bluuebunny/crossref_metadata_2025 huggingface dataset:
Using a Workshop Format for Physiatry Trainees in the Management of Acute Sports-Related Concussion
Authors: Lamm Adam G. , Babu Ashwin , Zafonte Ross , Iaccarino Mary Alexis
Published: October 2018

Select residency and medical student training programs have developed and researched skill-based workshops, focusing on mastering a surgical or communication skill; however, they are less frequently studied in physiatry residency programs. Given the importance of concussion care in physiatric practice, this study sought to measure the effectiveness of a novel sports-related concussion workshop. Based on the 5th International Consensus Statement on Concussion in Sport, a 6-hr concussion workshop was developed. Participants were administered a preworkshop and postworkshop questionnaire to gauge level of comfort managing various aspects of concussion, case-based questions to assess participant knowledge, and questions regarding satisfaction with workshop-based training sessions. Sixteen participants, ranging from PGY-2 to PGY-5, were included in the analyses, with significant gains (P< 0.0001 toP= 0.0045) made in all measures of comfort managing sports-related concussion; the study was unable to detect a statistically significant improvement in knowledge as assessed by the patient vignettes (P= 0.17), but participants did report high levels of satisfaction with workshop-based training sessions. Thus, workshop-based physiatry trainee education sessions can be used to teach trainees certain skills or provide comprehensive training in the management of a specific condition. Participants demonstrated improved comfort managing concussion, a trend toward improved knowledge, and a high degree of satisfaction with the content's method delivery.
Costs and consequences of chronic pain due to musculoskeletal disorders from a health system perspective in Chile
Authors: Vargas Constanza , Bilbeny Norberto , Balmaceda Carlos , Rodríguez María Francisca , Zitko Pedro , Rojas Rubén , Eberhard María Eliana , Ahumada Marisol , Espinoza Manuel Antonio
Published: October 2018

Background:

Chronic pain is a prevalent and distressing condition caused by an unceasing pain lasting more than 3 months or a pain that persists beyond the normal healing time. There is evidence of inadequate management partly explained by the unawareness regarding the magnitude of the problem.

Objectives:

To estimate the annual expected costs and consequences of chronic pain caused by musculoskeletal diseases from the health system perspective in Chile.

Methods:

A Markov cohort model was built to represent chronic pain and estimate expected costs and consequences over 1-year time horizon. Transition probabilities were obtained through expert elicitation. Consequences examined were: years lost to disability (YLD), depression, anxiety, and productivity losses. Direct health care costs were estimated using local sources. Probabilistic sensitivity analysis was performed to characterize second-order uncertainty.

Results:

The annual expected cost due to musculoskeletal chronic pain was estimated in USD $1387.2 million, equivalent to 0.417% of the national GDP. Lower back pain and osteoarthritis of the knee explained the larger proportion of the total cost, 31.8% and 27.1%, respectively. Depression attributed to chronic pain is another important consequence accounting for USD $94 million (Bayesian credibility interval 95% $49.1–$156.26). Productivity losses were also important cost, although early retirement and presenteeism were not measured. Chronic pain causes 137,037 YLDs.

Conclusion:

Chronic pain is not only an important cause of disability but also responsible for high social and financial burden in Chile. Public health programs focused on managing chronic pain may decrease burden of disease and possibly reduce costs.
Delayed onset of severe chronic pain in CASPR2 autoantibody–associated Morvan syndrome in a former UK swine abattoir worker
Authors: Goebel Andreas , Moore Austen Peter , Jacob Anu
Published: October 2018

Introduction:

Autoantibody-mediated autoimmunity directed against targets within the voltage-gated potassium channel complex (VGKCC autoantibodies) has been implicated in causing neuropathic pain.

Methods:

We report the case of a 76-year-old, United Kingdom male who was diagnosed with contactin-associated protein 2 (CASPR2) autoantibody–associated Morvan syndrome, a rare neurological condition.

Results:

He had previously worked in a swine abattoir; exposure to aerosol within swine abattoirs has been reported to elicit an immune response resulting in the production of these autoantibodies; however, unusually, his manifestations emerged with several years' latency. Although this patient's Morvan syndrome–associated seizures were well-controlled with antiepileptic drugs, his neuropathic pain and painful muscle fasciculations did not respond to pharmacological interventions. He refused pain management program treatment, but high-dose immunoglobulin treatment or treatment with rituximab, reported to be sometimes effective in this group, was not initiated because of concerns regarding his general frailty.

Discussion and Conclusion:

This case highlights issues around the identification and treatment of rare patients with chronic pain who have voltage-gated potassium channel complex autoantibodies; it also emphasizes the possibility that former swine abattoir workers might be at risk of developing neuropathic pain even years after their vocational exposure.
Granulocyte-macrophage colony-stimulating factor receptor expression in clinical pain disorder tissues and role in neuronal sensitization
Authors: Donatien Philippe , Anand Uma , Yiangou Yiangos , Sinisi Marco , Fox Michael , MacQuillan Anthony , Quick Tom , Korchev Yuri E. , Anand Praveen
Published: October 2018

Introduction:

Granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) is highly expressed in peripheral macrophages and microglia, and is involved in arthritis and cancer pain in animal models. However, there is limited information on GM-CSFR expression in human central nervous system (CNS), peripheral nerves, or dorsal root ganglia (DRG), particularly in chronic pain conditions.

