bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating Sizes of Key Populations at the National Level: Considerations for Study Design and Analysis
Authors: Edwards Jessie K. , Hileman Sarah , Donastorg Yeycy , Zadrozny Sabrina , Baral Stefan , Hargreaves James R. , Fearon Elizabeth , Zhao Jinkou , Datta Abhirup , Weir Sharon S.
Published: August 2018

Background:

National estimates of the sizes of key populations, including female sex workers, men who have sex with men, and transgender women are critical to inform national and international responses to the HIV pandemic. However, epidemiologic studies typically provide size estimates for only limited high priority geographic areas. This article illustrates a two-stage approach to obtain a national key population size estimate in the Dominican Republic using available estimates and publicly available contextual information.

Methods:

Available estimates of key population size in priority areas were augmented with targeted additional data collection in other areas. To combine information from data collected at each stage, we used statistical methods for handling missing data, including inverse probability weights, multiple imputation, and augmented inverse probability weights.

Results:

Using the augmented inverse probability weighting approach, which provides some protection against parametric model misspecification, we estimated that 3.7% (95% CI = 2.9, 4.7) of the total population of women in the Dominican Republic between the ages of 15 and 49 years were engaged in sex work, 1.2% (95% CI = 1.1, 1.3) of men aged 15–49 had sex with other men, and 0.19% (95% CI = 0.17, 0.21) of people assigned the male sex at birth were transgender.

Conclusions:

Viewing the size estimation of key populations as a missing data problem provides a framework for articulating and evaluating the assumptions necessary to obtain a national size estimate. In addition, this paradigm allows use of methods for missing data familiar to epidemiologists.
Autologous Fat Transfer as a Treatment for Peripheral Neuropathic Pain without Apparent Cause
Authors: Beugels Jip , Hommes Juliette E. , Balthasar Andrea J.R. , van der Hulst René R.W.J. , Piatkowski de Grzymala Andrzej A.
Published: August 2018

Neuropathic pain has a far-reaching effect on the daily lives of patients. Recently, autologous fat transfer (AFT) has demonstrated promising results in patients with painful scars or after neuroma excision. However, there is a subgroup of patients who do not show any apparent cause for the pain. We hypothesized that in these patients, AFT alone in the area around the affected nerve might lead to beneficial results. Patients with clearly demarcated neuropathic pain and who had exhausted all other treatment options were referred by a pain specialist. Fourteen patients who met the inclusion criteria received AFT in the area of the affected nerve. Pain scored on the visual analog scale, patient satisfaction, and quality of sleep were recorded before and after surgery. To investigate long-term effects, a second follow-up was planned at least 1 year later. Patient satisfaction was 93% after the first follow-up and 86% after more than 1 year. The mean VAS score was 7.4 before surgery and significantly decreased to 3.8 after autologous fat grafting (P < 0.0001) and 4.3 (P = 0.0017) at long-term follow-up. The quality of sleep improved in 50% of the patients, whereas the remainder indicated no difference. No complications were registered. The results show that AFT alone, even over a longer period of time and in patients refractory to multiple treatment modalities, can be useful to treat peripheral neuropathic pain without apparent cause. For definitive evidence, a larger prospective study is warranted.
Preoperative Staging by EBUS in cN0/N1 Lung Cancer
Authors: Leong Tracy L. , Loveland Paula M. , Gorelik Alexandra , Irving Louis , Steinfort Daniel P.
Published: August 2018

Background:

Performance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for staging the radiologically normal mediastinum has been reported with inconsistent findings. We assessed the sensitivity of systematic staging using EBUS-TBNA for detection of radiologically occult mediastinal metastases in cN0/N1 lung cancer.

Methods:

Studies evaluating EBUS-TBNA for systematic mediastinal staging in cN0/N1 lung cancer were identified by systematic review. Data extracted included: participant age and sex; EBUS-TBNA protocol; stage determined by radiology, EBUS-TBNA and surgery; 2×2 tables. Primary outcome was diagnostic accuracy of EBUS-TBNA for detection of unsuspected N2/N3 disease.

Results:

We identified 1173 articles. In total, 13 were included in a qualitative review and 9 (1146 patients) in a quantitative meta-analysis. Mean prevalence of N2/N3 disease was 15% (6% to 24%). EBUS-TBNA had pooled sensitivity of 49% [95% confidence interval (CI), 41%-57%], pooled specificity of 100% (95% CI, 99%-100%), mean negative predictive value 91% (82% to 100%) for detection of unsuspected N2/N3 metastases. Number needed to test to detect occult N2/N3 disease was 14 (95% CI, 10.8-16.3), which halved with addition of per-esophageal endoscopic ultrasound.

Conclusion:

Preoperative systematic staging by EBUS-TBNA of early lung cancer can reduce postoperative upstaging. Sensitivity for detection of radiologically occult mediastinal metastases seems lower than selective sampling of pathologic lymph nodes. Verification of negative results by mediastinoscopy in selected cases remains of value.
Do we need biomarkers for the follow-up and shortening of antibiotic treatment duration?
Authors: Dianti Milagros , Luna Carlos M.
Published: August 2018

Purpose of review

Clinical and laboratory parameters are useful tools for the diagnosis, follow-up and evaluation of resolution, and to predict outcomes when measured at different time-points onset and serially during follow-up in patients with hospital-acquired pneumonia and/or ventilator-associated pneumonia (HAP/VAP).

