bluuebunny/crossref_metadata_2025 huggingface dataset:
The Usefulness of Continuously Variable View Rigid Endoscope in Lacrimal Surgeries: First Intraoperative Experience
Authors: Ali Mohammad Javed , Singh Swati , Naik Milind N.
Published: August 2016

Aims:

The aims of this study were to illustrate the techniques and usefulness of a new rigid, variable-view endoscope in lacrimal surgeries.

Methods:

A 4-mm continuously variable view rigid endoscope (EndoCAMeleon) was used to assess 4 intraoperative scenarios in lacrimal surgeries. The endoscope offers variable views from 15° to 90° in one single plane while remaining shape invariant. Multiple planes were assessed after changing the direction of the endoscopic shaft. The ease of handling and optical performance was noted in each plane.

Results:

Enhanced visualization over a wide angle range without moving the endoscope was found to be very beneficial intraoperatively. Accurate assessment of extent of cicatrization or synechiae causes of dacryocystorhinostomy failure, monitoring of internal common opening during trephination, and postoperative ostium evaluation was possible with wider and superior visualization. A complete endoscopic overview in one plane without the need of multiple angled endoscopes made the inspections detailed and less time consuming. Because the tip of the endoscope does not move, it was found to be effective in narrow working spaces without causing any collision with the tissues in the vicinity.

Conclusion:

Enhanced field of vision, quicker assessment, and ability to optimize visualization in a continuous mode are advantages of using a variable-view endoscope in lacrimal surgeries.
Parabrachial complex links pain transmission to descending pain modulation
Authors: Roeder Zachary , Chen QiLiang , Davis Sophia , Carlson Jonathan D. , Tupone Domenico , Heinricher Mary M.
Published: August 2016

The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation and exerts antinociceptive and pronociceptive influences mediated by 2 distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a “burst” of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified. The present experiments were designed to test the hypothesis that nociceptive input to the RVM is relayed through the parabrachial complex (PB). In electrophysiological studies, ON- and OFF-cells were recorded in the RVM of lightly anesthetized male rats before and after an infusion of lidocaine or muscimol into PB. The ON-cell burst and OFF-cell pause evoked by noxious heat or mechanical probing were substantially attenuated by inactivation of the lateral, but not medial, parabrachial area. Retrograde tracing studies showed that neurons projecting to the RVM were scattered throughout PB. Few of these neurons expressed calcitonin gene-related peptide, suggesting that the RVM projection from PB is distinct from that to the amygdala. These data show that a substantial component of “bottom-up” nociceptive drive to RVM pain-modulating neurons is relayed through the PB. While the PB is well known as an important relay for ascending nociceptive information, its functional connection with the RVM allows the spinoparabrachial pathway to access descending control systems as part of a recurrent circuit.
Involvement of the NADPH Oxidase NOX2–Derived Brain Oxidative Stress in an Unusual Fatal Case of Cocaine-Related Neurotoxicity Associated With Excited Delirium Syndrome
Authors: Schiavone Stefania , Riezzo Irene , Turillazzi Emanuela , Trabace Luigia
Published: August 2016

Here, we investigated the possible role of the Nicotinamide Adenine Dinucleotide Phosphate oxidase NOX2–derived brain oxidative stress in a fatal case of cocaine-related neurotoxicity, associated to excited delirium syndrome. We detected a strong NOX2 immunoreactivity, mainly in cortical GABAergic neurons and astrocytes, with a minor presence in microglia, glutamatergic and dopaminergic neurons as well as a significant immunostaining for other markers of oxidative stress (8OhDG, HSP70, HSP90, and NF-κB) and apoptotic phenomena. These results support a crucial role of NOX2-derived brain oxidative stress in cocaine-induced brain dysfunctions and neurotoxicity.
Effect of inflammatory mediators on cardiovascular function
Authors: Müller-Werdan Ursula , Prondzinsky Roland , Werdan Karl
Published: August 2016

Purpose of review

Inflammatory mediators can interfere with cardiovascular system. This article describes some recent findings in this field.

Recent findings

In septic cardiomyopathy, direct and indirect interactions of endotoxin with the pacemaker current contribute to cardiac autonomic dysfunction and inadequately high heart rate, worsening prognosis. In myocardial infarction, inflammatory blood cells correlate with impaired coronary microvascular reperfusion. In cardiogenic shock, systemic inflammation and development of multiorgan dysfunction syndrome have a major impact on mortality. Shock patients have low levels of activated protein C and high levels of the endogenous danger signal molecule peroxiredoxin 1; both conditions might represent further therapeutic targets. As major cause of cytopathic hypoxia, mitochondrial dysfunction has also been identified in mitochondria from peripheral blood mononuclear cells in paediatric septic shock. Transcatheter aortic valve endocarditis, a new endocarditis entity after transcatheter aortic valve implantation in old and very old patients, needs our special attention, because immunosenescence may modify the clinical course in a negative sense. Systemic spreading of endocarditis to septic shock adds to the local valve infection the problem of septic shock.

