later stage.

Conclusions

Our results demonstrated the feasibility of the proposed model-based approach for the personalization of robot-aided rehabilitation therapy. The pilot test with two subacute stroke patients further supported our approach, while providing auspicious results for the applicability in clinical settings.

Trial registration

This study is registered in ClinicalTrials.gov (NCT02770300, registered 30 March 2016,https://clinicaltrials.gov/ct2/show/NCT02770300).
ADAMTS-family protease MIG-17 regulates synaptic allometry by modifying the extracellular matrix and modulating glia morphology during growth
Authors: Ji Tingting , Wang Kai , Fan Jiale , Huang Jichang , Wang Mengqing , Dong Xiaohua , Shi Yanjun , Manning Laura , Zhang Xumin , Shao Zhiyong , Colón-Ramos Daniel A.
Published: August 2019

Synapses are largely established during embryogenesis and maintained during growth. The mechanisms that regulate synaptic allometry—the maintenance of synaptic positions during growth—are largely unknown. We performed forward genetic screens inC. elegansfor synaptic allometry mutants and identifiedmig-17, a secreted metalloprotease of the conserved ADAMTS family. Through proteomic mass spectrometry analyses, cell biological and genetic studies we determined that MIG-17 is expressed by muscle cells to modulate glia location and morphology. Glia are proximal to synapses, and the glial location and morphology determine synaptic position during growth.Mig-17regulates synapse allometry by influencing epidermal-glia crosstalk through the regulation of basement membrane proteins, including collagen type IV, SPARC and fibulin. Our findings underscore the importance of glia location in the maintenance of synaptic allometry, and uncover a muscle-epidermal-glia signaling axis, mediated through the extracellular matrix, in the regulation of glia morphology and synaptic positions during growth.
CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration
Authors: Walker Kirsti L. , Rinella Sean P. , Hess Nicholas J. , Turicek David P. , Kabakov Sabrina A. , Zhu Fen , Bouchlaka Myriam N. , Olson Sydney L. , Cho Monica M. , Quamine Aicha E. , Feils Arika S. , Gavcovich Tara B. , Rui Lixin , Capitini Christian M.
Published: August 2019

Targeting the JAK/STAT and BCL2 pathways in patients with relapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect on T-ALL individually, but combination treatment reduces survival and proliferation of T-ALL in vitro. Using a xenograft model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite on-target inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS) as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that ruxolitinib and venetoclax insufficiently cross into the CNS. The addition of the CXCR4 inhibitor plerixafor with ruxolitinib and venetoclax reduces clinical scores and enhances survival. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis may be needed to maximize the possibility of complete remission.
New method for high-throughput measurements of viscosity in submicrometer-sized membrane systems
Authors: Chwastek Grzegorz , Petrov Eugene P. , Sáenz James Peter
Published: August 2019

In order to unravel the underlying principles of membrane adaptation in small systems like bacterial cells, robust approaches to characterize membrane fluidity are needed. Currently available relevant methods require advanced instrumentation and are not suitable for high throughput settings needed to elucidate the biochemical pathways involved in adaptation. We developed a fast, robust, and financially accessible quantitative method to measure microviscosity of lipid membranes in bulk suspension using a commercially available plate reader. Our approach, which is suitable for high-throughput screening, is based on the simultaneous measurements of absorbance and fluorescence emission of a viscosity-sensitive fluorescent dye DCVJ incorporated into a lipid membrane. We validated our method using artificial membranes with various lipid compositions over a range of temperatures and observed values that were in good agreement with previously published results. Using our approach, we were able to detect a lipid phase transition in the ruminant pathogenMycoplasma mycoides.
A role of oligodendrocytes in information processing independent of conduction velocity
Authors: Moore Sharlen , Meschkat Martin , Ruhwedel Torben , Tzvetanova Iva D. , Trevisiol Andrea , Battefeld Arne , Kusch Kathrin , Kole Maarten , Strenzke Nicola , Möbius Wiebke , de Hoz Livia , Nave Klaus-Armin
Published: August 2019