Recent findings

Both, the 2017 ERS/ESICM/ESCMID/Asociación Latino Americana de Tórax (EEEAG) and the 2016 IDSA/ATS guidelines (IAG) for the management of HAP/VAP recommend using clinical criteria alone, rather than biomarkers for diagnosis. Several studies were conducted to assess the value of serum biomarker concentration and kinetics for predicting the outcome in HAP/VAP, including C-reactive protein and procalcitonin (PCT). Although the EEEAG do not recommend routinely performing biomarker determinations in addition to bedside clinical assessment in patients receiving antibiotic treatment for VAP or HAP to predict adverse outcomes and clinical response, the IAG recommend that routine bedside clinical assessment should be accompanied by measurements of PCT to guide antimicrobial therapy. Additionally, the 2016 Surviving Sepsis Campaign also suggests that PCT levels can be used to support the shortening of antibiotic therapy.

Current evidence indicate that there is no recommendation to use biomarkers systematically to guide every decision. However, in some circumstances they might add some relevant information to our everyday practice.
The Iceberg Map of germline mutations in childhood cancer: focus on primary immunodeficiencies
Authors: Kindler Oliver , Quehenberger Franz , Benesch Martin , Seidel Markus G.
Published: August 2018

Purpose of review

The risk of cancer is higher, and its outcome is worse in patients with primary immunodeficiency (PID) than in members of the general population. Thus, the inter-relationship of malignant diseases with PIDs requires more study.

Recent findings

Large genetic screens identified a vast number of germline mutations in childhood cancer patient samples. Although TP53 was the most frequent single gene identified as mutated, many PID disorders like DNA repair defects are among the inborn causes of childhood cancer. We provide a comprehensive analysis of compiled data from seven recent studies that focused on germline genetic landscapes and preexisting conditions in pediatric oncology. As potentially causal germline variants were identified in ≈8% of malignancies in children and adolescents, we visualized this proportion as the ‘tips of the icebergs’. The results of additional network analyses showed the shared patterns of germline mutations in various malignancies and yielded a spatial distribution of the ‘icebergs’.

The ‘iceberg map of germline mutations in childhood cancers’ was created to increase the awareness of the inborn genetic underpinnings of childhood malignancies and their relationships with immunodeficiencies. Needs and perspectives of clinical immunologists and pediatric oncologists to both improve patient care and guide research at this critical interface are discussed.

Video Abstract

http://links.lww.com/MOP/A32
Urinary tract infections: raising problem in developing countries
Authors: Shiralizadeh Somayeh , Taghizadeh Sepehr , Asgharzadeh Mohammad , Shokouhi Behrooz , Gholizadeh Pourya , Rahbar Mohammad , Samadi Kafil Hossein
Published: August 2018

Urinary tract infections are the most common infections worldwide, which can involve the urethra, bladder and kidney and are caused by Gram-negative bacteria, followed by Gram-positive bacteria or fungi. Escherichia coli and Klebsiella species are the most common uropathogens. Misuse of antibiotics and passage of resistance genes between uropathogens play main role in increasing drug resistance. Increase of multidrug resistance and emergence of extended-spectrum beta-lactamases among uropathogens are concerned worldwide. Antimicrobial resistance patterns vary from time-to-time and across different regions. Hence, treatments must be conducted according to local prevalence of causative uropathogens, risk factors for multidrug-resistance and antimicrobial-resistance patterns of bacterial strains. This review discusses urinary tract infections in developing countries, including their mechanisms and risk factors.
A Tale of Confusion From Overlapping Confidence Intervals
Authors: Mittal Nimish , Bhandari Mohit , Kumbhare Dinesh
Published: August 2018

In clinical research presentations, study results are commonly reported in the form of P values and confidence intervals as an estimate of association and treatment effect. The interpretation of confidence intervals that overlap can be confusing and difficult for the reader to draw clinically meaningful conclusions. In this brief report, we describe the basics of confidence intervals and present an example from a recently published randomized control trial to illustrate a common confusion that overlapping confidence intervals between the means of two independent groups may not necessarily reject the true significant difference of effect. It is recommended that investigators use the direct difference of means between groups for confidence interval estimation to reduce type II errors. Clinicians should interpret overlapping confidence intervals with caution and avoid the assumption that overlapping confidence intervals always implies a lack of difference of treatment effect to decide application of treatment.
Integrated Rehabilitation for Breast Cancer Survivors
Authors: Cheville Andrea L. , McLaughlin Sarah A. , Haddad Tufia C. , Lyons Kathleen D. , Newman Robin , Ruddy Kathryn J.
Published: August 2018