Not only in septic shock, but also in classic heart diseases like cardiogenic shock and endocarditis, the detrimental role of inflammatory mediators becomes more and more evident, whereas effective anti-inflammatory treatment concepts are still missing.
Transplantation for thalassemia major: alternative donors
Authors: Locatelli Franco , Merli Pietro , Strocchio Luisa
Published: August 2016

Purpose of review

Lack of a human leukocyte antigen (HLA)-matched family donor is a major obstacle limiting the use of allogeneic hematopoietic stem cell transplantation (HSCT) to cure thalassemia major. Use of alternative donors, if found well tolerated enough, may be a viable option for transplantation in this setting, allowing to expand the number of patients treatable by HSCT. This review will provide an overview of alternative HSCT approaches in thalassemia major.

Recent findings

With the introduction of high-resolution molecular HLA-typing techniques, the outcome of matched unrelated donor HSCT recipients has become comparable with that of patients given matched family donor HSCT. On the contrary, the use of unrelated cord blood transplantation has been limited by the risk of graft failure and slow hematopoietic recovery, although novel techniques of ex vivo graft manipulation are emerging as promising strategies for overcoming these obstacles. Although experience with haploidentical HSCT in thalassemia major is still limited, currently explored platforms hold the potential to extend the access to HSCT to thalassemia major patients lacking an HLA-matched either related or unrelated donor.

The significant advances achieved in transplantation techniques, both in the matched unrelated and in the haploidentical setting, are expected to significantly broaden the applicability of HSCT to patients with thalassemia major.
Changes in Weight and Body Composition Among Women With Breast Cancer During and After Adjuvant Treatment
Authors: Pedersen Birgith , Delmar Charlotte , Bendtsen Mette Dahl , Bosaeus Ingvar , Carus Andreas , Falkmer Ursula , Groenkjaer Mette
Published: August 2016

Background:

Antineoplastic adjuvant treatment for breast cancer can cause changes in women’s weight and body composition and influence their general health and survival.

Objective:

The aim of this study is to investigate the extent and patterns of change in weight and body composition after current standard adjuvant antineoplastic treatment for breast cancer.

Methods:

Data on weight and body composition from 95 women with breast cancer Stage I to III were obtained during 18 months on a bioelectric impedance analyzer. Changes and odds ratio (OR) were calculated by a linear mixed model and logistic regression.

Results:

At 18 months, there was an increase in weight of 0.9 kg (95% confidence interval [CI], 0.3–1.5; P = .003) and an average positive association of 0.35 kg/cm increased waist circumference (95% CI, 0.29–0.42 kg; P < .0001). Relative weight changes ranged from −12.7% to 20.5%. Weight gains related to increased body fat were observed mainly in premenopausal women receiving chemotherapy (1.4 kg; 95% CI, 0.4–2.4; P = .007). For menopausal status, OR was 2.9 (95% CI, 1.14–7.1; P = .025), and for chemotherapy, OR was 2.6 (95% CI, 1.03–6.41; P = .043). The OR for weight loss in Stage III breast cancer was 12.5 (95% CI, 1.21–128.84; P = .034) and 4.3 (CI, 1.07–17.24; P = .40) for comorbidity.

Conclusions:

Results demonstrate that weight changes in a pooled sample are overestimated. However, premenopausal women receiving anthracycline-based chemotherapy show a tendency toward a body composition with increasing fat mass.

Implications for Practice:

A scheduled assessment of changes in weight and body composition is relevant at 18 months after treatment. To compare future studies, common measuring and cutoff points are needed.
A Comparison of Spectacles Purchased Online and in UK Optometry Practice
Authors: Alderson Alison J. , Green Alison , Whitaker David , Scally Andrew J. , Elliott David B.
Published: August 2016

Purpose

To compare spectacles bought online with spectacles from optometry practices.

Methods

Thirty-three participants consisting of single vision spectacle wearers with either a low (N = 12, mean age 34 ± 14 years) or high prescription (N = 11, mean age 28 ± 9 years) and 10 presbyopic participants (mean age 59 ± 4 years) wearing progressive addition lenses (PALs) purchased 154 pairs of spectacles online and 154 from UK optometry practices. The spectacles were compared via participant-reported preference, acceptability, and safety; the assessment of lens, frame, and fit quality; and the accuracy of the lens prescriptions to international standard ISO 21987:2009.

Results

Participants preferred the practice spectacles (median ranking 4th, IQR 1–6) more than online (6th, IQR 4–8; Mann-Whitney U = 7345, p < 0.001) and practice PALs (median ranking 2nd, IQR 1–4) were particularly preferred (online 6.5th, IQR 4–9, Mann-Whitney U = 455, p < 0.001). Of those deemed unacceptable and unsafe, significantly more were bought online (unacceptable: online 43/154 vs. practice 15/154, Fisher’s exact p = 0.0001; unsafe: online 14/154 vs. practice 5/154, Fisher’s exact p = 0.03).

Conclusions

Participants preferred spectacles from optometry practice rather than those bought online, despite lens quality and prescription accuracy being similar. A greater number of online spectacles were deemed unsafe or unacceptable because of poor spectacle frame fit, poor cosmetic appearance, and inaccurate optical centration. This seems particularly pertinent to PAL lenses, which are known to increase falls risk. Recommendations are made to improve both forms of spectacle provision.
Item Banking Enables Stand-Alone Measurement of Driving Ability
Authors: Khadka Jyoti , Fenwick Eva K. , Lamoureux Ecosse L. , Pesudovs Konrad
Published: August 2016

Purpose

To explore whether large item sets, as used in item banking, enable important latent traits, such as driving, to form stand-alone measures.

