bluuebunny/crossref_metadata_2025 huggingface dataset:
Rilpivirine Plasma and Cervicovaginal Concentrations in Women During Pregnancy and Postpartum
Authors: Eke Ahizechukwu C. , Chakhtoura Nahida , Kashuba Angela , Best Brookie M. , Sykes Craig , Wang Jiajia , Stek Alice M. , Smith Elizabeth , Calabrese Samantha , Capparelli Edmund V. , Mirochnick Mark ,   IMPAACT P1026s Protocol Team
Published: March 2018

Background:

Concentrations of antiretrovirals in the genital tract play a key role in preexposure prophylaxis. This study aims to describe rilpivirine (Edurant) concentrations in the genital tract in pregnant and postpartum women.

Methods:

International Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1026s is an ongoing, prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women that include a cohort receiving rilpivirine combination regimen. Intensive pharmacokinetics evaluations were performed at steady state during the second and third trimester, and postpartum. Plasma and directly aspirated cervicovaginal fluid (CVF) samples were collected at 4 time points around an observed dose and measured using high-performance liquid chromatography with ultraviolet detection, [plasma; lower limit of quantification (LLQ) = 10 ng/mL] or liquid chromatography-tandem mass spectrometry (CVF; LLQ = 1 ng/mL).

Results:

A total of 24 women were included in the analysis. For all time points combined, median (interquartile range) rilpivirine concentrations were 70 ng/mL (23–121) in CVF and 92 ng/mL (49–147) in plasma. The CVF to plasma AUC(0–4) ratios were significantly higher in the second (0.90, 90% CI: 0.61 to 1.46) and third trimesters of pregnancy compared with postpartum (0.40, 90% CI: 0.19 to 0.87). Three of 189 (1.6%) plasma samples in 2 women were below the LLQ and the corresponding CVF concentrations. Seventeen additional CVF concentrations (10.6%) were below LLQ in 13 participants. No major safety concerns were noted.

Conclusions:

Rilpivirine concentrations were higher in the CVF during pregnancy compared with postpartum. CVF Rilpivirine is likely to achieve inhibitory concentrations effective for preventing peripartum HIV transmission.
Assessment of Low-Grade Meniscal and Cartilage Damage of the Knee at 7 T
Authors: Friebe Björn , Richter Martin , Penzlin Susanne , Stärke Christian , Kropf Siegfried , Lohmann Christoph , Fischbach Frank , Speck Oliver
Published: March 2018

Objectives

The aim of this study was to compare the assessment of low-grade meniscal tears and cartilage damage in ultrahigh-field magnetic resonance imaging (MRI) at 7 T to routine clinical MRI at 3 T.

Materials and Methods

This study was approved by the local ethics committee, and written informed consent was obtained from each patient. Forty-one patients with suspected meniscal damage or mild osteoarthritis (Kellgren-Lawrence score, 0–2) received 7 T as well as routine clinical 3 T consecutively. The imaging protocol at both field strengths consisted of PD-weighted imaging with more than doubled resolution at 7 T. Images were read blinded regarding field strength and patient characteristics by 3 readers with different experience in musculoskeletal MRI (3 years, 6 years, and 10 years) according to a modified whole-organ MRI score of the knee in osteoarthritis and the Score of the International Cartilage Repair Society. Arthroscopic reports as a criterion standard were available for 12 patients. A multifactorial mixed model analysis was performed.

Results

The mean cumulated diagnostic score at 7 T was significantly closer to the criterion standard compared with 3 T in patients where criterion standard was available (P < 0.001). In all 41 patients, the damages were rated more severely at 7 T reflected by a mean higher cumulative score in cartilage (P < 0.001) and in the meniscus (P < 0.001). No difference in interreader variability between 3 T and 7 T was observed. Imaging acquisition time was nearly identical.

Conclusions

Morphologic imaging of cartilage and meniscal damage of the knee in ultrahigh-field MRI at 7 T with PD-weighted TSE sequences seemed to have a significantly higher diagnostic accuracy than 3 T and can be performed with equal acquisition times while exploiting higher resolution of 7 T.
Large-Scale Study of Long-Term Vertical Skeletal Stability in a Surgery-First Orthognathic Approach Without Presurgical Orthodontic Treatment: Part II
Authors: Jeong Woo Shik , Lee Jang Yeol , Choi Jong Woo
Published: March 2018

The surgery-first approach (SFA) is a new paradigm in orthognathic surgery. In our experience over the last 10 years, SFA, particularly for the correction of the class III dentofacial deformity and facial asymmetry, has demonstrated high success rates without any major complications. However, many craniofacial surgeons remain concerned about the skeletal stability of SFA. In the present study, the authors aimed to compare the traditional and SFA with regard to the long-term outcomes of vertical skeletal stability using large-scale data. The authors enrolled patients with skeletal class III dentofacial deformities who had undergone and completed orthognathic surgery between December 2007 and December 2015. The inclusion criteria were based on the presurgical simulation of the dental model, and the authors predicted the potential of the SFA based on this preoperative simulation model. Patients with cleft-related syndromes, and those who had undergone orthognathic surgeries for facial asymmetry or class II deformity were excluded. A total of 104 and 51 class III patients were enrolled in the surgery-first and traditional orthodontics-first groups, respectively. Satisfactory results were achieved in all 155 patients with dentofacial deformity. The initial preoperative measurements of cephalometric analysis, particularly vertical skeletal stability, were similar and well maintained after the procedure in both groups. In conclusion, the SFA without any presurgical orthodontic treatment for correcting dentofacial deformities can achieve similar long-term vertical stability results to the orthodontic treatment-first approach.
Painful Neuroma Treatment of the Supraorbital Nerve and Forehead Neurotization Using Human Cadaveric Nerve Allograft
Authors: Bassilios Habre Samer , Depew James Bradford , Wallace Robert D. , Konofaos Petros
Published: March 2018