The physical and psychological side effects of breast cancer therapies can have substantial impact on survivors' physical and social functioning. Roughly half of the more than 3 million Americans alive with a history of breast cancer report adverse, function-degrading sequelae related to their oncologic treatments. Care delivery models for the timely delivery of rehabilitation services have been proposed yet limitedly vetted or implemented. These include the prospective surveillance model, procedure-linked referrals, survivorship care plans, and risk stratification. Patients' capacity to engage in the rehabilitative process varies during cancer therapy and into survivorship. Perioperative attention generally focuses on managing premorbid impairments and normalizing shoulder function. In contrast, during chemotherapy and radiation therapy, symptom control, constructive coping, and role preservation may become more salient. Risk-stratified, individualized screening and prevention activities for specific impairments have become increasingly feasible through predictive models and analytics. Impairments' severity deleterious impact can be mitigated, as has been established for lymphedema, shoulder dysfunction, chemotherapy-induced peripheral neuropathy, cognitive dysfunction, fatigue, and sexual side effects. Integrated rehabilitative programs, often initiated after the completion of cancer treatment, are available in some countries outside of the United States and may offer survivors vital vocation- and avocation-directed services.
Combinations of Bevacizumab With Cancer Immunotherapy
Authors: Chen Daniel S. , Hurwitz Herbert
Published: August 2018

Cancer immunotherapy (CIT) has transformed cancer treatment. In particular, immunotherapies targeting the programmed death ligand 1 (PD-L1)/programmed death 1 pathway have demonstrated durable clinical benefit in some patients. However, CIT combinations may create a more favorable environment in which to maximize the potential of the immune system to eliminate cancer. Here we describe 3 key mechanisms related to vascular endothelial growth factor (VEGF)–mediated immunosuppression: inhibition of dendritic cell maturation, reduction of T-cell tumor infiltration, and promotion of inhibitory cells in the tumor microenvironment; supporting data are also described. In addition, we discuss immunomodulatory properties observed within tumors following bevacizumab treatment. Combining anti–PD-L1 and anti-VEGF therapies has shown synergy and positive outcomes in phases I to III studies, particularly in settings where high VEGF levels are known to play an important role in tumor growth. We also review data from key studies supporting combination of bevacizumab and CIT, with a focus on PD-L1/programmed death 1 inhibitors.
Antiangiogenic Therapy in Colorectal Cancer
Authors: Mody Kabir , Baldeo Candice , Bekaii-Saab Tanios
Published: August 2018

Colorectal carcinoma is the third most common cancer worldwide. Approximately 20% of patients with colorectal cancer will have metastatic disease at the time of initial diagnosis, and approximately 30% to 50% of patients with primary colon cancer will relapse and die of metastatic cancer. The 5-year survival rate of metastatic colorectal cancer remains disappointing at approximately 10%.

Angiogenesis plays a significant role in tumor growth and metastasis in colorectal carcinoma. There are currently 4 US Food and Drug Administration–approved antiangiogenic agents for metastatic colorectal cancer. Bevacizumab is the only antiangiogenic agent approved by the US Food and Drug Administration for first-line treatment of metastatic colorectal cancer. Other antiangiogenic agents include ramucirumab, ziv-aflibercept, and regorafenib. We review the data supporting the use of antiangiogenics in this disease.
Clinical management of cystic echinococcosis: state of the art and perspectives
Authors: Stojković Marija , Weber Tim F. , Junghanss Thomas
Published: August 2018

Purpose of review

This review draws attention to patients with cystic echinococcosis migrating from highly endemic to non-endemic countries with limited experience in cystic echinococcosis management, to ultrasound-based cyst staging, and to the WHO cyst classification as a powerful, to date underused tool to triage patients into the four currently available treatment modalities.

Recent findings

In non- and low-prevalence countries, cystic echinococcosis is often misclassified. Differential diagnoses, such as simple cysts and other benign and malignant space-occupying lesions, have similar appearances on imaging. Serology is confirmatory but often disappointing due to sensitivity and specificity problems. There is increasing confidence in assigning uncomplicated cystic echinococcosis cysts to the four treatment modalities [drug treatment (benzimidazoles), percutaneous methods, surgery, watch and wait] on the basis of cyst stage (WHO cyst classification), size and location. However, current best practice is still not widely implemented outside cystic echinococcosis treatment centres, and further consolidation is needed by well-designed clinical trials. Recently published long-term follow-up studies have shown that patients with inactive cyst stages CE4 and CE5 benefit, especially since they do not need any treatment at all if they have not received prior benzimidazole or percutaneous therapy. Instead, cysts that have reached cyst stages CE4 and CE5 through drug treatment do need careful follow-up as they often relapse. Surgical procedures in which the cysts are opened and percutaneous approaches require very careful control of cyst content spillage to the peritoneum, pleura and intravascularly to prevent dissemination – a still too often neglected issue with severe consequences for patients.