Methods

The 88-item activity limitation (AL) domain of the glaucoma module of the Eye-tem Bank was interviewer-administered to patients with glaucoma. Rasch analysis was used to calibrate all items in AL domain on the same interval-level scale and test its psychometric properties. Based on Rasch dimensionality metrics, the AL scale was separated into subscales. These subscales underwent separate Rasch analyses to test whether they could form stand-alone measures. Independence of these measures was tested with Bland and Altman (B&A) Limit of Agreement (LOA).

Results

The AL scale was completed by 293 patients (median age, 71 years). It demonstrated excellent precision (3.12). However, Rasch analysis dimensionality metrics indicated that the domain arguably had other dimensions which were driving, luminance, and reading. Once separated, the remaining AL items, driving and luminance subscales, were unidimensional and had excellent precision of 4.25, 2.94, and 2.22, respectively. The reading subscale showed poor precision (1.66), so it was not examined further. The luminance subscale demonstrated excellent agreement (mean bias, 0.2 logit; 95% LOA, −2.2 to 3.3 logit); however, the driving subscale demonstrated poor agreement (mean bias, 1.1 logit; 95% LOA, −4.8 to 7.0 logit) with the AL scale.

Conclusions

These findings indicate that driving items in the AL domain of the glaucoma module were perceived and responded to differently from the other AL items, but the reading and luminance items were not. Therefore, item banking enables stand-alone measurement of driving ability in glaucoma.
The Influence of Induced Astigmatism on the Depth of Focus
Authors: Leube Alexander , Ohlendorf Arne , Wahl Siegfried
Published: August 2016

Purpose

To evaluate whether an induced astigmatism influences the subjective depth of focus.

Methods

Fifty-one participants aged 18 to 35 years and with a mean spherical equivalent refractive error of −0.51 ± 2.35 DS participated in the study. The accommodation was blocked with three drops of 1% cyclopentolate. Refractive errors were corrected after subjective refraction with a 4-mm artificial pupil. To evaluate the depth of focus (DoF), defocus curves with a spherical range of ±1.5 DS were assessed. The DoF was calculated as the horizontal distance at a threshold level of +0.1 logMAR from the maximum visual acuity (VA). Defocus curves were estimated binocularly during distance (500 cm) and a near vision (40 cm) for two induced axis (ATR in 0° and WTR in 90°) and for a fixed amount of astigmatic defocus of −0.5 DC.

Results

The mean natural DoF was 0.885 ± 0.316 D for far vision and 0.940 ± 0.400 D for near vision. With induced astigmatism, the DoF for far vision was significantly increased to 1.095 ± 0.421 D (p = 0.006, ANOVA) for the WTR astigmatism but not for the ATR astigmatism (1.030 ± 0.395 D; p = 0.164, ANOVA). The induced WTR astigmatism enhanced the DoF for near vision significantly to 1.144 ± 0.338 D (p = 0.04, ANOVA), and DoF with induced ATR astigmatism (0.953 ± 0.318 D) was not significantly different (p = 1.00, ANOVA). ATR-astigmatism reduced VA by +0.08 ± 0.08 logMAR (p < 0.01, t-test).

Conclusions

With an induced WTR astigmatism of −0.5 DC, the DoF can be enhanced in the near viewing distance with a marginal loss in binocular VA. The approach of using induced WTR astigmatism can lead to novel optical treatments for presbyopia.
Use of Postoperative Radiographs following Operative Fixation of Distal Radius Fractures
Authors: Johnson Shepard P. , Chung Kevin C. , Zhong Lin , Sears Erika D. , Waljee Jennifer F.
Published: August 2016

Background:

Recent studies show that routine postoperative films after open reduction and internal fixation for distal radius fractures rarely alter clinical management. This population study evaluates the use of postoperative radiographs after distal radius fracture fixation.

Methods:

The authors studied insurance claims from the Truven MarketScan databases to identify patients aged 18 years and older who underwent open reduction and internal fixation for a distal radius fracture between 2009 and 2011. Two years of postoperative data were collected to determine the number and timing of postoperative radiographs and related clinical events, including complications and reoperation. The authors also compared outcomes between cohorts who did and did not undergo radiography on the day of surgery.

Results:

The authors identified 20,041 patients who met study criteria. On average, 3.8 ± 2.1 radiographs per patient were obtained during the 2-year follow-up, with 3.0 ± 1.4 being obtained within the first 3 months; 59, 81, and 91 percent of patients did not undergo further imaging after 3, 6, and 12 months postoperatively, respectively. Radiographs were obtained on the day of surgery in 47 percent of patients (n = 9372), and more were obtained overall for these patients in the postoperative period (4.4 versus 3.2). Early reoperation rates (within 14 days) following distal radius fractures between patients who did and did not undergo same-day radiography were 5 percent versus 3 percent.