Objectives:

Immunohistochemistry was used to quantify GM-CSFR expression levels in human tissues, and functional sensory effects of GM-CSF were studied in cultured DRG neurons.

Results:

Granulocyte-macrophage colony-stimulating factor receptor was markedly increased in microglia at lesional sites of multiple sclerosis spinal cords (P = 0.01), which co-localised with macrophage marker CD68 (P = 0.009). In human DRG, GM-CSFR was expressed in a subset of small/medium diameter cells (30%) and few large cells (10%), with no significant change in avulsion-injured DRG. In peripheral nerves, there was a marked decrease in axonal GM-CSFR after chronic painful nerve injury (P = 0.004) and in painful neuromas (P = 0.0043); CD-68–positive macrophages were increased (P = 0.017) but did not appear to express GM-CSFR. Although control synovium showed absent GM-CSFR immunostaining, this was markedly increased in macrophages of painful osteoarthritis knee synovium. Granulocyte-macrophage colony-stimulating factor receptor was expressed in 17 ± 1.7% of small-/medium-sized cultured adult rat DRG neurons, and in 27 ± 3.3% of TRPV1-positive neurons. Granulocyte-macrophage colony-stimulating factor treatment sensitized capsaicin responses in vitro, which were diminished by p38 MAPK or TrkA inhibitors.

Conclusion:

Our findings support GM-CSFR as a therapeutic target for pain and hypersensitivity in clinical CNS and peripheral inflammatory conditions. Although GM-CSFR was decreased in chronic painful injured peripheral nerves, it could mediate CNS neuroinflammatory effects, which deserves study.
Synthetic 2-Dimensional Mammography Can Replace Digital Mammography as an Adjunct to Wide-Angle Digital Breast Tomosynthesis
Authors: Clauser Paola , Baltzer Pascal A.T. , Kapetas Panagiotis , Woitek Ramona , Weber Michael , Leone Federica , Bernathova Maria , Helbich Thomas H.
Published: October 2018

Objectives

The aim of this study was to evaluate the detection rate and diagnostic performance of 2-dimensional synthetic mammography (SM) as an adjunct to wide-angle digital breast tomosynthesis (WA-DBT) compared with digital mammography (DM) alone or to DM in combination with WA-DBT.

Materials and Methods

There were 205 women with 179 lesions included in this retrospective reader study. Patients underwent bilateral, 2-view (2v) DM and WA-DBT between March and June 2015. The standard of reference was histology and/or 1-year stability at follow-up. Four blinded readers randomly evaluated images according to the BI-RADS lexicon from 3 different protocols: 2v DM alone, 2v DM with 2v WA-DBT, and 2v SM with 2v WA-DBT. Detection rate, sensitivity, specificity, and accuracy were calculated and compared using multivariate analysis. Readers' confidence and image quality were evaluated.

Results

The detection rate ranged from 68.7% to 79.9% for DM, 76.5% to 84.4% for DM with WA-DBT, and 73.2% to 84.9% for SM with WA-DBT. Sensitivity and accuracy were significantly higher when DBT was available (P < 0.001). Specificity did not differ significantly between DM only, DM with WA-DBT, or SM with WA-DBT (P ≥ 0.846). Wide-angle DBT combined readings did not differ between SM and DM in terms of sensitivity, specificity, and accuracy (P ≥ 0.341). Readers' confidence and image quality was rated good to excellent.

Conclusions

Wide-angle DBT combined with DM or SM increases sensitivity and accuracy without reducing specificity compared with DM alone. Wide-angle DBT combined readings did not differ between SM and DM; therefore, SM should replace DM for combined readings with WA-DBT.
Study on Hair Distribution in Healthy Males for Hair Restoration Design
Authors: Bao Yunqi , Wu Kejia , Lin Jinran , Chen Yuchong , Wu Wenyu
Published: October 2018

Background:

The incidence of hair loss among Chinese male has increased to 21.3 per hundred. Hair restoration has been an effective technique. Detailed hair distribution has a tremendous impact on the surgery design.

Objective:

To investigate the pattern of hair distribution in Chinese young adult males.

Methods:

A total of 1000 males without hair disease were enrolled. We evaluated the locations of the main anatomical marks at different sites on the scalp and analyzed the hair density and follicular unit structure using the standard photographs and trichoscope.

Results:

The hairline shapes were classified as: linear (48.7%), linear with central protrusion (27.9%), round (9.8%), round with central protrusion (13.7%). The average height of the median line was 6.78 ± 0.75 cm, the ratio of the median line and the forehead height was 0.333. The average distance from the parietal whorl to the vertical bimeatal line was 7.05 ± 3.32 cm, and most of the PWs were on the right (51.4%) and had a clockwise pattern (73.3%). The hair density was 171.12 ± 18.32 hairs/cm2 in the vertex. 1-hair follicular units were (75.90% and 56.39%) in anterior hairline and temporal area.

Conclusion:

Our study clearly assisted understanding of scalp anatomy and hair distribution in Chinese young adult males.
Intracorporeal Septorhinoplasty: Technique and Outcome
Authors: Nassar Ahmed Tharwat
Published: October 2018

Objective:

Septal deformities usually associated with functional and aesthetic nasal consequences. Multiple techniques were described to correct these deformities. Using less invasive and at the same time competent technique with loge standing results is important. This study aimed to assess intracorporeal correction for septal deviation with assessment of its competence in managing deferent degrees of deviation and to show concomitant patient-dependant internal valve manipulation used.