Neuroma pain can be severe, persistent, and treatment-resistant. Forehead and scalp anesthesia is troublesome for patients. Following an iatrogenic ablative injury to the right supraorbital nerve, with subsequent painful neuroma formation, a human cadaveric nerve allograft (AxoGen, Alachua, FL) was used to restore sensation of the right forehead and treat pain. At 1-year follow-up, the patient was pain-free, and protective sensation to the right forehead was recovered with comparable static and dynamic 2-point discrimination between the injured (20 mm, 12 mm respectively) and the normal side (15 mm, 10 mm respectively). This is the first reported case of using a cadaver nerve allograft for successful direct neurotization of the skin and restoration of sensation in the upper part of the face, and for treating painful neuromas. Moreover, a brief review of the available techniques for treating neuromas of the supraorbital and supratrochlear nerves is provided.
One-Piece Mandibuloplasty Compared to Conventional Mandibuloplasty With Narrowing Genioplasty
Authors: Kim Sung Chan , Kwon Jin Geun , Jeong Woo Shik , Na Diane , Choi Jong Woo
Published: March 2018

Background:

Recently, the mandibular body and chin shape are known to be important issue as well as the mandibular angle. The authors have performed the one-piece mandibuloplasty from the mandibular angle to the most anterior part of chin to achieve the change of the whole mandibular shape as a one-piece.

Methods:

All of 14 patients who complaint prominent mandibular angle and chin were randomly allocated into 2 groups. Group I (n = 7) was treated with conventional mandibuloplasty with narrowing genioplasty and Group II (n = 7) was treated with one-piece mandibuloplasty. Pre- and postoperative clinical photography, cephalometry, computed tomography scan, 3-dimensional photography were taken and occurrence of secondary angle, patient's satisfaction, and operative time were evaluated.

Results:

The mean volume reduction per side was 41.8 cc on one-piece mandibuloplasty and 36.5 cc on conventional mandibuloplasty with narrowing genioplasty. Furthermore, average lower facial decreased from 64.3 to 61.0 after 6 months postoperatively and was maintained until 3 years on average after the operation. In one-piece mandibuloplasty group shows a little higher satisfaction about mandible body, and it was estimated that the presence of secondary angle makes dissatisfaction. The authors’ treatment approach resulted in a shorter total surgery time than conventional technique (70.57 versus 105.14 min, P = 0.002).

Conclusions:

One-piece mandibuloplasty based on 3-dimensional printing model turned out to be very successful for the natural shaping of the lower jaw in the patients with the prominent mandible in terms of the technical efficiency and the aesthetic point of view.
Vascular Malformation Enlargement During Menopause
Authors: Maclellan Reid A. , Goss Jeremy A. , Greene Arin K.
Published: March 2018

Vascular malformations enlarge overtime, particularly during adolescence when follicle-stimulating hormone (FSH) rises. Lesions contain the receptor for follicle-stimulating hormone. FSH also becomes elevated during menopause. We present a patient with a venous malformation of the lip that presented for the first time after she entered menopause which was temporally related to a significant increase in her serum FSH levels that were measured. This observation supports the hypothesis that FSH might influence the pathophysiology of vascular malformations.
Surgical Resection of Vascular Lesions Involving the Buccal Fat Pad
Authors: Baldin André Victor , Telich Tarriba José E. , Velázquez Zabaleta Enrique , Apellaniz Campo Armando , Martinez Wagner Rogélio , Cardenas-Mejía Alexander
Published: March 2018

Vascular abnormalities are localized structural irregularities, which are performed during vasculogenesis, angiogenesis, and lymphangiogenesis. The involvement of soft tissue in such vascular malformations is frequent; however, the compromising of the buccal fat pads (Bichat bags) is uncommon, even in specialized centers, such as the plastic clinic of our institution, in which very few patients have been reported in the literature. The purpose of this article is to present a series of 2 patients in which vascular malformations involving the buccal fat pads, which were extracted by intraoral approach.
Changing the Paradigm in Medial Canthal Reconstruction: The Bridge Principle and the Croissant-Like Keystone Island Perforator Flap as An Alternative for Medium Size Soft Tissue Defects in Internal Canthus Reconstruction
Authors: Kostopoulos Epameinondas , Agiannidis Christos , Konofaos Petros , Kotsakis Ioannis , Hatzigianni Panagiota , Georgopoulos Gerasimos , Papadatou Zoe , Konstantinidou Chara , Champsas Gregorios , Papadopoulos Othon , Casoli Vincent
Published: March 2018

Introduction:

Medial canthus is a common area of skin cancer prevalence. Defects in this region represent a challenging reconstructive task. The nasal version of keystone perforator island flap (KPIF) has proven its versatility. The aim of the present study was to expand its utilization in the neighbor medial canthus area. A modified croissant-like KPIF (CKPIF) was used resolving inner convexity-related problems. The presence of procerus in the glabella area, bridging a surface from nasalis up to the frontalis, changed the traditional dissecting flap technique. Thus, the authors introduce the bridge principle, which consists of the indirect transfer of the flap to the defect site through a muscular “bridge” (the procerus). The authors report their experience in medial canthal reconstruction combining a modified KPIF with a new dissecting “principle.”