Conclusions:

On average, four radiographs per patient were obtained following open reduction and internal fixation for a closed distal radius fracture. Nearly 50 percent of individuals underwent radiography on the day of surgery, despite low reoperation rates in the early postoperative period. An evidence-based approach to postoperative radiography has the potential to reduce distal radius fracture–related health care use.
Strategies for Soft-Tissue Management of Complex Joint Revision Arthroplasty: A 10-Year Experience
Authors: Leckenby Jonathan I. , Grobbelaar Adriaan O.
Published: August 2016

Background:

Approximately 160,000 joint replacements are performed each year in the United Kingdom. After multiple revisions, soft tissues become suboptimal and chronic wounds develop, causing infection or metalwork extrusion. The authors present their experience with 155 patients at a tertiary orthopedic hospital.

Methods:

A chart review of patients who required reconstruction as a result of complex joint revision surgery was performed between January of 2006 and January of 2015. All primary joint replacements were excluded.

Results:

One hundred nineteen flaps were performed, 28 were managed conservatively, and eight were treated with primary amputations. Eighty-four of the patients (71 percent) who had soft-tissue reconstruction were healed at 1-year follow-up. Seven primary free flap failures occurred (11 percent); of these, four of seven patients underwent a second successful free flap reconstruction. A further 12 patients underwent secondary amputation as a result of persistent periprosthetic infection, and 11 patients were managed with long-term oral antimicrobial therapy after declining amputation.

Conclusions:

The best results are achieved using a combined approach with multidisciplinary input from orthopedic and plastic surgeons with constant specialist clinical microbiology input. All patients had deep tissue samples taken, a long line inserted and, according to microbiology advice, a tailored 6-week regimen of intravenous antibiotics. The data support that early plastic surgery involvement achieved better patient outcomes.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Evaluation of the Upper Limb Lymphatic System: A Prospective Lymphoscintigraphic Study in Melanoma Patients and Healthy Controls
Authors: Rossi Matteo , Grassi Rita , Costa Renato , Di Rosa Luigi , D’Arpa Salvatore , Moschella Francesco , Cordova Adriana
Published: August 2016

Background:

Current research on the upper limb lymphatic system mainly studies breast cancer patients with unilateral lymphedema. Without preoperative lymphoscintigraphy, the contralateral limb is used as a control, assuming that it is functionally intact. Few lymphoscintigraphic studies investigate patients before any axillary surgery. The purpose of this study was to evaluate, through lymphoscintigraphy, the preoperative condition of the upper limb lymphatic system in melanoma patients and healthy controls.

Methods:

Two groups were studied: the study group (16 patients with trunk/upper limb melanoma candidates for axillary sentinel lymph node biopsy) and the control group (10 healthy volunteers). All subjects underwent upper limb lymphoscintigraphy. Lymphoscintigraphic images were classified into three patterns based on the tracer appearance time in the axillary nodes. Type I, 20 minutes; type II, 60 minutes; and type III, 120 minutes. Statistical analysis was used to assess the relationship between lymphoscintigraphic patterns and clinical variables and to compare patterns of distribution.

Results:

Lymphoscintigraphic patterns were asymmetric in 37.5 percent (study group) and 50 percent (control group). Type III was the most common pattern. There was no significant association between lymphoscintigraphic patterns and considered clinical variables. There was no significant difference in the lymphoscintigraphic pattern distribution of the two groups (p = 0.870).

Conclusion:

The authors’ findings show wide differences and an often “slow” tracer appearance time in patients with intact lymphatic system, questioning the use of contralateral limb as control and transportation time greater than 30 minutes as criteria for identification of lymphatic alterations.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Diagnostic, IV.
Systematic Analysis of Clinical Outcomes of Bilateral Sagittal Split Ramus Osteotomy With Preoperative Modeling and Postoperative Orthodontic in the Treatment of Mandibular Protrusion
Authors: Li Yawei , Sun Xiaomei , Teng Li , Xu Jiajie , Lu Jianjian , Ding Bo , Zhang Chao , Xie Fang , Sun Xuejian
Published: August 2016

The purpose of this study was to determine the changes in hard tissues, soft tissues, and teeth after bilateral sagittal split ramus osteotomy and orthodontic treatment for the treatment of mandibular protrusion. Cephalometric analysis was used to evaluate the aesthetic effects and occlusal relationships obtained. The subjects included 11 women and 9 men (aged 18–27 years; average, 20 years) with mandibular protrusion who underwent bilateral sagittal split ramus osteotomy. Based on a preoperative computer-aided manufacturing/design-assisted, model surgical design and an occlusal guide plate, new occlusal relationships were established for the patients. In addition, the preoperative and the end of postoperative orthodontic treatment cephalometric radiographs were systematically analyzed. In all patients, the surgical incisions underwent primary healing, with no infection or osteonecrosis. Significant differences were observed in the preoperative and the end of postoperative orthodontic treatment values of all hard tissue and teeth parameters, except for SNA°, ANB°, GoGn-SN°, SE (mm), NP-FH°, SGn-FH°, OP-FH°, 1−-MP°, Li-E (mm). The most obvious significant differences were seen in SNB°, SND°, 1_-NA°, 1_-NA (mm), 1−-NB (mm), 1−-NB°, Po-NB (mm), NA-PA°, AB-NP°, 1−-OP°, Ui-E (mm), and S-N’-B’° (P < 0.001). Postoperative follow-up lasted for 10 to 12 months. All patients eventually achieved normal downjaw relationship, tooth arch forms, and spee curves. There were no evident irregularities of teeth arrangement or abnormal occlusal relationships were observed. All patients were satisfied with their facial appearance and occlusal relationships at the end of postoperative orthodontic treatment. The authors found a precise preoperative model surgical design combined with postoperative orthodontic treatment is a simple and time-saving technique. It can be used to correct mandibular protrusion with satisfactory occlusal relationship, facial appearance, and minimal postoperative complications.
Amyotrophic lateral sclerosis: recent genetic highlights
Authors: White Matthew A. , Sreedharan Jemeen
Published: August 2016