Methods:

Intracorporeal correction of septal deviation was used in 35 patients which was performed at plastic surgery departments of Menoufia University Hospital and Mawada Privet Hospital, Egypt. The study was carried out between July 2014 and July 2017.

Results:

Thirty-five patients with variable types of septal deformities, 16 of them were females and 19 were males, were included in the study. Age of patients was between 18 and 55 years (mean 24.9, standard deviation 7.9). Etiology was found as follows: 15 (about 43%) posttraumatic septal deviation, 8 (about 23%) patients had postcleft septal deviation, and the remaining 12 had idiopathic septal deviation. Spreader graft was in 22 (about 63%) patients. Septal hematoma followed by septal perforation occurred in 1 patient (2.8%), while dorsal irregularities were found in 3 (8.4%) patients. Recurrent septal deviation occurred in 2 (5.6%) patients. Concerning functional outcome, no residual nasal obstruction was found in all patients with negative Cottle sign postoperative.

Conclusion:

Intracorporeal correction of septal deformities in open rhinoplasty technique is still found to be effective and less invasive option even with sever septal deviation.
Incidence of Foramen Tympanicum (of Huschke): Comparing Cadaveric and Radiologic Studies
Authors: Pękala Jakub R. , Pękala Przemysław A. , Satapathy Bikash , Henry Brandon Michael , Skinningsrud Bendik , Paziewski Mateusz , Tubbs R. Shane , Tomaszewski Krzysztof A.
Published: October 2018

Purpose:

The foramen tympanicum (FT) represents a developmental anomaly that forms due to incomplete fusion of processes of the tympanic ring. Its presence in the population is controversial and it has been associated with a number of otologic complications. The aim of this study was to systematically analyze the prevalence, anatomical characteristics, and ethnic variations of the FT and compare these parameters in cadaveric and radiologic studies.

Methods:

An extensive search was conducted through the major electronic databases, and identified articles were separated into 2 groups based on their methodology: cadaveric and radiologic studies. Data extracted included study modality, prevalence data, ethnicity, gender, side, laterality, and diameter.

Results:

A total of 8 studies (n = 2671 patients) were included into our meta-analysis. The main findings revealed that the prevalence of the FT in the population is 14.9%, it is more often unilateral (62.5%) than bilateral (37.5%), it is most often reported in Asia (21.4%), and it is more prevalent in cadavers (21.2%) than in radiologic studies (8.8%) (not statistically significant).

Conclusion:

As the FT is present in more than one-tenth of the population, it is important to consider the possibilities of its presence when undertaking surgical procedures in the temporomandibular joint and ear region and plan accordingly to avoid injuries. Clinicians should keep it as one of the possible diagnoses while confronted with patients presenting with otologic complications. The use of newer imaging techniques was recommended, such as cone-beam computer tomography to detect the FT prior to surgery.
Congenital Cleft Earlobe: Technique for Repair of a Triple-Lobe Type Defect
Authors: Stanley Sharon S. , Thaller Seth R.
Published: October 2018

Congenital cleft earlobe is a rare clinical entity that results from failure of fusion during embryologic development. In contrast to acquired earlobe clefts, congenital defects are usually associated with tissue loss, thereby complicating surgical repair. The authors present the case of a 22-year-old female with a triple-lobe type of congenital cleft earlobe and discuss their technique for repair.
Reconstruction of Wegener Granulomatosis Nose Deformity Using Fascia Lata Graft
Authors: Lasso Jose M. , La Cruz Esther Deleyto
Published: October 2018

Wegener granulomatosis (WG) is a necrotizing vasculitis that involves the upper respiratory tract, the lungs, and the kidneys. It also causes deformities of the nose in practically all patients, altering the cartilaginous and bony structure as well as the inner lining of the nose.

The surgical repair of these nasal distortions is a challenge mainly due to the impairment of wound healing and graft take that is caused both by the disease itself and by the prolonged immunosuppressant treatment.

Many different reconstruction plans have been developed, using costal or calvarial bone grafts, cartilage grafts and local skin and mucosa flaps. Results have been diverse.

The authors present the case of a 56-year-old patient who suffered from WG and consulted for nasal sequelae. She initially underwent several failed attempts at reconstruction; finally, the authors performed a nasal repair using a double strip of fascia lata as a dorsal graft, with no complications and a good aesthetic result.

Fascia lata graft is a new and good option for nasal reconstruction in patients with WG because it is easily obtainable, it can be set in place through closed rhinoplasty and it can achieve good vascularization with low risk of resorption or disease reactivation.
Impact of Heart Transplantation on the Recovery of Peripheral and Respiratory Muscle Mass and Strength in Patients With Chronic Heart Failure
Authors: Fernandes Lenise C. B. C. , de Oliveira Italo M. , Fernandes Paula Frassinetti C. B. C. , de Souza Neto João David , Farias Maria do Socorro Q. , de Freitas Nilce A. , Magalhães Nasser C. , Bacal Fernando
Published: October 2018

Background

To assess the impact of heart transplantation (HT) on the recovery of peripheral and respiratory muscle mass and strength in patients with congestive heart failure.