Though a neglected disease with predominantly expert-opinion-based treatment strategies, cystic echinococcosis patients can greatly benefit from interdisciplinary management in cystic echinococcosis treatment centres and cyst-stage-based assignment of treatment modalities. Increased suspicion for cystic echinococcosis in migrants from endemic to non-endemic countries is urgently needed at the current level of global mobility.
Gadoxetic Acid–Enhanced Hepatobiliary-Phase Magnetic Resonance Imaging for Delineation of Focal Nodular Hyperplasia: Superiority of High-Flip-Angle Imaging
Authors: Sheng Ruofan , Palm Viktoria , Mayer Philipp , Mokry Theresa , Berger Anne Katrin , Weiss Karl Heinz , Longerich Thomas , Kauczor Hans Ulrich , Weber Tim Frederik
Published: August 2018

Objective

The aim of this study was to investigate whether hepatobiliary-phase (HBP) flip-angle (FA) increase to 25° improves conspicuity of focal nodular hyperplasia (FNH) and enables HBP delay reduction.

Methods

This was a retrospective study of 23 patients with 46 FNHs. In each patient, HBP was performed with reduced-delay high FA (early/high), standard-delay high FA (late/high), and standard-delay standard FA (standard). Relative enhancement of liver and FNH periphery, FNH periphery–to–liver contrast ratio, and FNH periphery–to–central scar contrast ratio were compared between each HBP.

Results

Early/high, late/high, and standard HBPs were performed after 13.00 ± 2.12, 19.12 ± 3.10, and 19.68 ± 3.22 minutes, respectively. Liver and FNH periphery relative enhancement, FNH periphery–to–liver contrast ratio, and FNH periphery–to–central scar contrast ratio were higher for early/high and late/high than for standard HBP (P < 0.001 to P = 0.0048).

Conclusions

Increasing FA to 25° improves delineation of FNHs in HBP. Combining FA increase with delay reduction is superior to standard HBP and is sufficient for FNH characterization.
Accuracy of Digital Tomosynthesis of the Chest in Detection of Interstitial Lung Disease Comparison With Digital Chest Radiography
Authors: Kruamak Temphon , Edwards Rachael , Cheng Stephanie , Hippe Daniel S. , Raghu Ganesh , Pipavath Sudhakar N. J.
Published: August 2018

Purpose

The aim of the study was to assess the ability of chest digital tomosynthesis (DTS) for detection of interstitial lung disease (ILD) compared with conventional chest radiography.

Materials and Methods

We retrospectively reviewed 78 patients (60 males, 18 females, mean age = 53.05 years, range, 19–83 years) who underwent chest DTS for a 5-year interval (January 1, 2009–December 31, 2014). Of the 78 patients, 33 (42.3%) carried a diagnosis of ILD and 45 (57.7%) were not ILD. All computed tomography reports and medical records were reviewed. The conventional chest radiography and DTS were separately reviewed by 2 radiologists for the presence of ILD and the confidence in diagnosis.

Results

The diagnostic accuracy of DTS for the detection of ILD was better than conventional chest radiography (P < 0.05). Digital tomosynthesis had a sensitivity of 83.3% and negative predictive value of 89.0% that were statistically significantly better than conventional chest radiography (43.9% and 70.9%, respectively). Confidence in diagnosing ILD at DTS was higher than conventional chest radiography (P < 0.001) and had higher interobserver agreement than conventional chest radiography (P < 0.01).

Conclusions

Digital tomosynthesis improves diagnostic performance and confidence in diagnosing ILD compared with conventional chest radiography. Digital tomosynthesis can be suggested as the initial diagnostic technique for patients with suspected ILD.
How much does reduced food intake contribute to cancer-associated weight loss?
Authors: Martin Lisa , Kubrak Catherine
Published: August 2018

Purpose of review

An international consensus group defined cancer cachexia as a syndrome of involuntary weight loss, characterized by loss of skeletal muscle (with or without fat loss), which is driven by a variable combination of reduced food intake and altered metabolism.

This review presents recent studies that evaluated the contribution of reduced food intake to cancer-associated weight loss.

Recent findings

Four studies examined food intake in relation to weight loss. Heterogeneity among studies rendered aggregation and interpretation of results challenging. Despite these limitations, reduced food intake had consistent significant, independent associations with weight loss. However, reduced food intake did not explain all the variation in weight loss; and limited data suggests factors related to alterations in metabolism (e.g. increased resting energy expenditure, systemic inflammation) are also contributing to weight loss.

Reduced food intake is a significant contributor to cancer-associated weight loss. Understanding the magnitude of the association between food intake and weight loss may improve when it is possible to account for alterations in metabolism. Efforts to align clinical assessments of food intake to reduce heterogeneity are needed.
Functionalizing cell-mimetic giant vesicles with encapsulated bacterial biosensors
Authors: Trantidou Tatiana , Dekker Linda , Polizzi Karen , Ces Oscar , Elani Yuval
Published: August 2018