Purpose of review

Amyotrophic lateral sclerosis (ALS), like other neurodegenerative diseases, remains incurable, but gene mutations linked to ALS are providing clues as to how to target therapies. It is important for researchers to keep abreast of the rapid influx of new data in ALS, and we aim to summarize the major genetic advances made in the field over the past 2 years.

Recent findings

Significant variation in seven genes has recently been found in ALS: TBK1, CCNF, GLE1, MATR3, TUBA4A, CHCHD10 and NEK1. These have mostly been identified through large exome screening studies, though traditional linkage approaches and candidate gene screening remain important. We briefly update C9orf72 research, noting in particular the development of reagents to better understand the normal role of C9orf72 protein.

Striking advances in our understanding of the genetic heterogeneity of ALS continue to be made, year on year. These implicate proteostasis, RNA export, nuclear transport, the cytoskeleton, mitochondrial function, the cell cycle and DNA repair. Functional studies to integrate these hits are needed. By building a web of knowledge with interlinked genes and mechanisms, it is hoped we can better understand ALS and work toward effective therapies.
Advances in serological diagnostics of inflammatory myopathies
Authors: Benveniste Olivier , Stenzel Werner , Allenbach Yves
Published: August 2016

Purpose of review

Inflammatory myopathies are rare diseases. Their diagnosis criteria are historically based on their clinical phenotype (topography of the muscle weakness, presence of skin lesions and/or of extra-skin/muscle signs) and the presence of inflammatory infiltrates on muscle biopsy. However, the recent discovery of different myositis-specific antibodies (MSA) or myositis-associated antibodies (MAA) permitted to revisit these old classifications. This review covers recent findings in clinical and pathological phenotypes regarding prognosis, associated cancer and response to the treatment based on MSA/MAA categorization.

Recent findings

Since the mid-1970s, about 20 MSA or MAA were discovered year after year (by immunoprecipitation). Now commercial kits (mainly dot line assays) permit their detection routinely which is clearly a help for the diagnosis but also give some key indications on clinical features, risk of associated cancers and response to the treatments.

Overlap myositis is associated with antisynthetase antibodies (Abs) or those associated with sclerodermia (anti-RNP, Ku and PM-ScL). Dermatomyositis is associated with anti-Mi2, small ubiquitin-like modifier activating enzyme (SAE), nuclear matrix protein-2 (NXP2), TIF-1γ or melanoma differentiation-associated gene 5 (MDA5) Abs. Immune-mediated necrotizing myopathies are associated with anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) Abs. One third of inclusion body myositis’ patients also presented anti-cytosolic 5′-nucleotidase 1A (cN1A) Abs. The risk of associated cancers is elevated with anti-TIF-1γ, NXP2 or HMGCR Abs.
Ultraviolet B radiation alters movement and thermal selection of zebrafish (
Danio rerio
)
Authors: Seebacher Frank , Kazerouni Ensiyeh Ghanizadeh , Franklin Craig E.
Published: August 2016

Temperature and ultraviolet B (UV-B) interact in causing cellular damage and impairing locomotor performance. Here, we test the hypothesis that movement and thermal selection of zebrafish (
Danio rerio
) change in the presence of UV-B, and in particular, that fish which were chronically exposed to UV-B avoid high and low temperature extremes to maximize activities of antioxidant enzymes. Fish chronically (two to three weeks) exposed to UV-B had increased reactive oxygen species (ROS)-induced damage to proteins and membranes, and reduced swimming performance at high (more than 26°C) temperatures. In an open field arena with a thermal gradient, chronically exposed fish avoided high and low temperature extremes compared with control fish. Additionally, both control and chronically exposed fish showed slower voluntary swimming speeds in the presence of UV-B. We suggest that in the presence of UV-B fish may reduce muscular activity to minimize intrinsic ROS production. Our data show that the interaction between UV-B and temperature determines movement and microhabitat selection of fish, which is therefore of ecological importance particularly in anthropogenically modified environments.
Human leukocyte Antigen-DM polymorphisms in autoimmune diseases
Authors: Alvaro-Benito Miguel , Morrison Eliot , Wieczorek Marek , Sticht Jana , Freund Christian
Published: August 2016