Methods

The study included 23 patients with an indication for HT (patients in the waiting list [WL] group). These patients were monitored for 1.5 to 3 years after HT; 8 died before 6 months of follow-up, 15 patients completed the early follow-up period of 6 months after HT (FU6m group), 4 died between 6 months and 3 years after HT, and 11 patients completed the late follow-up period 1.5 to 3 years after HT (FU1.5-3y group). Twenty-three healthy subjects were included in the control group. The study variables included inspiratory muscle strength, expressed as the maximum inspiratory pressure (MIP); expiratory muscle strength, expressed as the maximum expiratory pressure (MEP); peripheral muscle strength, expressed as bilateral handgrip strength (bHGS); and the cross-sectional area of the bilateral psoas major muscle (CSAbPm).

Results

The results showed a reduction in the CSAbPm (1238.9 ± 312.3 mm2), a reduction in the bHGS (27.0 ± 5.7 kg/f), a reduction in the MIP (60.2 ± 29.8 cmH2O), and a reduction in the MEP (75.2 ± 33.4 cmH2O) in patients in the WL group compared with the healthy controls. In the time series comparison, for patients in the WL, FU6m, and FU1.5-3y groups, increases were found in the CSAbPm (1305.4 vs 1458.1 vs 1431.3 mm2, respectively), bHGS (27.3 vs 30.2 vs 34.7 kg/f, respectively), MIP (59.5 vs 85.5 vs 90.9 cmH2O, respectively), and MEP (79.5 vs 93.2 vs 101.8 cmH2O, respectively) (P < 0.00).

Conclusions

Sarcopenia was observed in patients in the WL group. Patients recovered peripheral and respiratory muscle mass and strength at 3 years after HT.
Diverse Pathophysiological Processes Converge on Network Disruption in Mania
Authors: Lee Ivy , Nielsen Kathryn , Hall Mei-Hua , Öngür Dost , Keshavan Matcheri , Brady Roscoe
Published: October 2018

Background

Neuroimaging of psychiatric disease is challenged by the difficulty of establishing the causal role of neuroimaging abnormalities. Lesions that cause mania present a unique opportunity to understand how brain network disruption may cause mania in both lesions and in bipolar disorder.

Methods

A literature search revealed 23 case reports with imaged lesions that caused mania in patients without history of bipolar disorder. We traced these lesions and examined resting-state functional Magnetic Resonance Imaging (rsfMRI) connectivity to these lesions and control lesions to find networks that would be disrupted specifically by mania-causing lesions. The results were then used as regions-of-interest to examine rsfMRI connectivity in patients with bipolar disorder (n=16) who underwent imaging longitudinally across states of both mania and euthymia alongside a cohort of healthy participants scanned longitudinally. We then sought to replicate these results in independent cohorts of manic (n=26) and euthymic (n=21) participants with bipolar disorder.

Results

Mania-inducing lesions overlap significantly in network connectivity. Mania-causing lesions selectively disrupt networks that include orbitofrontal cortex, dorsolateral prefrontal cortex, and temporal lobes. In bipolar disorder, the manic state was reflected in strong, significant, and specific disruption in network communication between these regions and regions implicated in bipolar pathophysiology: the amygdala and ventro-lateral prefrontal cortex.

Limitations

The was heterogeneity in the clinical characterization of mania causing lesions.

Conclusions

Lesions causing mania demonstrate shared and specific network disruptions. These disruptions are also observed in bipolar mania and suggest a convergence of multiple disorders on shared circuit dysfunction to cause mania.
An information thermodynamic approach quantifying MAPK-related signaling cascades by average entropy production rate
Authors: Tsuruyama Tatsuaki
Published: October 2018

Information thermodynamics has recently greatly developed the application for analysis of biological phenomenon. During the signal transduction, entropy production from phosphorylation of signal molecule is produced at individual step production. Using this value, average entropy production rate (AEPR) is computable.

In the current study, AEPR in each signal step was analyzed using experimental data from previously reported studies of the mitogen-activated protein kinases (MAPK) cascade. The result revealed that the differences of AEPR is smaller when using ligands, suggesting that AEPR is one of the attributes of the given cascade and useful for quantitative analysis. This consistency of AEPR suggests that the number of signal events is maximized, in other words, signaling efficiency is maximized. In conclusion, the current information theoretical approach provides not only a quantitative means for comparison of responses to a specified extracellular stimulation, but also a method for evaluation of active cascades.

Synopsis

A variety of methods for quantifying intracellular signal transduction have been proposed. Herein, a novel method of quantification by integrated analysis consisting of kinetics, non-equilibrium thermodynamics, fluctuation theorem and graph theory was attempted.

Signal transduction can be computed by entropy production amount from the fluctuation in the phosphorylation reaction of signaling molecules.