Methods:

From November 2016 to July 2017, a series of patients presenting soft tissue defects of various dimensions in the medial canthus, secondary to tumor extirpation, sustained reconstruction with a CKPIF dissected with the bridge principle.

Results:

A total of 15 patients were treated with this new technique. Their mean age was 75.3 years. The mean size of the defect was 2.08 cm (length) × 1.5 cm (width). All flaps survived without any sign of venous congestion. A transient epiphora presented in 4 patients (4/15 or 26.6%), which was subsided 2 months later.

Conclusion:

A new approach following a novel paradigm was introduced to resolve an old problem. Initial outcomes are encouraging. However, longer series are needed to extract definitive and safer conclusion.
Comparison of the Recurrence Rates of Nonparasitic Hepatic Cysts Treated With Laparoscopy or With Open Fenestration: A Meta-Analysis
Authors: Zhang Jian-Ying , Liu Yan , Liu Hong-Yan , Chen Long , Su Dai-Wen , Wang Yun-Bing
Published: March 2018

Objective:

This study aimed to compare the recurrence rates of nonparasitic hepatic cysts that were treated with laparoscopy or open fenestration.

Materials and Methods:

PubMed, Embase, Cochrane Library, Web of Science, Wan-fang data, CNKI, CqVip, and CBM were searched for randomized controlled trials, cohort, and case-control studies that reported on the treatment of nonparasitic hepatic cysts with laparoscopy or with open fenestration. Studies that were published from the establishment of the databases to October 1, 2016 were retrieved. STATA software (version 13) was utilized for statistical analysis.

Results:

A total of 31 studies were included. Meta-analysis showed that the recurrence rates of hepatic cysts between the laparoscopy-deroofing and open-deroofing groups had no difference (odds ratio, 0.72; 95% confidence interval, 0.50-1.02; P=0.061). This result was in agreement with the result of subgroup analysis for solitary and multiple hepatic cyst.

Conclusions:

These findings underscore the distinct role of laparoscopy deroofing in the treatment of hepatic cysts because of the certainty of its long-term curative effect.
Pelvic Drain After Laparoscopic Low Anterior Resection for Rectal Cancer in Patients With Diverting Stoma
Authors: Matsuda Kenji , Yokoyama Shozo , Hotta Tsukasa , Watanabe Takashi , Tamura Koichi , Iwamoto Hiromitsu , Mizumoto Yuki , Yamaue Hiroki
Published: March 2018

Background:

This study is intended to assess whether the use of pelvic drain reduces incidence of pelvic sepsis in the era of laparoscopic low anterior resection (LAR).

Patients and Methods:

In total, 200 of consecutive patients who underwent laparoscopic LAR for rectal cancer with diverting stoma were analyzed.

Results:

Pelvic sepsis occurred in 14 of 110 patients (12.7%) in the drain group and in 9 of 90 patients (10.0%) in the no drain group (P=0.548). Furthermore, there were no differences in the incidence of anastomotic leakage, time to diagnosis of pelvic sepsis, and type of treatments for pelvic sepsis.

Conclusions:

Prophylactic pelvic drain use after laparoscopic LAR in patients with diverting stoma does not reduce incidence of pelvic sepsis. Routine use of pelvic drain is not recommended. This study was registered at UMIN (Registration Number: UMIN000026076).
A selective placement strategy for surgical feeding tubes benefits trauma patients
Authors: Marcotte Joseph , Hazelton Joshua P. , Arya Chirag , Dalton Michael , Batool Amber , Gaughan John , Nguyen Linh , Porter John , Fox Nicole
Published: March 2018

BACKGROUND

The indications for surgical feeding tube (SFT) placement in trauma patients are poorly defined. Patient selection is critical as complications from SFTs have been reported in up to 70% of patients. A previous analysis by our group determined that 25% of the SFTs we placed were unnecessary and that older patients, patients with head and spinal cord injuries, and patients who needed a tracheostomy were more likely to require long-term SFTs. Following this study, we modified our institutional guidelines for SFT placement. We hypothesized that a more selective placement strategy would result in fewer unnecessary SFTs.

METHODS

A retrospective review of all adult patients from 2012 to 2016 with an intensive care unit length of stay longer than 4 days and an SFT placed during admission was conducted. This group was compared to data collected prior to our change in practice (2007–2010). Data from 2011 were excluded as a washout period. “Necessary” SFT use was defined per established guidelines as either daily use of the SFT through discharge or for 28 days or longer and “unnecessary” SFT use as all others.

RESULTS

Two hundred fifty-seven SFTs were placed from 2007 to 2010 and 244 from 2012 to 2016. Following implementation of our selective SFT placement strategy, unnecessary SFT placement decreased from 25% in 2007 to 2010 to 8% in 2012 to 2016 (p < 0.0001). Significant predictors of necessary SFT placement by univariate regression were as follows: increasing age (odds ratio [OR] 1.03/year; 95% confidence interval [CI], 1.01–1.04), head injury (OR, 2.80; 95% CI, 1.71–4.60), cervical spinal cord injury (OR, 4.42; 95% CI, 1.34–14.50), and need for tracheostomy (OR, 1.41; 95% CI, 2.21–7.67). The overall complication rate was 11% (9% in the selective group vs. 13% in the preselective group, p = 0.2574) and was highest following open SFT placement (22%).