Classical MHC class II (MHCII) proteins present peptides for CD4+T-cell surveillance and are by far the most prominent risk factor for a number of autoimmune disorders. To date, many studies have shown that this link between particular MHCII alleles and disease depends on the MHCII's particular ability to bind and present certain peptides in specific physiological contexts. However, less attention has been paid to the non-classical MHCII molecule human leucocyte antigen-DM, which catalyses peptide exchange on classical MHCII proteins acting as a peptide editor. DM function impacts the presentation of both antigenic peptides in the periphery and key self-peptides during T-cell development in the thymus. In this way, DM activity directly influences the response to pathogens, as well as mechanisms of self-tolerance acquisition. While decreased DM editing of particular MHCII proteins has been proposed to be related to autoimmune disorders, no experimental evidence for different DM catalytic properties had been reported until recently. Biochemical and structural investigations, together with new animal models of loss of DM activity, have provided an attractive foundation for identifying different catalytic efficiencies for DM allotypes. Here, we revisit the current knowledge of DM function and discuss how DM function may impart autoimmunity at the organism level.
Discrete dislocation plasticity analysis of loading rate-dependent static friction
Authors: Song H. , Deshpande V. S. , Van der Giessen E.
Published: August 2016

From a microscopic point of view, the frictional force associated with the relative sliding of rough surfaces originates from deformation of the material in contact, by adhesion in the contact interface or both. We know that plastic deformation at the size scale of micrometres is not only dependent on the size of the contact, but also on the rate of deformation. Moreover, depending on its physical origin, adhesion can also be size and rate dependent, albeit different from plasticity. We present a two-dimensional model that incorporates both discrete dislocation plasticity inside a face-centred cubic crystal and adhesion in the interface to understand the rate dependence of friction caused by micrometre-size asperities. The friction strength is the outcome of the competition between adhesion and discrete dislocation plasticity. As a function of contact size, the friction strength contains two plateaus: at small contact length

(
≲
0.6
 
μ
m
)

, the onset of sliding is fully controlled by adhesion while for large contact length

(
≳
10
 
μ
m
)

, the friction strength approaches the size-independent plastic shear yield strength. The transition regime at intermediate contact size is a result of partial de-cohesion and size-dependent dislocation plasticity, and is determined by dislocation properties, interfacial properties as well as by the loading rate.
Constructor theory of probability
Authors: Marletto Chiara
Published: August 2016

Unitary quantum theory, having no Born Rule, is
non-probabilistic
. Hence the notorious problem of reconciling it with the
unpredictability
and
appearance of stochasticity
in quantum measurements. Generalizing and improving upon the so-called ‘decision-theoretic approach’, I shall recast that problem in the recently proposed
constructor theory of information—
where quantum theory is represented as one of a class of
superinformation theories
, which are
local
,
non-probabilistic
theories conforming to certain constructor-theoretic conditions. I prove that the unpredictability of measurement outcomes (to which constructor theory gives an exact meaning) necessarily arises in superinformation theories. Then I explain how the appearance of stochasticity in (finitely many) repeated measurements can arise under superinformation theories. And I establish sufficient
conditions
for a superinformation theory to inform decisions (made under it)
as if
it were probabilistic, via a Deutsch–Wallace-type argument—thus defining a class of
decision-supporting
superinformation theories. This broadens the domain of applicability of that argument to cover constructor-theory compliant theories. In addition, in this version some of the argument's assumptions, previously construed as merely decision-theoretic, follow from
physical properties
expressed by constructor-theoretic principles.
Influence of nursery microhabitats on the future abundance of a coral reef fish
Authors: Wilson Shaun K. , Depczynski Martial , Fulton Christopher J. , Holmes Thomas H. , Radford Ben T. , Tinkler Paul
Published: August 2016

Species habitat associations are often complex, making it difficult to assess their influence on populations. Among coral reef fishes, habitat requirements vary among species and with ontogeny, but the relative importance of nursery and adult-preferred habitats on future abundances remain unclear. Moreover, adult populations may be influenced by recruitment of juveniles and assessments of habitat importance should consider relative effects of juvenile abundance. We conducted surveys across 16 sites and 200 km of reef to identify the microhabitat preferences of juveniles, sub-adults and adults of the damselfish
Pomacentrus moluccensis
. Microhabitat preferences at different life-history stages were then combined with 6 years of juvenile abundance and microhabitat availability data to show that the availability of preferred juvenile microhabitat (corymbose corals) at the time of settlement was a strong predictor of future sub-adult and adult abundance. However, the influence of nursery microhabitats on future population size differed spatially and at some locations abundance of juveniles and adult microhabitat (branching corals) were better predictors of local populations. Our results demonstrate that while juvenile microhabitats are important nurseries, the abundance of coral-dependent fishes is not solely dependent on these microhabitats, especially when microhabitats are readily available or following large influxes of juveniles.
Glaciations, gradients, and geography: multiple drivers of diversification of bush frogs in the Western Ghats Escarpment
Authors: Vijayakumar S. P. , Menezes Riya C. , Jayarajan Aditi , Shanker Kartik
Published: August 2016