The design of vesicle microsystems as artificial cells (bottom-up synthetic biology) has traditionally relied on the incorporation of molecular components to impart functionality. These cell mimics have reduced capabilities compared with their engineered biological counterparts (top-down synthetic biology), as they lack the powerful metabolic and regulatory pathways associated with living systems. There is increasing scope for using whole intact cellular components as functional modules
within
artificial cells, as a route to increase the capabilities of artificial cells. In this feasibility study, we design and embed genetically engineered microbes (
Escherichia coli
) in a vesicle-based cell mimic and use them as biosensing modules for real-time monitoring of lactate in the external environment. Using this conceptual framework, the functionality of other microbial devices can be conferred into vesicle microsystems in the future, bridging the gap between bottom-up and top-down synthetic biology.
Membrane remodelling by a lipidated endosomal sorting complex required for transport-III chimera,
in vitro
Authors: Marklew C. J. , Booth A. , Beales P. A. , Ciani B.
Published: August 2018

The complexity of eukaryotic cells is underscored by the compartmentalization of chemical signals by phospholipid membranes. A grand challenge of synthetic biology is building life from the ‘bottom-up’, for the purpose of generating systems simple enough to precisely interrogate biological pathways or for adapting biology to perform entirely novel functions. Achieving compartmentalization of chemistries in an addressable manner is a task exquisitely refined by nature and embodied in a unique membrane remodelling machinery that pushes membranes away from the cytosol, the ESCRT-III (endosomal sorting complex required for transport-III) complex. Here, we show efforts to engineer a single ESCRT-III protein merging functional features from its different components. The activity of such a designed ESCRT-III is shown by its ability to drive the formation of compartments encapsulating fluorescent cargo. It appears that the modular nature of ESCRT-III allows its functional repurposing into a minimal machinery that performs sophisticated membrane remodelling, therefore enabling its use to create eukaryotic-like multi-compartment architectures.
Adhesion to nanofibers drives cell membrane remodeling through 1D wetting
Authors: Charles-Orszag Arthur , Tsai Feng-Ching , Bonazzi Daria , Manriquez Valeria , Sachse Martin , Mallet Adeline , Salles Audrey , Melican Keira , Staneva Ralitza , Bertin Aurélie , Millien Corinne , Goussard Sylvie , Lafaye Pierre , Shorte Spencer , Piel Matthieu , Krijnse-Locker Jacomine , Brochard-Wyart Françoise , Bassereau Patricia , Duménil Guillaume
Published: August 2018

The shape of cellular membranes is highly regulated by a set of conserved mechanisms. These mechanisms can be manipulated by bacterial pathogens to infect cells. Human endothelial cell plasma membrane remodeling by the bacteriumNeisseria meningitidisis thought to be essential during the blood phase of meningococcal infection, but the underlying mechanisms are unknown. Here we show that plasma membrane remodeling occurs independently of F-actin, along meningococcal type IV pili fibers, by a novel physical mechanism we term “ onedimensional” membrane wetting. We provide a theoretical model that gives the physical basis of 1D wetting and show that this mechanism occurs in model membranes interacting with model nanofibers, and in human cells interacting with model extracellular matrices. It is thus a new general principle driving the interaction of cells with their environment at the nanoscale that is diverted by meningococcus during infection.
Novel small molecule agonists of anAedes aegyptineuropeptide Y receptor block mosquito biting behavior
Authors: Duvall Laura B. , Ramos-Espiritu Lavoisier , Barsoum Kyrollos E. , Glickman J. Fraser , Vosshall Leslie B.
Published: August 2018

FemaleAedes aegyptimosquitoes bite humans to obtain a blood-meal to develop their eggs. Remarkably, strong attraction to humans is suppressed for several days after the blood-meal by an unknown mechanism. We investigated a role for neuropeptide Y (NPY)-related signaling in this long-term behavioral suppression, and discovered that drugs targeting human NPY receptors modulate mosquito host-seeking behavior. In a screen of all 49 predictedAe. aegyptipeptide receptors, we identified NPY-like receptor 7 (NPYLR7) as the sole target of these human drugs. To obtain small molecule agonists selective for NPYLR7, we carried out a high-throughput cell-based assay of 265,211 compounds, and isolated 6 highly selective NPYLR7 agonists that inhibit mosquito attraction to humans.NPYLR7CRISPR-Cas9 null mutants are defective in behavioral suppression, and resistant to these drugs. Finally, we show that these drugs are capable of inhibiting biting and blood-feeding on a live host, suggesting a novel approach to control infectious disease transmission by controlling mosquito behavior.
Correlation between the aberrant human testicular germ-cell gene expression and disruption of spermatogenesis leading to male infertility
Authors: Baksi Arka , Jain Ruchi , Manjithaya Ravi , S Vasan S , Kondaiah Paturu , Dighe Rajan R.
Published: August 2018