CONCLUSION

A selective placement strategy for SFTs in our trauma population resulted in fewer unnecessary SFTs and a trend toward fewer complications. Surgical feeding tubes should be placed through a percutaneous approach whenever possible.

LEVEL OF EVIDENCE

Therapeutic study, level IV.
A negative computed tomography may be sufficient to safely discharge patients with abdominal seatbelt sign from the emergency department: A case series analysis
Authors: Barmparas Galinos , Patel Deven C. , Linaval Nikhil T. , Dhillon Navpreet K. , Patel Kavita A. , Margulies Daniel R. , Ley Eric J.
Published: March 2018

BACKGROUND

The presence of an abdominal seatbelt sign (ASBS) following a motor vehicle collision (MVC) is associated with a high risk for occult intra-abdominal injury, prompting imaging studies and a prolonged period of clinical observation. The aim of this study was to determine how a negative computed tomography (CT) of the abdomen/pelvis (A/P) can serve in the safe disposition of these patients. Our hypothesis was that in the setting of a negative CT, the presence of occult intra-abdominal injuries requiring a delayed intervention is extremely unlikely.

METHODS

The medical charts of patients admitted from January 2014 to December 2016 to a Level I trauma center following an MVC were reviewed for a documentation of an ASBS. Patients who did not have a CT A/P upon admission were excluded. The CT A/P of the remaining patients were then classified as negative if there were no findings of acute vascular, visceral or bony injury or positive if any of these findings was present. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CT A/P for the presence of an intra-abdominal injury were calculated.

RESULTS

Over the 3-year study period, 1,108 patients were admitted after an MVC. Of those, 196 (17.7%) had an ASBS upon presentation and 183 (93.4%) of 196 underwent a CT A/P. A total of 114 (62.3%) of 183 had a negative CT A/P. These patients remained hospitalized for a median of 2 (1–35) days with none (0.0%) requiring a delayed laparotomy. The sensitivity of CT A/P in identifying patients requiring an exploratory laparotomy was 100.0%, specificity was 67.9%, NPV was 100.0%, and PPV was 21.7%. The negative likelihood ratio was 0.00.

CONCLUSION

For patients with an ASBS following an MVC, a negative CT A/P may be sufficient for safe discharge from the emergency department without any need for additional clinical observation.

LEVEL OF EVIDENCE

Therapuetic, level IV.
The contemporary timing of trauma deaths
Authors: Bardes James M. , Inaba Kenji , Schellenberg Morgan , Grabo Daniel , Strumwasser Aaron , Matsushima Kazuhide , Clark Damon , Brown Niquelle , Demetriades Demetrios
Published: March 2018

BACKGROUND

The distribution of trauma deaths was classically described as trimodal. With advances in both technology and trauma systems, this was reevaluated and found to be bimodal in the early 2000s. Over the last decade there have been continued improvements in trauma and intensive care unit (ICU) care, related to damage control techniques and evidence based ICU pathways. A better understanding of the distribution of trauma deaths may be used to improve trauma systems. This study aimed to evaluate the contemporary distribution of trauma deaths after the widespread implementation of modern trauma and critical care principles.

METHODS

This study included patients entered in the NTDB from 2008 to 2014. For dead patients, hospital length of stay was equated to time until death. Additional data was collected to include demographics, mechanism of injury, Injury Severity Score, and Abbreviated Injury Scale score. Histograms were plotted to demonstrate peaks in deaths. Survival analysis was performed with Kaplan-Meier curves and Gehan-Breslow generalized Wilcoxon tests.

RESULTS

4,185,009 patients were analyzed. Thirty-four percent of all deaths occurred within the first 24 hours of admission. The factors most associated with death in the first 24 hours were severe abdominal trauma (73%), penetrating trauma (55%), and severe extremity trauma (58%). Among patients with penetrating trauma and an abdominal Abbreviated Injury Scale score of 4 or higher, 83% of deaths occurred within 24 hours. When plotted, the distribution of deaths was seen to fall rapidly after the first 24 hours and continued to be flat for 30 days in all subgroups analyzed.

CONCLUSION

In this study, the distribution of trauma deaths no longer appears to be trimodal. This may reflect advances in trauma and ICU care, and the widespread adaption of damage control principles. Early deaths, however, remains a significant challenge, specifically from non-compressible abdominal hemorrhage and extremity trauma. Primary prevention and early hemorrhage control must continue to be a focus of research and trauma systems.

LEVEL OF EVIDENCE

Epidemiologic, level IV.
Harbour seals are regaining top-down control in a coastal ecosystem
Authors: Aarts Geert , Brasseur Sophie , Poos Jan Jaap , Schop Jessica , Kirkwood Roger , van Kooten Tobias , Mul Evert , Reijnders Peter , Rijnsdorp Adriaan D. , Tulp Ingrid
Published: March 2018

Historic hunting has led to severe reductions of many marine mammal species across the globe. After hunting ceased, some populations have recovered to pre-exploitation levels, and may again act as a top-down regulatory force on marine ecosystems. Also the harbour seal population in the international Wadden Sea grew at an exponential rate following a ban on seal hunting in 1960’s, and the current number ∼38,000 is close to the historic population size. Here we estimate the impact of the harbour seal predation on the fish community in the Wadden Sea and nearby coastal waters.