Myelinating oligodendrocytes enable fast impulse propagation along axons as revealed through studies of homogeneously myelinated white matter tracts. However, gray matter myelination patterns are different, with sparsely myelinated sections leaving large portions of the axons naked. The consequences of this patchy myelination for oligodendrocyte function are not understood but suggest other roles in information processing beyond the regulation of axonal conduction velocity. Here, we analyzed the contribution of myelin to auditory information processing using paradigms that are good predictors of speech understanding in humans. We compared mice with different degrees of dysmyelination using acute cortical multiunit recordings in combination with behavioral readouts. We identified complex alterations of neuronal responses that reflect fatigue and temporal acuity deficits. Partially discriminable but overall similar deficits were observed in mice with oligodendrocytes that can myelinate but cannot fully support axons metabolically. Thus, myelination contributes to sustained stimulus perception in temporally complex paradigms, revealing a role of oligodendrocytes in the CNS beyond the increase of axonal conduction velocity.
Modeling and treatingGRIN2Adevelopmental and epileptic encephalopathy in mice
Authors: Amador Ariadna , Bostick Christopher D. , Olson Heather , Peters Jurrian , Camp Chad R. , Krizay Daniel , Chen Wenjuan , Han Wei , Tang Weiting , Kanber Ayla , Kim Sukhan , Teoh Jia Jie , Petri Sabrina , Paek Hunki , Kim Ana , Lutz Cathleen M. , Yang Mu , Myers Scott J. , Bhattacharya Subhrajit , Yuan Hongjie , Goldstein David B. , Poduri Annapurna , Boland Michael J. , Traynelis Stephen F. , Frankel Wayne N.
Published: August 2019

NMDA receptors (NMDAR) play crucial roles in excitatory synaptic transmission. Rare variants ofGRIN2A, which encodes the GluN2A NMDAR subunit, are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). Ade novomissense variant, p.Ser644Gly (c.1930A>G), was identified in a child with DEE, andGrin2aknockin mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibit altered hippocampal morphology at two weeks of age, and homozygotes exhibit lethal tonic-clonic seizures in the third week. Heterozygous adult mice display a variety of distinct features, including resistance to electrically induced partial seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with these observations, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of modeling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their extended utility in identifying and evaluating new therapies.
Evolved differences incisandtransregulation between the maternal and zygotic mRNA complements in theDrosophilaembryo
Authors: Cartwright Emily L. , Lott Susan E.
Published: August 2019

How gene expression can evolve depends on the mechanisms driving gene expression. Gene expression is controlled in different ways in different developmental stages; here we ask whether different developmental stages show different patterns of regulatory evolution. To explore the mode of regulatory evolution, we used the early stages of embryonic development controlled by two different genomes, that of the mother and that of the zygote. During embryogenesis in all animals, initial developmental processes are driven entirely by maternally provided gene products deposited into the oocyte. The zygotic genome is activated later, when developmental control is handed off from maternal gene products to the zygote during the maternal-to-zygotic transition. Using hybrid crosses between sister species ofDrosophila(D. simulans,D. sechellia, andD. mauritiana) and transcriptomics, we find that the regulation of maternal transcript deposition and zygotic transcription evolve through different mechanisms. We find that patterns of transcript level inheritance in hybrids, relative to parental species, differ between maternal and zygotic transcripts, and maternal transcript levels are more likely to be conserved. Changes in transcript levels occur predominantly through differences intransregulation for maternal genes, while changes in zygotic transcription occur through a combination of bothcisandtransregulatory changes. Differences in the underlying regulatory landscape in the mother and the zygote are likely the primary determinants for how maternal and zygotic transcripts evolve.
An amino-terminal threonine/serine motif is necessary for activity of the Crp/Fnr homolog, MrpC, and forMyxococcus xanthusdevelopmental robustness
Authors: Feeley Brooke E. , Bhardwaj Vidhi , McLaughlin Maeve , Diggs Stephen , Blaha Gregor M. , Higgs Penelope I.
Published: August 2019

The Crp/Fnr family of transcriptional regulators play central roles in transcriptional control of diverse physiological responses. Activation of individual family members is controlled by a surprising diversity of mechanisms tuned to the particular physiological responses or lifestyles that they regulate. MrpC is a Crp/Fnr homolog that plays an essential role in controlling theMyxococcus xanthusdevelopmental program. A long-standing model proposed that MrpC activity is controlled by the Pkn8/Pkn14 serine/threonine kinase cascade which phosphorylates MrpC on threonine residue(s) located in its extreme amino terminus. In this study, we demonstrate that a stretch of consecutive threonine and serine residues, T21T22S23S24,is necessary for MrpC activity by promoting efficient DNA binding. Mass spectrometry analysis indicated the TTSS motif is not directly phosphorylated by Pkn14in vitrobut is necessary for efficient Pkn14-dependent phosphorylation on several residues in the remainder of the protein. Pkn8 and Pkn14 kinase activities do not play obvious roles in controlling MrpC activity in wild typeM. xanthusunder laboratory conditions, but likely modulate MrpC DNA binding in response to unknown environmental conditions. Interestingly, mutational analysis of the TTSS motif caused non-robust developmental phenotypes, revealing that MrpC plays a role in developmental buffering.
Oral RNAi of diap1 in a pest results in rapid reduction of crop damage
Authors: Chikami Yasuhiko , Kawaguchi Haruka , Suzuki Takamasa , Yoshioka Hirofumi , Sato Yutaka , Yaginuma Toshinobu , Niimi Teruyuki
Published: August 2019