By Bayesian analysis of the entropy production rates of individual steps, they are consistent through the signal cascade.
Epigenetic inactivation of oncogenic brachyury (TBXT) by H3K27 histone demethylase controls chordoma cell survival
Authors: Cottone Lucia , Hookway Edward S , Cribbs Adam , Wells Graham , Lombard Patrick , Ligammari Lorena , Tumber Anthony , Tirabosco Roberto , Amary Fernanda , Szommer Tamas , Johannson Catrine , Brennan Paul E , Pillay Nischalan , Oppermann Udo , Flanagan Adrienne M
Published: October 2018

The expression of the transcription factorbrachyury(TBXT) is normally restricted to embryonic development and its silencing after mesoderm development is epigenetically regulated. In chordoma, a rare tumour of notochordal differentiation, TBXT acts as a putative oncogene, and we hypothesised that its expression could be controlled through epigenetic inhibition. Screening of five chordoma cell lines revealed that only inhibitors of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (Jmjd3) reduceTBXTexpression and lead to cell death, findings validated in primary patient-derived culture systems. Pharmacological inhibition of KDM6 demethylases leads to genome-wide increases in repressive H3K27me3 marks, accompanied by significantly reduced TBXT expression, an effect that is phenocopied by the dual genetic inactivation ofKDM6A/Busing CRISPR/Cas9. Transcriptional profiles in response to a novel KDM6A/B inhibitor, KDOBA67, revealed downregulation of critical genes and transcription factor networks for chordoma survival pathways, whereas upregulated pathways were dominated by stress, cell cycle and pro-apoptotic response pathways.

This study supports previous data showing that the function of TBXT is essential for maintaining notochord cell fate and function and provides further evidence that TBXT is an oncogenic driver in chordoma. Moreover, the data suggest that TBXT can potentially be targeted therapeutically by modulating epigenetic control mechanisms such as H3K27 demethylases.
Pacific geoduck (Panopea generosa) resilience to natural pH variation
Authors: Spencer Laura H. , Horwith Micah , Lowe Alexander T. , Venkataraman Yaamini R. , Timmins-Schiffman Emma , Nunn Brook L. , Roberts Steven B.
Published: October 2018

Pacific geoduck aquaculture is a growing industry, however, little is known about how geoduck respond to varying environmental conditions, or how the industry will fare under projected climate conditions. To understand how geoduck production may be impacted by low pH associated with ocean acidification, multi-faceted environmental heterogeneity needs to be included to understand species and community responses. In this study, eelgrass habitats and environmental heterogeneity across four estuarine bays were leveraged to examine low pH effects on geoduck under different natural regimes, using targeted proteomics to assess physiology. Juvenile geoduck were deployed in eelgrass and adjacent unvegetated habitats for 30 days while pH, temperature, dissolved oxygen, and salinity were monitored. Across the four bays, pH was lower in unvegetated habitats compared to eelgrass habitats. However this did not impact geoduck growth, survival, or proteomic abundance patterns in gill tissue. Temperature and dissolved oxygen differences across all locations corresponded to differences in growth and targeted protein abundance patterns. Specifically, three protein abundance levels (trifunctional-enzyme β-subunit, puromycin-sensitive aminopeptidase, and heat shock protein 90-α) and shell growth positively correlated with dissolved oxygen variability and inversely correlated with mean temperature. These results demonstrate that geoduck may be resilient to low pH in a natural setting, but other abiotic factors (i.e. temperature, dissolved oxygen variability) may have a greater influence on geoduck physiology. In addition this study contributes to the understanding of how eelgrass patches influences water chemistry.
In vivo cerebral microdialysis validation of the acute central glutamate response in a translational rat model of concussion combining force and rotation
Authors: Massé Ian , Moquin Luc , Provost Chloé , Guay Samuel , Gratton Alain , De Beaumont Louis
Published: October 2018

Concussions/mild traumatic brain injury (mTBI) represent a major public health concern due to persistent behavioral and neurological effects. The mechanisms by which concussions lead to such effects are partly attributable to an hyperacute indiscriminate glutamate release. Cerebral microdialysis studies in rodents reported a peak of extracellular glutamate 10 minutes after injury. Microdialysis has the advantage of being one of the few techniques allowing the quantification of neurotransmitters in vivo and at different time points following injury. In addition to the clear advantages afforded by microdialysis, the Wayne State weight-drop model induces an impact on the skull of a subject unrestrained by the fall of a weight. The latter model allows rapid acceleration and deceleration of the head and torso, an essential feature in human craniocerebral trauma and a factor that is missing from many existing animal concussion models. In the present study, we applied the Wayne State procedure and microdialysis to document, in awake rats, the acute changes in extracellular hippocampal glutamate and GABA levels resulting from concussive trauma. We studied the dorsal CA1 hippocampal region as it contains a high density of glutamatergic terminal and receptors, thus making it vulnerable to excitotoxic insult. Using HPLC, dialysate levels of hippocampal glutamate and GABA were measured in adult male Sprague-Dawley rats in 10 min increments for 60 min prior to, during and for 90 min following concussive trauma induced by the Wayne State weight-drop procedure. Sham control animals were treated in the same manner but without receiving the concussive trauma procedure. Our results show that concussive trauma is followed, within 10 min, by a robust, transient 3-fold increase in hippocampal glutamate levels; such changes were not seen in controls. In contrast, GABA levels were unaffected by the concussive trauma procedure. The findings derived from the approach used here are generally consistent with those of previous other studies. They also provide a crucial in vivo validation of the Wayne State procedure as a model with promising translational potential for pre-clinical studies on early therapeutic responses to concussion.
Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance
Authors: Cirelli Kimberly M. , Carnathan Diane G. , Nogal Bartek , Rodriguez Oscar L. , Martin Jacob T. , Upadhyay Amit A. , Enemuo Chiamaka A. , Gebru Etse H. , Choe Yury , Viviano Federico , Nakao Catherine , Pauthner Matthias , Reiss Samantha , Cottrell Christopher A. , Bastidas Raiza , Gibson William , Wolabaugh Amber N. , Melo Mariane B. , Cosette Benjamin , Kuman Venkatesh , Patel Nirav , Tokatlian Talar , Menis Sergey , Kulp Daniel W. , Burton Dennis R. , Murrell Ben , Bosinger Steven E. , Schief William R. , Ward Andrew B. , Watson Corey T. , Silvestri Guido , Irvine Darrell J. , Crotty Shane
Published: October 2018