Spermatogenesis is characterized by sequential gene-expression at precise stages in progression of differentiation of the germ cells. Any alteration in expression of the critical genes is responsible for arrest of spermatogenesis associated with infertility. Inspite of advances the differential gene expression accompanying spermatogenesis, the corresponding regulatory mechanisms and their correlation to human infertility have not been clearly established. This study aims to identify the gene expression pattern of the human testicular germ cells from the patients either with obstructive azoospermia with complete intra-testicular spermatogenesis or non-obstructive azoospermia with spermatogenesis arrested at different stages and correlate the same to infertility. The testicular transcriptomes of 3 OA and 8 NOA patients and pooled testicular RNA (commercial source) were analyzed for their differential gene expression to identify potential regulators of spermatogenesis and the results were further validated in all of the 44 patients clinically diagnosed with azoospermia undergoing sperm retrieval surgery over the study period and 4 control samples included in this study. Analyses of the differential transcriptome led to identification of genes enriched in a specific testicular cell type and subsequently, several regulators of the diploid-double-diploid-haploid transitions in the human spermatogenesis were identified. Perturbations in the expression of these genes were identified as the potential causes of the spermatogenic arrest seen in azoospermia and thus the potential mediators of human male infertility. Another interesting observation was the increased autophagy in the testes of patients with non-obstructive azoospermia. The present study suggests that the regulation of the diploid-double-diploid-haploid transition is multigenic with the tandem alteration of several genes resulting in infertility. In conclusion, this study identified some of the genetic regulators controlling spermatogenesis using comparative transcriptome analyses of testicular tissues from azoospremic individuals and showed how alterations in several genes results in disruption of spermatogenesis and subsequent infertility. This study also provides interesting insights into the gene expression patterns of the Indian population that were not available earlier.
Minor isozymes tailor yeast metabolism to carbon availability
Authors: Bradley Patrick H. , Gibney Patrick A. , Botstein David , Troyanskaya Olga G. , Rabinowitz Joshua D.
Published: August 2018

Isozymes are enzymes that differ in sequence but catalyze the same chemical reactions. Despite their apparent redundancy, isozymes are often retained over evolutionary time for reasons that can be unclear. We find that, in yeast, isozymes are strongly enriched in central carbon metabolism. Using a gene expression compendium, we find that many isozyme pairs show anticorrelated expression during the respirofermentative shift, suggesting roles in adapting to changing carbon availability. Building on this observation, we assign function to two minor central carbon isozymes, aconitase 2 (ACO2) and pyruvate kinase 2 (PYK2).ACO2is expressed during fermentation and proves advantageous when glucose is limiting.PYK2is expressed during respiration and proves advantageous for growth on three-carbon substrates.PYK2’s deletion is rescued by expressing the major pyruvate kinase, but only if that enzyme carries mutations mirroringPYK2’s allosteric regulation. Thus, central carbon isozymes enable more precise tailoring of metabolism to changing nutrient availability.

Importance

Gene duplication is one of the main evolutionary drivers of new protein function. However, some gene duplicates have nevertheless persisted long-term without apparent divergence in biochemical function. Further, under standard lab conditions, many isozymes have subtle or no knockout phenotypes. These factors make it hard to assess the unique contributions of individual isozymes to fitness. We therefore developed a method to identify experimental perturbations that could expose such contributions, and applied it to yeast gene expression data, revealing a potential role for a set of yeast isozymes in adapting to changing carbon sources. Our experimental confirmation of distinct roles for two “minor” yeast isozymes, including one with no previously described knockout phenotype, highlight that even apparently redundant paralogs can have important and unique functions, with implications for genome-scale metabolic modeling and systems-level studies of quantitative genetics.
P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress
Authors: Bugai Andrii , Quaresma Alexandre J.C. , Friedel Caroline C. , Lenasi Tina , Sibley Christopher R. , Kukanja Petra , Fujinaga Koh , Blasius Melanie , Hennig Thomas , Ule Jernej , Dölken Lars , Barboric Matjaz
Published: August 2018

Cellular DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill-defined. Given the centrality of RNA polymerase II (Pol II) promoter-proximal pause release in transcriptional control, we evaluated its importance in DDR. Here we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates Pol II elongation and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by genotoxic stress-enhanced binding of RBM7 to 7SK snRNA (7SK), the scaffold of the 7SK small nuclear ribonucleoprotein (7SK snRNP) which inhibits P-TEFb. In turn, P-TEFb relocates from 7SK snRNP to chromatin to induce transcription of short units including key DDR genes and multiple classes of non-coding RNAs. Critically, interfering with RBM7 or P-TEFb provokes cellular hypersensitivity to DNA damage-inducing agents through activation of apoptotic program. By alleviating the inhibition of P-TEFb, RBM7 thus facilitates Pol II elongation to enable a pro-survival transcriptional response that is crucial for cell fate upon genotoxic insult. Our work uncovers a new paradigm in stress-dependent control of Pol II pause release, and offers the promise for designing novel anti-cancer interventions using RBM7 and P-TEFb antagonists in combination with DNA-damaging chemotherapeutics.
Characterization of segmental duplications and large inversions using Linked-Reads
Authors: Karaoglanoglu Fatih , Ricketts Camir , Rasekh Marzieh Eslami , Ebren Ezgi , Hajirasouliha Iman , Alkan Can
Published: August 2018

Many algorithms aimed at characterizing genomic structural variation (SV) have been developed since the inception of high-throughput sequencing. However, the full spectrum of SVs in the human genome is not yet assessed. Most of the existing methods focus on discovery and genotyping of deletions, insertions, and mobile elements. Detection of balanced SVs with no gain or loss of genomic segments (e.g., inversions) is particularly a challenging task. Long read sequencing has been leveraged to find short inversions but there is still a need to develop methods to detect large genomic inversions. Furthermore, currently there are no algorithms to predict the insertion locus of large interspersed segmental duplications.