Fish remains in faecal samples and published estimates on the seal’s daily energy requirement were used to estimate prey selection and the magnitude of seal consumption. Estimates on prey abundance were derived from demersal fish surveys, and fish growth was estimated using a Dynamic Energy Budget model. GPS tracking provided information on where seals most likely caught their prey.

Harbour seals from the Dutch Wadden Sea fed predominantly on demersal fish, e.g. flatfish species (flounder, sole, plaice, dab), but also sandeel, cod and whiting. Total fish biomass in the Wadden Sea was insufficient to sustain the estimated prey consumption of the entire seal population year-round. This probably explains why seals also acquire prey further offshore in the adjacent North Sea, only spending 13% of their diving time in the Wadden Sea. Still, seal predation was estimated to cause an average annual mortality of 43% and 60% on fish in the Wadden Sea and adjacent coastal zone, respectively. There were however large sources of uncertainty in the estimate, including the migration of fish between the North Sea and Wadden Sea, and catchability estimates of the fish survey sampling gear, particularly for sandeel and other pelagic fish species.

Our estimate suggested a considerable top-down control by harbour seals on demersal fish. However predation by seals may also alleviate density-dependent competition between the remaining fish, increasing fish growth, and partly compensating for the reduction in fish numbers. This study shows that recovering coastal marine mammal populations could potentially become an important component in the functioning of shallow coastal systems.
Coupling magnetically induced electric fields to neurons: longitudinal and transverse activation
Authors: Wang B. , Grill W. M. , Peterchev A. V.
Published: March 2018

We present a theory and computational models to couple the electric field induced by magnetic stimulation to neuronal membranes. The response of neuronal membranes to induced electric fields is examined under different time scales, and the characteristics of the primary and secondary electric fields from electromagnetic induction and charge accumulation on conductivity boundaries, respectively, are analyzed. Based on the field characteristics and decoupling of the longitudinal and transverse field components along the neural cable, quasi-potentials are a simple and accurate approximation for coupling of magnetically induced electric fields to neurons and a modified cable equation provides theoretical consistency for magnetic stimulation. The conventional and modified cable equations are used to simulate magnetic stimulation of long peripheral nerves by circular and figure-8 coils. Activation thresholds are obtained over a range of lateral and vertical coil positions for two nonlinear membrane models representing unmyelinated and myelinated axons and also for undulating myelinated axons. For unmyelinated straight axons, the thresholds obtained with the modified cable equation are significantly lower due to transverse polarization, and the spatial distributions of thresholds as a function of coil position differ significantly from predictions by the activating function. For myelinated axons, the transverse field contributes negligibly to activation thresholds, whereas axonal undulation can increase or decrease thresholds depending on coil position. The analysis provides a rigorous theoretical foundation and implementation methods for the use of the cable equation to model neuronal response to magnetically induced electric fields. Experimentally observed stimulation with the electric fields perpendicular to the nerve trunk cannot be explained by transverse polarization alone and is likely due to nerve fiber undulation and other geometrical inhomogeneities.
Comparison between O and OH intermediates of cytochrome c oxidase studied by FTIR spectroscopy
Authors: Gorbikova E. , Kalendar R.
Published: March 2018

Cytochrome c oxidase is terminal enzyme in the respiratory chain of mitochondria and many aerobic bacteria. It catalyzes reduction of oxygen to water. During its catalysis, CcO proceeds through several quite stable intermediates (R, A, PR/M, O/OH, E/EH). This work is concentrated on the elucidation of the differences between structures of oxidized intermediates O and OH in different CcO variants and at different pH values. Oxidized intermediates of wild type and mutated CcO from Paracoccus denitrificans were studied by means of static and time-resolved Fourier-transform infrared spectroscopy in acidic and alkaline conditions in the infrared region 1800-1000 cm-1. No reasonable differences were found between all variants in these conditions, and in this spectral region. This finding means that the binuclear center of oxygen reduction keeps a very similar structure and holds the same ligands in the studied conditions. The further investigation in search of differences should be performed in the 4000-2000 cm-1 IR region where water ligands absorb.

Abbreviations

A

ferrous-oxy intermediate

ATR

Attenuated total reflectance

BG

background

BNC

binuclear center

CcO

Cytochrome c oxidase

E

one-electron reduced intermediate

F

ferryl intermediate

FRCO

fully-reduced CO-inhibited enzyme

FTIR

Fourier transform infrared

IR

infrared

NHE

Normal Hydrogen Electrode

N-side

negatively charged side of the membrane

PR/M

“peroxy”

intermediates; P-side

positively charged side of the membrane

R

fully-reduced intermediate

TR

time-resolved

WT

wild type
Adhesion of active cytoskeletal vesicles
Authors: Maan R. , Loiseau E. , Bausch A. R.
Published: March 2018