The historical processes underlying high diversity in tropical biodiversity hotspots like the Western Ghats of Peninsular India remain poorly understood. We sampled bush frogs on 13 massifs across the Western Ghats Escarpment and examined the relative influence of Quaternary glaciations, ecological gradients and geological processes on the spatial patterns of lineage and clade diversification. The results reveal a large
in situ
radiation (more than 60 lineages), exhibiting geographical structure and clade-level endemism, with two deeply divergent sister clades, North and South, highlighting the biogeographic significance of an ancient valley, the Palghat Gap. A majority of the bush frog sister lineages were isolated on adjacent massifs, and signatures of range stasis provide support for the dominance of geological processes in allopatric speciation.
In situ
diversification events within the montane zones (more than 1800 m) of the two highest massifs suggest a role for climate-mediated forest-grassland persistence. Independent transitions along elevational gradients among sub-clades during the Miocene point to diversification along the elevational gradient. The study highlights the evolutionary significance of massifs in the Western Ghats with the high elevations acting as centres of lineage diversification and the low- and mid-elevations of the southern regions, with deeply divergent lineages, serving as museums.
Multi-trophic level response to extreme metal contamination from gold mining in a subarctic lake
Authors: Thienpont Joshua R. , Korosi Jennifer B. , Hargan Kathryn E. , Williams Trisha , Eickmeyer David C. , Kimpe Linda E. , Palmer Michael J. , Smol John P. , Blais Jules M.
Published: August 2016

Giant Mine, located in the city of Yellowknife (Northwest Territories, Canada), is a dramatic example of subarctic legacy contamination from mining activities, with remediation costs projected to exceed $1 billion. Operational between 1948 and 2004, gold extraction at Giant Mine released large quantities of arsenic and metals from the roasting of arsenopyrite ore. We examined the long-term ecological effects of roaster emissions on Pocket Lake, a small lake at the edge of the Giant Mine lease boundary, using a spectrum of palaeoenvironmental approaches. A dated sedimentary profile tracked striking increases (approx. 1700%) in arsenic concentrations coeval with the initiation of Giant Mine operations. Large increases in mercury, antimony and lead also occurred. Synchronous changes in biological indicator assemblages from multiple aquatic trophic levels, in both benthic and pelagic habitats, indicate dramatic ecological responses to extreme metal(loid) contamination. At the peak of contamination, all Cladocera, a keystone group of primary consumers, as well as all planktonic diatoms, were functionally lost from the sediment record. No biological recovery has been inferred, despite the fact that the bulk of metal(loid) emissions occurred more than 50 years ago, and the cessation of all ore-roasting activities in Yellowknife in 1999.
Next generation whole genome sequencing ofPlasmodium falciparumusing NextSeq500 technology in India
Authors: Mbengue Alassane , Namdev Pragya , Kumar Tarkeshwar , Haldar Kasturi , Bhattacharjee Souvik
Published: August 2016

Plasmodium falciparumis a protozoan parasite that causes the deadliest form of human malaria. Although, malaria burdens worldwide have decreased substantially over the last decade (WHO, 2014), genetic variation and adaptation by parasite strains against drugs and vaccines present significant challenges for the elimination of malaria (Ariey et al., 2014; Neafsey et al., 2015). India has formally launched a malaria elimination campaign (NVBDCP, 2016). Therefore, early in-country detection of drug resistance and/or immune evasion will be important for the program. Presently, the majority of surveillance methods in India detect a limited number of known polymorphisms (Campino et al., 2011; Chatterjee et al., 2016; Daniels et al., 2008; Mishra et al., 2015; Neafsey et al., 2012; Neafsey et al., 2008). A recently reported amplicon sequencing method enables targeted re-sequencing of a panel of genes (Rao et al., 2016). However, the capacity to identify new genes of resistance/immune evasion by whole genome sequencing (WGS) through next generation sequencing (NGS) in India, has remained elusive. Here we report the first WGS ofP. falciparumstrain performed by Eurofins Genomics India Pvt. Ltd at its Bengaluru division within 40 days of sample submission. Our data establish that timely, commercial WGS through NGS in India can be applied toP. falciparumto greatly empower the malaria elimination agenda in India.
Rare schizophrenia risk variants are enriched in genes shared with neurodevelopmental disorders
Authors: Singh Tarjinder , Walters James T. R. , Johnstone Mandy , Curtis David , Suvisaari Jaana , Torniainen Minna , Rees Elliott , Iyegbe Conrad , Blackwood Douglas , McIntosh Andrew M. , Kirov Georg , Geschwind Daniel , Murray Robin M. , Di Forti Marta , Bramon Elvira ,   INTERVAL Study,   UK10K Consortium, Palotie Aarno , O’Donovan Michael C. , Owen Michael J. , Barrett Jeffrey C.
Published: August 2016

By meta-analyzing rare coding variants in whole-exome sequences of 4,264 schizophrenia cases and 9,343 controls,de novomutations in 1,077 trios, and array-based copy number variant calls from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare damaging variants in a subset of 3,230 “highly constrained” genes previously identified as having near-complete depletion of protein truncating variants. Furthermore, rare variant enrichment analyses demonstrate that this burden is concentrated in known autism spectrum disorder risk genes, genes diagnostic of severe developmental disorders, and the autism-implicated sets of promoter targets ofCHD8, and mRNA targets ofFMRP. We further show that schizophrenia patients with intellectual disability have a greater enrichment of rare damaging variants in highly constrained genes and developmental disorder genes, but that a weaker but significant enrichment exists throughout the larger schizophrenia population. Combined, our results demonstrate that schizophrenia risk loci of large effect across a range of variant types implicate a common set of genes shared with broader neurodevelopmental disorders, suggesting a path forward in identifying additional risk genes in psychiatric disorders and further supporting a neurodevelopmental etiology to the pathogenesis of schizophrenia.
Molecular mechanisms of substrate-controlled ring dynamics and sub-stepping in a nucleic-acid dependent hexameric motor
Authors: Thomsen Nathan D. , Lawson Michael R. , Witkowsky Lea B. , Qu Song , Berger James M.
Published: August 2016