The observation that humans can produce broadly neutralizing antibodies (bnAbs) against HIV-1 has generated enthusiasm about the potential for a bnAb vaccine against HIV-1. Conventional immunization strategies will likely be insufficient for the development of a bnAb HIV vaccine and vaccines to other difficult pathogens, due to the significant immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. Using longitudinal lymph node fine needle aspirates, we found that two independent methods of slow delivery immunization of rhesus macaques (RM) resulted in larger GCs, more robust and sustained GC Tfh cell responses, and GC B cells with improved Env-binding, which correlated with the development of ~20 to 30-fold higher titers of tier 2 HIV-1 nAbs. Using a new RM genomic immunoglobulin loci reference sequence, we identified differential IgV gene usage between slow delivery immunized and conventional bolus immunized animals. The most immunodominant IgV gene used by conventionally immunized animals was associated with many GC B cell lineages. Ab mapping of those GC B cell specificities demonstrated targeting of an immunodominant non-neutralizing trimer base epitope, while that response was muted in slow delivery immunized animals. Thus, alternative immunization strategies appear to enhance nAb development by altering GCs and modulating immunodominance of non-neutralizing epitopes.
Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin
Authors: Miller Alexandria N. , Vaisey George , Long Stephen B.
Published: October 2018

Bestrophin (BEST1–4 in humans) channels are ligand gated chloride (Cl−) channels that are activated by calcium (Ca2+). Mutations in BEST1 cause retinal degenerative diseases. Partly because these channels have no sequence or structural similarity to other ion channels, the molecular mechanisms underlying gating are unknown. Here, we present a series of cryo-electron microscopy (cryo-EM) structures of chicken BEST1, determined at 3.1 Å resolution or better, that represent the principal gating states of the channel. Unlike other channels, opening of the pore is due to the repositioning of tethered pore-lining helices within a surrounding protein shell that dramatically widens a “neck” of the pore through a concertina of amino acid rearrangements within the protein core. The neck serves as both the activation and the inactivation gate. The binding of Ca2+ to a cytosolic domain instigates pore opening and the structures reveal that, unlike voltage-gated Na+ and K+ channels, similar molecular rearrangements are responsible for inactivation and deactivation. A single aperture within the 95 Å-long opened pore separates the cytosol from the extracellular milieu and controls anion permeability. The studies define the basis for Ca2+-activated Cl− channel function and reveal a new molecular paradigm for gating in ligand-gated ion channels.
Crystal structure and Hirshfeld surface analysis of tetraaquabis(isonicotinamide-κN
1)nickel(II) fumarate
Authors: Kansiz Sevgi , Golenya Irina A. , Dege Necmi
Published: October 2018

The reaction of NiCl2 with fumaric acid and isonicotinamide in a basic solution produces the title complex, [Ni(C6H6N2O)2(H2O)4](C4H2O4). The nickel(II) ion of the complex cation and the fumarate anion are each located on an inversion centre. The NiII ion is coordinated octahedrally by four water O atoms and two N atoms of isonicotinamide molecules. The fumarate anion is linked to neighbouring complex cations via Owater—H...Ofumarate hydrogen bonds. In the crystal, the complex cations are further linked by O—H...O, N—H...O and C—H...O hydrogen bonds, forming a three-dimensional supramolecular architecture. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyse the intermolecular interactions present in the crystal and indicate that the most important contributions for the crystal packing are from H...O/O...H (41.8%), H...H (35.3%) and H...C/C...H (10.2%) interactions.
Structure and function of a glycoside hydrolase family 8 endoxylanase fromTeredinibacter turnerae
Authors: Fowler Claire A. , Hemsworth Glyn R. , Cuskin Fiona , Hart Sam , Turkenburg Johan , Gilbert Harry J. , Walton Paul H. , Davies Gideon J.
Published: October 2018