Selecting an appropriate target gene is critical to the success of feeding RNA interference (f-RNAi)-based pest control. Gene targets have been chosen based on their ability to induce lethality. However, lethality induction by f-RNAi is slow-acting and crop damage can progress during this time. Here, we show that f-RNAi of death-associated inhibitor of apoptosis protein 1 (diap1), but not two conventional targets vacuolar ATPase subunit A and E, induces acute feeding cessation in the solanaceous pest, Henosepilachna vigintioctopunctata during 24–48 hours. We also found that the feeding cessation by diap1 f-RNAi has species-specificity and occurs with only 1.6 ng dsRNA. Our results suggest that diap1 is an appropriate target in the context of rapid reduction of crop damage. We propose that acute feeding disorder should be assessed as a novel criterion for selecting appropriate target genes for RNAi-based pest control in addition to the conventional criterion based on lethality.
Role of the imprinted allele of the p57Kip2 gene in mouse neocortical development
Authors: Imaizumi Yui , Furutachi Shohei , Watanabe Tomoyuki , Miya Hiroaki , Kawaguchi Daichi , Gotoh Yukiko
Published: August 2019

Imprinted genes are expressed from only one allele in a parent of origin–specific manner. The cyclin-dependent kinase inhibitor p57Kip2 (p57) is encoded by an imprinted gene, with the paternal allele being silenced. The possible expression and function of the paternal allele of p57 have remained little studied, however. We now show that the paternal allele of the p57 gene is expressed at a low level in the developing mouse neocortex. Surprisingly, the central nervous system-specific conditional deletion of the paternal allele (pat cKO) at the p57 locus resulted in a marked reduction in brain size. Furthermore, pat cKO gradually reduced the number of neural stem-progenitor cells (NPCs) during neocortical development, and thus reduced the number of upper-layer neurons, which were derived from late-stage NPCs. Our results thus show that the paternal allele of the p57 locus plays a key role in maintenance of NPCs during neocortical development.
Inducible transgene expression in PDX models in vivo identifies KLF4 as therapeutic target for B-ALL
Authors: Liu Wen-Hsin , Mrozek-Gorska Paulina , Herold Tobias , Schwarzkopf Larissa , Pich Dagmar , Völse Kerstin , Wirth Anna-Katharina , Melo-Narváez M. Camila , Carlet Michela , Hammerschmidt Wolfgang , Jeremias Irmela
Published: August 2019

Clinic-close methods are not available that prioritize and validate potential therapeutic targets in individual tumors from the vast bulk of descriptive expression data. We developed a novel technique to express transgenes in established patient-derived xenograft (PDX) models in vivo to fill this gap. With this technique at hand, we analyzed the role of transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive pre-clinical in vivo trials, we found that re-expression of wild type KLF4 reduced leukemia load in PDX models of B-ALL, with strongest effects after conventional chemotherapy at minimal residual disease (MRD). A non-functional KLF4 mutant had no effect in this model. Re-expressing KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. Of major translational relevance, Azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced Azacitidine-induced cell death, suggesting that Azacitidine can regulate KLF4 re-expression. These results support applying Azacitidine in patients with B-ALL to regulated KLF4 as a therapeutic option. Taken together, our novel technique allows studying the function of dysregulated genes in a highly clinic-related, translational context and testing clinically applicable drugs in a relevant pre-clinical model.
Gene prediction in heterogeneous cancer tissues and establishment of Least Absolute Shrinking and Selection Operator model of lung squamous cell carcinoma
Authors: Khaliq Ateeq Muhammed , Rg SharathChandra , Rajamohan Meenakshi
Published: August 2019

Background

This study is aimed to establish a Least Absolute Shrinking and Selection Operator (LASSO) model based on tumor heterogeneity to predict the best features of LUSC in various cancer subtypes.

Methods

The RNASeq data of 505 LUSC cancer samples were downloaded from the TCGA database. Subsequent to the identification of differentially expressed genes (DEGs), the samples were divided into two subtypes based on the consensus clustering method. The subtypes were estimated with the abundance of immune and non-immune stromal cell populations which infiltrated tissue. LASSO model was established to predict each subtype’s best genes. Enrichment pathway analysis was then carried out. Finally, the validity of the LUSC model for identifying features was established by the survival analysis.

Results

240 and 262 samples were clustered in Subtype-1 and Subtype-2 groups respectively. DEG analysis was performed on each subtype. A standard cutoff was applied and in total, 4586 genes were upregulated and 1495 were downregulated in case of subtype-1 and 5016 genes were upregulated and 3224 were downregulated in case of subtype-2. LASSO model was established to predict the best features from each subtypes, 49 and 34 most relevant genes were selected in subtype-1 and subtype-2. The abundance of tissue-infiltrates analysis distinguished the subtypes based on the expression pattern of immune infiltrates. Survival analysis showed that this model could effectively predict the best and distinct features in cancer subtypes.