Here we propose novel algorithms to characterize large (>40Kbp) interspersed segmental duplications and (>80Kbp) inversions using Linked-Read sequencing data. Linked-Read sequencing provides long range information, where Illumina reads are tagged with barcodes that can be used to assign short reads to pools of larger (30-50 Kbp) molecules. Our methods rely on split molecule sequence signature that we have previously described [11]. Similar to the split read, split molecules refer to large segments of DNA that span an SV breakpoint. Therefore, when mapped to the reference genome, the mapping of these segments would be discontinuous. We redesign our earlier algorithm, VALOR, to specifically leverage Linked-Read sequencing data to discover large inversions and characterize interspersed segmental duplications. We implement our new algorithms in a new software package, called VALOR2.

Availability

VALOR2 is available at https://github.com/BilkentCompGen/valor.
Dimensionality in recurrent spiking networks: global trends in activity and local origins in connectivity
Authors: Recanatesi Stefano , Ocker Gabriel Koch , Buice Michael A. , Shea-Brown Eric
Published: August 2018

The dimensionality of a network’s collective activity is of increasing interest in neuroscience. This is because dimensionality provides a compact measure of how coordinated network-wide activity is, in terms of the number of modes (or degrees of freedom) that it can independently explore. A low number of modes suggests a compressed low dimensional neural code and reveals interpretable dynamics [1], while findings of high dimension may suggest flexible computations [2, 3]. Here, we address the fundamental question of how dimensionality is related to connectivity, in both autonomous and stimulus-driven networks. Working with a simple spiking network model, we derive three main findings. First, the dimensionality of global activity patterns can be strongly, and systematically, regulated by local connectivity structures. Second, the dimensionality is a better indicator than average correlations in determining how constrained neural activity is. Third, stimulus evoked neural activity interacts systematically with neural connectivity patterns, leading to network responses of either greater or lesser dimensionality than the stimulus.

Author summary

New recording technologies are producing an amazing explosion of data on neural activity. These data reveal the simultaneous activity of hundreds or even thousands of neurons. In principle, the activity of these neurons could explore a vast space of possible patterns. This is what is meant by high-dimensional activity: the number of degrees of freedom (or “modes”) of multineuron activity is large, perhaps as large as the number of neurons themselves. In practice, estimates of dimensionality differ strongly from case to case, and do so in interesting ways across experiments, species, and brain areas. The outcome is important for much more than just accurately describing neural activity: findings of low dimension have been proposed to allow data compression, denoising, and easily readable neural codes, while findings of high dimension have been proposed as signatures of powerful and general computations. So what is it about a neural circuit that leads to one case or the other? Here, we derive a set of principles that inform how the connectivity of a spiking neural network determines the dimensionality of the activity that it produces. These show that, in some cases, highly localized features of connectivity have strong control over a network’s global dimensionality—an interesting finding in the context of, e.g., learning rules that occur locally. We also show how dimension can be much different than first meets the eye with typical “pairwise” measurements, and how stimuli and intrinsic connectivity interact in shaping the overall dimension of a network’s response.
Plasticity of Mitochondrial DNA Inheritance and its Impact on Nuclear Gene Transcription in Yeast Hybrids
Authors: Hewitt Sarah K. , Duangrattanalert Kobchai , Burgis Tim , Zeef Leo A.H. , Delneri Daniela
Published: August 2018

Mitochondrial DNA (mtDNA) in budding yeast is biparentally inherited, but colonies rapidly lose one type of parental mtDNA, becoming homoplasmic. Therefore, hybrids between different yeast species possess two homologous nuclear genomes, but only one type of mitochondrial DNA. We hypothesise that the choice of mtDNA retention is influenced by its contribution to hybrid fitness in different environments, and that the allelic expression of the two nuclear sub-genomes is affected by the presence of different mtDNAs in hybrids. Here, we crossedSaccharomyces cerevisiaewithS. uvarumunder different environmental conditions and examined the plasticity of the retention of mtDNA in each hybrid. We showed that on fermentable carbon sources at warm temperatures each parental mtDNA was equally likely to be retained, while at colder temperatures, hybrids preferentially retained mtDNA derived fromS. uvarum. On a non-fermentable carbon source, hybrids retainedS. cerevisiaemtDNA, independent of temperature. By acquiring transcriptome data and co-expression profiles for hybrids harbouring different mtDNA in a selection of environments, we found a clear pattern of concerted allelic transcription of one or the other sub-genome for specific biological pathways, supporting the notion that the hybrid cell works preferentially with one set of parental alleles or the other according to specific cellular functions. We argue that the type of mtDNA retained in hybrids affects the expression of the nuclear genome and the organism fitness in different environments, and therefore may have a role in driving the evolution of the hybrid nuclear genome in terms of gene retention and loss.
Incremental solidification (toward 3D-printing) of magnetically-confined metal-powder by localized microwave heating
Authors: Fugenfirov Mihael , Meir Yehuda , Shelef Amir , Nerovny Yuri , Aharoni Eli , Jerby Eli
Published: August 2018

Purpose

This paper aims to present an experimental and theoretical study oriented to investigate the potential use of localized microwave-heating (LMH) in 3D-printing and additive-manufacturing (AM) processes.