The biological conversion of lignocellulosic matter into high-value chemicals or biofuels is of increasing industrial importance as the sector slowly transitions away from nonrenewable sources. Many industrial processes involve the use of cellulolytic enzyme cocktails – a selection of glycoside hydrolases and, increasingly, polysaccharide oxygenases – to break down recalcitrant plant polysaccharides. ORFs from the genome ofTeredinibacter turnerae, a symbiont hosted within the gills of marine shipworms, were identified in order to search for enzymes with desirable traits. Here, a putativeT. turneraeglycoside hydrolase from family 8, hereafter referred to as TtGH8, is analysed. The enzyme is shown to be active against β-1,4-xylan and mixed-linkage (β-1,3,β-1,4) marine xylan. Kinetic parameters, obtained using high-performance anion-exchange chromatography with pulsed amperometric detection and 3,5-dinitrosalicyclic acid reducing-sugar assays, show that TtGH8 catalyses the hydrolysis of β-1,4-xylohexaose with akcat/Kmof 7.5 × 107 M−1 min−1but displays maximal activity against mixed-linkage polymeric xylans, hinting at a primary role in the degradation of marine polysaccharides. The three-dimensional structure of TtGH8 was solved in uncomplexed and xylobiose-, xylotriose- and xylohexaose-bound forms at approximately 1.5 Å resolution; the latter was consistent with the greaterkcat/Kmfor hexasaccharide substrates. A2,5Bboat conformation observed in the −1 position of bound xylotriose is consistent with the proposed conformational itinerary for this class of enzyme. This work shows TtGH8 to be effective at the degradation of xylan-based substrates, notably marine xylan, further exemplifying the potential ofT. turneraefor effective and diverse biomass degradation.
Co-crystallization of human inositol monophosphatase with the lithium mimetic L-690,330
Authors: Kraft Lucas , Roe S. Mark , Gill Raj , Atack John R.
Published: October 2018

Lithium, which is still the gold standard in the treatment of bipolar disorder, has been proposed to inhibit inositol monophosphatase (IMPase) and is hypothesized to exert its therapeutic effects by attenuating phosphatidylinositol (PI) cell signalling. Drug-discovery efforts have focused on small-molecule lithium mimetics that would specifically inhibit IMPase without exhibiting the undesired side effects of lithium. L-690,330 is a potent bisphosphonate substrate-based inhibitor developed by Merck Sharp & Dohme. To aid future structure-based inhibitor design, determination of the exact binding mechanism of L-690,330 to IMPase was of interest. Here, the high-resolution X-ray structure of human IMPase in complex with L690,330 and manganese ions determined at 1.39 Å resolution is reported.
Identification of the site of oxidase substrate binding inScytalidium thermophilumcatalase
Authors: Yuzugullu Karakus Yonca , Goc Gunce , Balci Sinem , Yorke Briony A. , Trinh Chi H. , McPherson Michael J. , Pearson Arwen R.
Published: October 2018

The catalase fromScytalidium thermophilumis a homotetramer containing a hemedin each active site. Although the enzyme has a classical monofunctional catalase fold, it also possesses oxidase activity towards a number of small organics, including catechol and phenol. In order to further investigate this, the crystal structure of the complex of the catalase with the classical catalase inhibitor 3-amino-1,2,4-triazole (3TR) was determined at 1.95 Å resolution. Surprisingly, no binding to the heme site was observed; instead, 3TR occupies a binding site corresponding to the NADPH-binding pocket in mammalian catalases at the entrance to a lateral channel leading to the heme. Kinetic analysis of site-directed mutants supports the assignment of this pocket as the binding site for oxidase substrates.
Crystallography on a chip – without the chip: sheet-on-sheet sandwich
Authors: Doak R. Bruce , Nass Kovacs Gabriela , Gorel Alexander , Foucar Lutz , Barends Thomas R. M. , Grünbein Marie Luise , Hilpert Mario , Kloos Marco , Roome Christopher M. , Shoeman Robert L. , Stricker Miriam , Tono Kensuke , You Daehyun , Ueda Kiyoshi , Sherrell Darren A. , Owen Robin L. , Schlichting Ilme
Published: October 2018

Crystallography chips are fixed-target supports consisting of a film (for example Kapton) or wafer (for example silicon) that is processed using semiconductor-microfabrication techniques to yield an array of wells or through-holes in which single microcrystals can be lodged for raster-scan probing. Although relatively expensive to fabricate, chips offer an efficient means of high-throughput sample presentation for serial diffraction data collection at synchrotron or X-ray free-electron laser (XFEL) sources. Truly efficient loading of a chip (one microcrystal per well and no wastage during loading) is nonetheless challenging. The wells or holes must match the microcrystal size of interest, requiring that a large stock of chips be maintained. Raster scanning requires special mechanical drives to step the chip rapidly and with micrometre precision from well to well. Here, a `chip-less' adaptation is described that essentially eliminates the challenges of loading and precision scanning, albeit with increased, yet still relatively frugal, sample usage. The device consists simply of two sheets of Mylar with the crystal solution sandwiched between them. This sheet-on-sheet (SOS) sandwich structure has been employed for serial femtosecond crystallography data collection with micrometre-sized crystals at an XFEL. The approach is also well suited to time-resolved pump–probe experiments, in particular for long time delays. The SOS sandwich enables measurements under XFEL beam conditions that would damage conventional chips, as documented here. The SOS sheets hermetically seal the sample, avoiding desiccation of the sample provided that the X-ray beam does not puncture the sheets. This is the case with a synchrotron beam but not with an XFEL beam. In the latter case, desiccation, setting radially outwards from each punched hole, sets lower limits on the speed and line spacing of the raster scan. It is shown that these constraints are easily accommodated.
Structural insights into the recognition of phosphorylated Hop1 by Mek1
Authors: Xie Changlin , He Chao , Jiang Yiyang , Yu Hailong , Cheng Lin , Nshogoza Gilbert , Ala Moududee Sayed , Tian Changlin , Wu Jihui , Shi Yunyu , Li Fudong
Published: October 2018