Discussion

This study suggests that the unsupervised clustering and LASSO model-based feature selection can be effectively used to predict relevant genes which might play an important role in cancer diagnosis.
Modelling the effects of leaky predator-exclusion fences and their surrounding halo
Authors: Agarwal Kanupriya , Bode Michael
Published: August 2019

Terrestrial fauna of the southern hemisphere, particularly Australia and New Zealand, have suffered significant declines and extinctions due to predation by introduced red foxesVulpes vulpesand catsFelis catus. Predator-exclusion fences offer protection to these threatened species and allow their populations to persist and even flourish within their boundaries. These fences have traditionally been designed to stop the movement of both the invasive predators (into the fence), and the native animals (out of the fence). However, recent theory and evidence suggest that when native animals are able to move across the fence, they can create a population beyond the fence boundary. This phenomena has been called a “halo effect”, and has the potential to both expand the direct and indirect benefits of predator-exclusion fences, and to reduce their negative effects. However, the conditions under which such an effect can be achieved are uncertain. They include questions about which native species could support a meaningful halo, what levels of predation outside the fence can be tolerated, and how permeable the fence would need to be. Here, we formulate this problem as both a simple two-patch model and a spatial partial differential equation model. We use the two approaches to explore the conditions under which a halo can deliver conservation benefits, and offer clear insights into the problem.
Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction
Authors: Vafadarnejad Ehsan , Rizzo Giuseppe , Krampert Laura , Arampatzi Panagiota , Nugroho Vallery Audy , Schulz Dirk , Roesch Melanie , Alayrac Paul , Vilar Jose , Silvestre Jean-Sébastien , Zernecke Alma , Saliba Antoine-Emmanuel , Cochain Clément
Published: August 2019

Objective

After myocardial infarction, neutrophils rapidly and massively infiltrate the heart, where they can promote both tissue healing and damage. Here, we investigated the dynamics of cardiac neutrophil heterogeneity after infarction.

Methods and results

We employed single-cell transcriptomics (scRNA-seq) to investigate temporal neutrophil heterogeneity in the heart after murine myocardial infarction. At day 1, 3, and 5 after infarction, neutrophils could be delineated into six distinct clusters with specific time-dependent patterning and proportions. While the majority of neutrophils at day 1 were characterized by high expression of chemokines (e.g.Cxcl3,Ccl6), and putative activity of transcriptional regulators involved in hypoxic response (Hif1a) and emergency granulopoiesis (Cebpb), two major subsets ofSiglecfhi(enriched for e.g.Icam1andTnf) andSiglecflow(Slpi, Ifitm1) neutrophils were found at 3 and 5 days. Flow cytometry analysis confirmed the presence of LY6G+SIGLECFhiand LY6G+SIGLECFlowneutrophils in the heart from 3 days after infarction onwards. LY6G+SIGLECFhineutrophils were absent from the bone marrow, blood and spleen, suggesting local acquisition of surface SIGLECF. Acquisition of the SIGLECFhistate was paralleled by features of neutrophil ageing and activation (ICAM1hiCXCR4hiCD49dhiCD62Llow). scRNA-seq of atherosclerotic aortas revealed two neutrophil subsets with gene expression patterns reminiscent of the majorSiglecfhiandSiglecflowcardiac neutrophil subpopulations, revealing that these populations may be present across distinct contexts of cardiovascular inflammation.

Conclusion

Altogether, our data provide a time-resolved census of neutrophil diversity and gene expression dynamics in the mouse ischemic heart at the single-cell level, and suggests that temporal neutrophil heterogeneity is in part driven by local transition to a SIGLECFhistate.
Release of stem cells from quiescence reveals multiple gliogenic domains in the adult brain
Authors: Delgado Ana C. , Maldonado-Soto Angel R. , Silva-Vargas Violeta , Mizrak Dogukan , Känel Thomas von , Paul Alex , Madar Aviv , Cuervo Henar , Kitajewski Jan , Lin Chyuan-Sheng , Doetsch Fiona
Published: August 2019

Quiescent neural stem cells (NSCs) in the adult ventricular-subventricular zone (V-SVZ) have a regional identity and undergo activation to generate neurons. The domains for gliogenesis are less explored. Here we show that Platelet-Derived Growth Factor Receptor beta (PDGFRβ) is expressed by adult V-SVZ NSCs that generate olfactory bulb interneurons and glia with slow baseline kinetics. Selective deletion of PDGFRβ in adult V-SVZ NSCs leads to their release from quiescence uncovering multiple domains in the septal wall for oligodendrocyte and astrocyte formation. Unexpectedly, we identify a novel intraventricular oligodendrocyte progenitor inside the brain ventricles. Together our findings reveal different NSC spatial domains for gliogenesis in the adult V-SVZ that are largely quiescent under homeostasis and may have key functions for brain plasticity.