Ring-shaped hexameric helicases and translocases support essential DNA, RNA, and protein-dependent transactions in all cells and many viruses. How such systems coordinate ATPase activity between multiple subunits to power conformational changes that drive the engagement and movement of client substrates is a fundamental question. Using theE. coliRho transcription termination factor as a model system, we have employed solution and crystallographic structural methods to delineate the range of conformational changes that accompany distinct substrate and nucleotide cofactor binding events. SAXS data show that Rho preferentially adopts an open-ring state in solution, and that RNA and ATP are both required to cooperatively promote ring closure. Multiple closed-ring structures with different RNA substrates and nucleotide occupancies capture distinct catalytic intermediates accessed during translocation. Our data reveal how RNA-induced ring closure templates a sequential ATP-hydrolysis mechanism, provide a molecular rationale for how the Rho ATPase domains distinguishes between distinct RNA sequences, and establish the first structural snapshots of substepping events in a hexameric helicase/translocase.

SIGNIFICANCE

Hexameric, ring-shaped translocases are molecular motors that convert the chemical energy of ATP hydrolysis into the physical movement of protein and nucleic acid substrates. Structural studies of several distinct hexameric translocases have provided insights into how substrates are loaded and translocated; however, the range of structural changes required for coupling ATP turnover to a full cycle of substrate loading and translocation has not been visualized for any one system. Here, we combine low-and high-resolution structural studies of the Rho helicase, defining for the first time the ensemble of conformational transitions required both for substrate loading in solution and for substrate movement by a processive hexameric translocase.
Accurate eQTL prioritization with an ensemble-based framework
Authors: Zeng Haoyang , Edwards Matthew D. , Guo Yuchun , Gifford David K.
Published: August 2016

Expression quantitative trait loci (eQTL) analysis links sequence variants with gene expression change and serves as a successful approach to fine-map variants causal for complex traits and understand their pathogenesis. In this work, we present an ensemble-based computational framework, EnsembleExpr, for eQTL prioritization. When trained on data from massively parallel reporter assays (MPRA), EnsembleExpr accurately predicts reporter expression levels from DNA sequence and identifies sequence variants that exhibit significant allele-specific reporter expression. This framework achieved the best performance in the “eQTL-causal SNPs” open challenge in the Fourth Critical Assessment of Genome Interpretation (CAGI 4). We envision EnsembleExpr to be a powerful resource for interpreting non-coding regulatory variants and prioritizing disease-associated mutations for downstream validation.
Ligand-induced and small molecule control of substrate loading in a hexameric helicase
Authors: Lawson Michael R. , Dyer Kevin , Berger James M.
Published: August 2016

Processive, ring-shaped protein and nucleic acid protein translocases control essential biochemical processes throughout biology, and are considered high-prospect therapeutic targets. TheE. coliRho factor is an exemplar hexameric RNA translocase that terminates transcription in bacteria. Like many ring-shaped motor proteins, Rho activity is modulated by a variety of poorly understood mechanisms, including small molecule therapeutics, protein-protein interactions, and the sequence of its translocation substrate. Here, we establish the mechanism of action of two Rho effectors, the antibiotic bicyclomycin and nucleic acids that bind to Rho’s ‘primary’ mRNA recruitment site. Using SAXS and a novel reporter assay to monitor the ability of Rho to switch between open-ring (RNA loading) and closed-ring (RNA translocation) states, bicyclomycin is found to be a direct antagonist of ring closure. Reciprocally, the binding of nucleic acids to its N-terminal RNA recruitment domains is shown to promote the formation of a closed-ring Rho state, with increasing primary site occupancy providing additive stimulatory effects. This study establishes bicyclomycin as a conformational inhibitor of Rho ring dynamics, highlighting the utility of developing assays that read out protein conformation as a prospective screening tool for ring-ATPase inhibitors. Our findings further show that the RNA sequence specificity used for guiding Rho-dependent termination derives in part from an intrinsic ability of the motor to couple the recognition of pyrimidine patterns in nascent transcripts to RNA loading and activity.

SIGNIFICANCE

Many processive, ring-ATPase motor proteins rely on substrate-dependent conformational changes to assist with the loading of client substrates into the central pore of the enzyme and subsequent translocation. Using theE. coliRho transcription terminator as a model hexameric helicase, we show that two distinct ligands – the antibiotic bicyclomycin and pyrimidine-rich nucleic acids – alternatively repress or promote, respectively, the transition of Rho from an open, RNA-loading configuration to a closed-ring, active helicase. Our findings explain several mechanisms by which Rho activity is controlled, and provide a general illustration of how intrinsic and extrinsic factors can regulate ring-type ATPase dynamics through diverse mechanisms.