Regulation of adhesion is a ubiquitous feature of living cells, observed during processes such as motility, antigen recognition or rigidity sensing. At the molecular scale, a myriad of mechanisms are necessary to recruit and activate the essential proteins, while at the cellular scale efficient regulation of adhesion relies on the cell’s ability to adapt its global shape. To understand the role of shape remodeling during adhesion, we use a synthetic biology approach to design a minimal model, starting with a limited number of building blocks. We assemble cytoskeletal vesicles whose size, reduced volume, and cytoskeleton contractility can be independently tuned. We are able to show that these cytoskeletal vesicles can sustain strong adhesion to solid substrates only if molecular motors are able to actively remodel the actin cortex. When the cytoskeletal vesicles are deformed under hypertonic osmotic pressure, they develop a crumpled geometry with huge deformations. In the presence of molecular motors, these deformations are dynamic in nature and can compensate for an absence of excess membrane area needed for adhesion to take place. When the cytoskeletal deformations are able to compensate for lack of excess membrane area, the cytoskeletal vesicles are able to attach to the rigid glass surfaces even under strong adhesive forces. The balance of deformability and adhesion strength is identified to be key to enable cytoskeletal vesicles to adhere to solid substrates.
Transition from actin-driven to water-driven cell migration dependson external hydraulic resistance
Authors: Li Y. , Sun S.X.
Published: March 2018

In vivo, cells can reside in diverse physical and biochemical environments. For example, epithelial cells typically live in a two-dimensional (2D) environment while metastatic cancer cells can move through dense three-dimensional (3D) matrices. These distinct environments impose different kinds of mechanical forces on cells, and thus potentially can influence the mechanism of cell migration. For example, cell movement on 2D flat surfaces is mostly driven by forces from focal adhesion and actin polymerization, while in confined geometries, it can be driven by water permeation. In this work, we utilize a two-phase model of the cellular cytoplasm, where the mechanics of the cytosol and the F-actin network are treated on an equal footing. Using conservation laws and simple force balance considerations, we are able to describe the contribution of water flux, actin polymerization and flow, and focal adhesions to cell migration in both 2D surfaces and in confined spaces. The theory shows how cell migration can seamlessly transition from a focal adhesion- and actin-based mechanism on 2D surfaces to a water-based mechanism in confined geometries.
Fast Parallel Algorithm for Large Fractal Kinetic Models with Diffusion
Authors: Popov A. A. , Lee S.-C. , Kuksa P. P. , Glickson J. D. , Shestovb A. A.
Published: March 2018

Chemical kinetic simulations are usually based on the law of mass action that applies to behavior of particles in solution. Molecular interactions in a crowded medium as in a cell, however, are not easily described by such conventional mathematical treatment. Fractal kinetics is emerging as a novel method for simulating kinetic reactions in such an environment. To date, there has not been a fast, efficient, and, more importantly, parallel algorithm for such computations. Here, we present an algorithm with several novel features for simulating large (with respect to size and time scale) fractal kinetic models. We applied the fractal kinetic technique and our algorithm to a canonical substrate-enzyme model with explicit phase-separation in the product, and achieved a speed-up of up to 8 times over previous results with reasonably tight bounds on the accuracy of the simulation. We anticipate that this technique and algorithm will have important applications to simulation of intra-cell biochemical reactions with complex dynamic behavior.
Investigating established EEG parameter during real-world driving
Authors: Protzak Janna , Gramann Klaus
Published: March 2018

In real life, behavior is influenced by dynamically changing contextual factors and is rarely limited to simple tasks and binary choices. For a meaningful interpretation of brain dynamics underlying more natural cognitive processing in active humans, ecologically valid test scenarios are essential. To understand whether brain dynamics in restricted artificial lab settings reflect the neural activity in complex natural environments, we systematically tested the eventrelated P300 in both settings. We developed an integrative approach comprising an initial P300-study in a highly controlled laboratory set-up and a subsequent validation within a realistic driving scenario. Using a simulated dialog with a speech-based input system, increased P300 amplitudes reflected processing of infrequent and incorrect auditory feedback events in both the laboratory setting and the real world setup. Environmental noise and movement-related activity in the car driving scenario led to higher data rejection rates but revealed no effect on signal-to-noise ratio in theta and alpha frequency band or the amplitudes of the event-related P300. Our results demonstrate the possibility to investigate cognitive functions like context updating in highly adverse driving scenarios and encourage the consideration of more realistic task settings in prospective brain imaging approaches.
Sonic Hedgehog is a member of the Hh/DD-peptidase family that spans the eukaryotic and bacterial domains of life
Authors: Roelink Henk
Published: March 2018

Sonic Hedgehog (Shh) coordinates Zn2+ in a manner that resembles that of peptidases. The ability of Shh to undergo autoproteolytic processing is impaired in mutants that affect the Zn2+ coordination, while mutating residues essential for catalytic activity results in more stable forms of Shh. The residues involved in Zn2+ coordination in Shh are found mutated in some individuals with the congenital birth defect holoprosencephaly, demonstrating their importance in development. Highly conserved Shh domains are found a parts of some bacterial proteins that are members of the larger family of DD-peptidases, supporting the notion that Shh acts as a peptidase. Whereas this Hh/DD-peptidase motif is present in Hedgehog (Hh) proteins of nearly all animals, it is not present in Drosophila Hh, indicating that Hh signaling in fruit flies is derived, and perhaps not a good model for vertebrate Shh signaling. Sequence analysis of Hh proteins and their possible evolutionary precursors suggest that the evolution of modern Hh might have involved horizontal transfer of a bacterial gene coding of a Hh/DD-peptidase into a Cnidarian ancestor, recombining to give rise to modern Hh.
Cost of resistance: an unreasonably expensive concept
Authors: Lenormand Thomas , Harmand Noémie , Gallet Romain
Published: March 2018

This preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (https://doi.org/10.24072/pci.evolbiol.100052). The cost of resistance, or the fitness effect of resistance mutation in absence of the drug, is a very widepsread concept in evolutionary genetics and beyond. It has represented an important addition to the simplistic view that resistance mutations should solely be considered as beneficial mutations. Yet, this concept also entails a series of serious difficulties in its definition, interpretation and current usage. In many cases, it may be simpler, clearer, and more insightful to study, measure and analyze the fitness effects of mutations across environments and to better distinguish those effects from ‘pleiotropic effects’ of those mutations.
A streamlined method for transposon mutagenesis ofRickettsia parkeriyields numerous mutations that impact infection
Authors: Lamason Rebecca L. , Kafai Natasha M. , Welch Matthew D.
Published: March 2018

The rickettsiae are obligate intracellular alphaproteobacteria that exhibit a complex infectious life cycle in both arthropod and mammalian hosts. As obligate intracellular bacteria,Rickettsiaare highly adapted to living inside a variety of host cells, including vascular endothelial cells during mammalian infection. Although it is assumed that the rickettsiae produce numerous virulence factors that usurp or disrupt various host cell pathways, they have been challenging to genetically manipulate to identify the key bacterial factors that contribute to infection. Motivated to overcome this challenge, we sought to expand the repertoire of available rickettsial loss-of-function mutants, using an improvedmariner-based transposon mutagenesis scheme. Here, we present the isolation of over 100 transposon mutants in the spotted fever group speciesRickettsia parkeri. These mutants targeted genes implicated in a variety of pathways, including bacterial replication and metabolism, hypothetical proteins, the type IV secretion system, as well as factors with previously established roles in host cell interactions and pathogenesis. Given the need to identify critical virulence factors, forward genetic screens such as this will provide an excellent platform to more directly investigate rickettsial biology and pathogenesis.
Differentiation of Alzheimer’s disease based on local and global parameters in personalized Virtual Brain models
Authors: Zimmermann J , Perry A , Breakspear M , Schirner M , Sachdev P , Wen W , Kochan N.A. , Mapstone M. , Ritter P. , McIntosh A.R. , Solodkin A
Published: March 2018

Alzheimer’s disease (AD) is marked by cognitive dysfunction emerging from neuropathological processes impacting brain function. AD affects brain dynamics at the local level, such as changes in the balance of inhibitory and excitatory neuronal populations, as well as long-range changes to the global network. Individual differences in these changes as they relate to behaviour are poorly understood. Here, we use a multi-scale neurophysiological model, “The Virtual Brain (TVB)”, based on empirical multi-modal neuroimaging data, to study how local and global dynamics correlate with individual differences in cognition. In particular, we modeled individual resting-state functional activity of 124 individuals across the behavioral spectrum from healthy aging, to amnesic Mild Cognitive Impairment (MCI), to AD. The model parameters required to accurately simulate empirical functional brain imaging data correlated significantly with cognition, and exceeded the predictive capacity of empirical connectomes.
Magnesium increases homoeologous crossover frequency inZIP4(Ph1) mutant wheat-wild relative hybrids
Authors: Rey María-Dolores , Martín Azahara C. , Smedley Mark , Hayta Sadiye , Harwood Wendy , Shaw Peter , Moore Graham
Published: March 2018

Wild relatives provide an important source of useful traits in wheat breeding. Wheat and wild relative hybrids have been widely used in breeding programs to introduce such traits into wheat. However, successful introgression is limited by the low frequency of homoeologous crossover (CO) between wheat and wild relative chromosomes. Hybrids between wheat carrying a 70Mb deletion on chromosome 5B (ph1b) and wild relatives, have been exploited to increase the level of homoeologous CO, allowing chromosome exchange between their chromosomes. Inph1b-rye hybrids, CO number increases from a mean of 1 CO to 7 COs per cell. CO number can be further increased up to a mean of 12 COs per cell in theseph1bhybrids by treating the plants with Hoagland solution. More recently, it was shown that the major meiotic crossover geneZIP4on chromosome 5B (TaZIP4-B2) within the 70Mb deletion, was responsible for the restriction of homoeologous COs in wheat-wild relative hybrids, confirming theph1bphenotype as a completeTazip4-B2deletion mutant (Tazip4-B2 ph1b). In this study, we have identified the particular Hoagland solution constituent responsible for the increased chiasma frequency inTazip4-B2 ph1bmutant-rye hybrids and extended the analysis toTazip4-B2TILLING and CRISPR mutant-Ae variabilishybrids. Chiasma frequency at meiotic metaphase I, in the absence of each Hoagland solution macronutrient (NH4H2PO4, KNO3, Ca (NO3)2·4H2O or Mg SO4·7H2O) was analysed. A significant decrease in homoeologous CO frequency was observed when the Mg2+ion was absent. A significant increase of homoeologous CO frequency was observed in all analysed hybrids, when plants were irrigated with a 1mM Mg2+solution. These observations suggest a role for magnesium supplementation in improving the success of genetic material introgression from wild relatives into wheat.
Slow peak alpha frequency and corticomotor depression linked to high pain susceptibility in transition to sustained pain
Authors: Seminowicz DA , Thapa T , Furman AJ , Summers SJ , Cavaleri R , Fogarty JS , Steiner GZ , Schabrun SM
Published: March 2018