Design/methodology/approach

Following a previous study by the authors, a magnetic confinement technique is developed here as a non-contact support for the incremental solidification by LMH of small metal-powder batches. This approach, which saves the need for a mechanic support in contact with the powder-batch during the microwave heating, may significantly simplify the LMH–AM process.

Findings

The powder properties are characterized, and a theoretical LMH model is used to simulate the LMH mechanism dominated here by magnetic eddy currents.

Originality/value

The experimental products are analyzed, and their hardness, porosity and oxidation are evaluated. Practical considerations and further improvements of the non-contact LMH–AM process are discussed.
Analysis of an iron-core and ironless railguns powered sequentially
Authors: Waindok Andrzej , Piekielny Pawel
Published: August 2018

Purpose

The purpose of this paper is to calculate and measure transients for two different constructions of electrodynamic accelerators (ironless and iron-core) supplied by a three-section power system (three capacitor banks). The optimization of power supply parameters (switch-on times and capacitances of individual sections) in terms of system efficiency has been carried out.

Design/methodology/approach

Calculations have been carried out using a field-circuit model. For three-dimensional magnetostatic analysis, the Maxwell software and finite element method (FEM) were used, while for circuit model, the Matlab/Simulink software was implemented. For optimization of the supply system parameters, the genetic algorithm was used. The mathematical models were verified experimentally by using the original laboratory stand.

Findings

The efficiency of the system is much higher in case of iron-core accelerator. In both cases, the results obtained for optimized supply settings are only slightly better than those obtained by simultaneously switching on the thyristors and for symmetrical capacity division.

Research limitations/implications

Due to the presented field-circuit model, eddy currents in rails have been neglected. In the field model, there was no possibility to combine current flow calculations with moving of the projectile.

Originality/value

Using the presented filed-circuit model, both electrical and mechanical transients could be calculated with sufficient precision. Thus, it could be used in the optimization of supply system. The solution time is low compared with the solution time of the transient field model.
Topological and topical characterisation of Twitter user communities
Authors: Gadek Guillaume , Pauchet Alexandre , Malandain Nicolas , Vercouter Laurent , Khelif Khaled , Brunessaux Stéphan , Grilhères Bruno
Published: August 2018

Purpose

Most of the existing literature on online social networks (OSNs) either focuses on community detection in graphs without considering the topic of the messages exchanged, or concentrates exclusively on the messages without taking into account the social links. The purpose of this paper is to characterise the semantic cohesion of such groups through the introduction of new measures.

Design/methodology/approach

A theoretical model for social links and salient topics on Twitter is proposed. Also, measures to evaluate the topical cohesiveness of a group are introduced. Inspired from precision and recall, the proposed measures, called expertise and representativeness, assess how a set of groups match the topic distribution. An adapted measure is also introduced when a topic similarity can be computed. Finally, a topic relevance measure is defined, similar to tf.idf (term-frequency, inverse document frequency).

Findings

The measures yield interesting results, notably on a large tweet corpus: the metrics accurately describe the topics discussed in the tweets and enable to identify topic-focused groups. Combined with topological measures, they provide a global and concise view of the detected groups.

Originality/value

Many algorithms, applied on OSN, detect communities which often lack of meaning and internal semantic cohesion. This paper is among the first to quantify this aspect, and more precisely the topical cohesion and topical relevance of a group. Moreover, the proposed indicators can be exploited for social media monitoring, to investigate the impact of a group of people: for instance, they could be used for journalism, marketing and security purposes.
Blinded by the sand of its burrowing? Examining fans’ intentions to follow one-day cricket on TV with a moderating effect of social influence
Authors: Kashif Muhammad , Fernando P.M.P , Wijenayake S.I.
Published: August 2018

Purpose

The purpose of this paper is to investigate the effect of patriotism, nostalgia, drama and excitement of the game, and interest in star players to predict fans’ intentions to follow one-day cricket in near future. Furthermore, social influence is positioned as a moderator to enrich the understanding of fans’ motives to follow one-day cricket.

Design/methodology/approach

The data are collected by means of a cross-sectional survey conducted among 609 university students enroled in Pakistani and Sri Lankan universities. The collected data are analysed by employing a structural equation modelling procedures to reach meaningful conclusions.

Findings

The variables of patriotism, nostalgic associations, excitement and drama of the game, and interest in star players are found to positively relate to the fans’ intentions to follow one-day cricket in near future. However, the moderating effects of social influence only moderated with interest in star players, which has practical and theoretical implications.

Originality/value

The study is an original contribution to the field of sports marketing. The proposed relationships are based on social identity theory paradigm. Furthermore, the moderating effects of social influence and a multi-country data are unique to this study. Finally, in previous studies, football fans’ motivation and test-match cricket fans’ motivations are studied, hence one-day cricket as a context is also unique to this study.