The FHA domain-containing protein Mek1 is a meiosis-specific kinase that is involved in the regulation of interhomolog recombination in meiosis inSaccharomyces cerevisiae. The recruitment and activation of Mek1 require the phosphorylation of the chromosome axis protein Hop1 at Thr318 (pT318), which is necessary for recognition by the Mek1 FHA domain. Here, crystal structures of the Mek1 FHA domain in the apo state and in complex with the Hop1 pT318 peptide are presented, demonstrating that the hydrophobic residues Phe320 and Val321 at the pT+2 and pT+3 positions in the ligand contribute to the preferential recognition. It was further found that inSchizosaccharomyces pombeMek1 FHA binds both pT15 in its N-terminal SQ/TQ cluster domain (SCD) and pT270 in the Hop1 SCD. The results revealed the structural basis for the preferential recognition of phosphorylated Hop1 by Mek1 inS. cerevisiaeand facilitate the understanding of the interaction between theS. pombeMek1 FHA domain and its binding targets.
A numerical study into the longitudinal dynamic stability of the tailless aircraft
Authors: Kwiek Agnieszka
Published: October 2018

Purpose

The purpose of this research is a study into a mathematical approach of a tailless aircraft dynamic stability analysis. This research is focused on investigation of influence of elevons (elevator) on stability derivatives and consequently on the aircraft longitudinal dynamic stability. The main research question is to determine whether this impact should be taken into account on the conceptual and preliminary stage of the analysis of the longitudinal dynamic stability.

Design/methodology/approach

Aerodynamic coefficients and longitudinal stability derivatives were computed by Panukl (panel methods). The analysis of the dynamic stability of the tailless aircraft was made by the Matlab code and SDSA package.

Findings

The main result of the research is a comparison of the dynamic stability of the tailless aircraft for different approaches, with and without the impact of elevator deflection on the trim drag and stability derivatives.

Research limitations/implications

This paper presents research that mostly should be considered on the preliminary stage of aircraft design and dynamic stability analysis. The impact of elevons deflection on the aircraft moment of inertia has been omitted.

Practical implications

The results of this research will be useful for the further design of small tailless unmanned aerial vehicles (UAVs).

Originality/value

This research reveals that in case of the analysis of small tailless UAVs, the impact of elevons deflection on stability derivatives is bigger than the impact of a Mach number. This impact should be taken into consideration, especially for a phugoid mode.
Aerodynamic and flight dynamic interaction in spin
Authors: Marcinkiewicz Ewa , Goraj Zdobyslaw Jan , Figat Marcin
Published: October 2018

Purpose

The purpose of this paper is to describe an integrated approach to spin analysis based on 6-DOF (degrees of freedom) fully nonlinear equations of motion and a three-dimensional multigrid Euler method used to specify a flow model. Another purpose of this study is to investigate military trainer performance during a developed phase of a deliberately executed spin, and to predict an aircraft tendency while entering a spin and its response to control surface deflections needed for recovery.

Design/methodology/approach

To assess spin properties, the calculations of aerodynamic characteristics were performed through an angle-of-attack range of −30 degrees to +50 degrees and a sideslip-angle range of −30 degrees to +30 degrees. Then, dynamic equations of motion of a rigid aircraft together with aerodynamic loads being premised on stability derivatives concept were numerically integrated. Finally, the examination of light turboprop dynamic behaviour in post-stalling conditions was carried out.

Findings

The computational method used to evaluate spin was positively verified by comparing it with the experimental outcome. Moreover, the Euler code-based approach to lay down aerodynamics could be considered as reliable to provide high angles-of-attack characteristics. Conclusions incorporate the results of a comparative analysis focusing especially on comprehensive assessment of output data quality in relation to flight tests.

Originality/value

The conducted calculations take into account aerodynamic and flight dynamic interaction of an aerobatic-category turboprop in spin conditions. A number of manoeuvres considering different aircraft configurations were simulated. The computational outcomes were subsequently compared to the results of in-flight tests and the collected data were thoroughly analysed to draw final conclusions.
A new fuel-balanced formation keeping reference trajectories planning method
Authors: Wang Jihe , Zhang Dexin , Chen GuoZhong , Shao Xiaowei
Published: October 2018

Purpose

The purpose of this paper is to propose a new fuel-balanced formation keeping reference trajectories planning method based on selecting the virtual reference center(VRC) in a fuel-balanced sense in terms of relative eccentricity and inclination vectors (E/I vectors).

Design/methodology/approach

By using the geometrical intuitive relative E/I vectors theory, the fuel-balanced VRC selection problem is reformulated as the geometrical problem to find the optimal point to equalize the distances between the VRC and the points determined by the relative E/I vectors of satellites in relative E/I vectors plane, which is solved by nonlinear programming method.

Findings

Numerical simulations demonstrate that the new proposed fuel-balanced formation keeping strategy is valid, and the new method achieves better fuel-balanced performance than the traditional method, which keeps formation with respect to geometrical formation center.

Research limitations/implications

The new fuel-balanced formation keeping reference trajectories planning method is valid for formation flying mission whose member satellite is in circular or near circular orbit in J2 perturbed orbit environment.

Practical implications

The new fuel-balanced formation keeping reference trajectories planning method can be used to solve formation flying keeping problem, which involves multiple satellites in the formation.

Originality/value

The fuel-balanced reference trajectories planning problem is reformulated as a geometrical problem, which can provide insightful way to understand the dynamic nature of the fuel-balanced reference trajectories planning issue.