Mechanisms that predict an individual’s susceptibility to pain, before pain is present or in the first few days following pain onset, are unknown. We utilised a clinically-relevant human transitional pain model (intramuscular injections of nerve growth factor) to examine brain mechanisms that predict pain susceptibility. Resting state EEG and corticomotor excitability measured by TMS were evaluated longitudinally in healthy individuals as pain developed and resolved over 21 days. Whereas pre-pain central peak alpha frequency (PAF) correlated with peak pain occurring 4-6 days later, altered corticomotor excitability developed several days after pain onset and showed two distinct patterns (facilitation, depression). Individuals with combined slow PAF and corticomotor depression developed more severe pain. These data provide the first evidence of the temporal profile of key brain mechanisms as pain progressively develops. PAF and corticomotor excitability could represent biomarkers for susceptibility to high pain severity and subsequently, the development of chronic pain.
A systematic study of repetitive transcranial magnetic stimulation to enhance working memory manipulation abilities
Authors: Beynel L. , Davis S.W. , Crowell C.A. , Hilbig S.A. , Lim W. , Nguyen D. , Peterchev A.V. , Luber B. , Lisanby S.H. , Cabeza R. , Appelbaum L.G.
Published: March 2018

A core element of human working memory (WM) is the ability to perform mental operations on information that is stored in a flexible, limited capacity buffer. Given the profound importance of such WM manipulation (WM-M) abilities, there is a concerted effort aimed at developing approaches to improve them. Past research has identified neural substrates of WM-M centered in the dorsolateral prefrontal cortex (DLPFC), thereby providing a plausible and accessible target for noninvasive neuromodulatory stimulation that can be used to alter cortical excitability and potentially lead to facilitation of WM-M. In the current study, 5Hz online repetitive transcranial magnetic stimulation (rTMS), applied over the left DLPFC, was used to test the hypothesis that active rTMS would lead to significant improvements in memory recall accuracy compared to sham stimulation, and that these effects would be most pronounced in the WM-M conditions with the highest cognitive demand (registered Clinical Trial: #NCT02767323). Participants performed a delayed response alphabetization task with three individually-titrated levels of difficulty during active and sham rTMS. Analyses revealed that active rTMS led to numerically greater accuracy relative to sham stimulation for the hardest condition; however, this effect did not survive Bonferroni correction over all task conditions. Despite the lack of robust, study-wise significant effects, when considered in isolation, the magnitude of behavioral improvement in the hardest condition was negatively correlated with parametric difficulty-related fMRI activity in the targeted brain region, suggesting that individuals with less activation benefit more from rTMS. The present findings therefore suggest evidence towards the hypothesis that active rTMS can enhance performance during difficult memory manipulation conditions; however, firm conclusions cannot be drawn given the lack of overall significant effects. These findings are discussed in the context of individualized targeting and other factors that might moderate rTMS effects.
Selection removes Shine-Dalgarno-like sequences from within protein coding genes
Authors: Hockenberry Adam J. , Amaral Luίs AN , Jewett Michael C. , Wilke Claus O.
Published: March 2018

The Shine-Dalgarno (SD) sequence motif facilitates translation initiation and is frequently found upstream of bacterial start codons. However, thousands of instances of this motif occur throughout the middle of protein coding genes in a typical bacterial genome. Here, we use comparative evolutionary analysis to test whether SD sequences located within genes are functionally constrained. We measure the conservation of SD sequences across Gammaproteobacteria, and find that they are significantly less conserved than expected. Further, the strongest SD sequences are the least conserved whereas we find evidence of conservation for the weakest possible SD sequences given amino acid constraints. Our findings indicate that most SD sequences within genes are likely to be deleterious and removed via selection. To illustrate the origin of these deleterious costs, we show that ATG start codons are significantly depleted downstream of SD sequences within genes, highlighting the potential for these sequences to promote erroneous translation initiation.
Non-Random Mis-Segregation of Human Chromosomes
Authors: Worrall J. T. , Tamura N. , Shaikh N. , Mazzagatti A. , van Lingen T. , Bakker B. , Spierings D. C. J. , Vladimirou E. , Foijer F. , McClelland S. E.
Published: March 2018

Recurrent patterns of chromosomal changes (aneuploidy) are widespread in cancer. These patterns are mainly attributed to selection processes due to an assumption that human chromosomes carry equal chance of being mis-segregated into daughter cells when fidelity of cell division is compromised. Human chromosomes vary widely in size, gene density and other parameters that might generate bias in mis-segregation rates, however technological limitations have precluded a systematic and high throughput analysis of chromosome-specific aneuploidy. Here, using fluorescenceIn-Situhybridization (FISH) imaging of specific centromeres coupled with high-throughput single cell analysis, as well as single-cell sequencing we show that human chromosome mis-segregation is non-random. Merotelic kinetochore attachment induced by nocodazole washout leads to elevated aneuploidy of a subset of chromosomes, and high rates of anaphase lagging of chromosomes 1 and 2. Mechanistically, we show that these chromosomes are prone to cohesion fatigue that results in anaphase lagging upon release from nocodazole or Eg5 inhibition. Our findings suggest that inherent properties of specific chromosomes can influence chromosome mis-segregation and aneuploidy, with implications for studies on aneuploidy in human disease.