bluuebunny/crossref_metadata_2025 huggingface dataset:
Helicobacter pylori‐induced miR‐135b‐5p promotes cisplatin resistance in gastric cancer
Authors: Shao Linlin , Chen Zheng , Soutto Mohammed , Zhu Shoumin , Lu Heng , Romero-Gallo Judith , Peek Richard , Zhang Shutian , El-Rifai Wael
Published: July 2018

Helicobacter pylori infection is a major risk factor for the development of gastric cancer. Aberrant expression of microRNAs is strongly implicated in gastric tumorigenesis; however, their contribution in response to H. pylori infection has not been fully elucidated. In this study, we evaluated the expression of miR‐135b‐5p and its role in gastric cancer. We describe the overexpression of miR‐135b‐5p in human gastric cancer tissue samples compared with normal tissue samples. Furthermore, we found that miR‐135b‐5p is also up‐regulated in gastric tumors from the trefoil factor 1‐knockout mouse model. Infection with H. pylori induced the expression of miR‐135b‐5p in the in vitro and in vivo models. miR‐135b‐5p induction was mediated by NF‐κB. Treatment of gastric cancer cells with TNF‐α induced miR‐135b‐5p in a NF‐κB–dependent manner. Mechanistically, we found that miR‐135b‐5p targets Krüppel‐like factor 4 (KLF4) and binds to its 3′ UTR, leading to reduced KLF4 expression. Functionally, high levels of miR‐135b‐5p suppress apoptosis and induce cisplatin resistance. Our results uncovered a mechanistic link between H. pylori infection and miR‐135b‐5p‐KLF4, suggesting that targeting miR‐135b‐5p could be a potential therapeutic approach to circumvent resistance to cisplatin.—Shao, L., Chen, Z., Soutto, M., Zhu, S., Lu, H., Romero‐Gallo, J., Peek, R., Zhang, S., El‐Rifai, W. Helicobacter pylori‐induced miR‐135b‐5p promotes cisplatin resistance in gastric cancer. FASEB J. 33, 264–274 (2019). www.fasebj.org
High‐depth transcriptomic profiling reveals the temporal gene signature of human mesenchymal stem cells during chondrogenesis
Authors: Huynh Nguyen P. T. , Zhang Bo , Guilak Farshid
Published: July 2018

Mesenchymal stem/stromal cells (MSCs) provide an attractive cell source for cartilage repair and cell therapy; however, the underlying molecular pathways that drive chondrogenesis of these populations of adult stem cells remain poorly understood. We generated a rich data set of high‐throughput RNA sequencing of human MSCs throughout chondrogenesis at 6 different time points. Our data consisted of 18 libraries with 3 individual donors as biologic replicates, with each library possessing a sequencing depth of 100 million reads. Computational analyses with differential gene expression, gene ontology, and weighted gene correlation network analysis identified dynamic changes in multiple biologic pathways and, most importantly, a chondrogenic gene subset, whose functional characterization promises to further harness the potential of MSCs for cartilage tissue engineering. Furthermore, we created a graphic user interface encyclopedia built with the goal of producing an open resource of transcriptomic regulation for additional data mining and pathway analysis of the process of MSC chondrogenesis.—Huynh, N. P. T., Zhang, B., Guilak, F. High‐depth transcriptomic profiling reveals the temporal gene signature of human mesenchymal stem cells during chondrogenesis. FASEB J. 33, 358–372 (2019). www.fasebj.org
Factors Associated With Informative Redraw After an Initial No Result in Noninvasive Prenatal Testing
Authors: Benn Peter , Valenti Elizabeth , Shah Shailen , Martin Kimberly , Demko Zachary
Published: July 2018

OBJECTIVE:

Noninvasive prenatal testing (NIPT) sometimes fails to provide a test result, usually as a result of low cell-free DNA fetal fraction. We investigated how initial fetal fraction, maternal weight, gestational age, and time between blood sampling contribute to obtaining an informative result when a redraw is performed.

METHODS:

We performed a retrospective data review of NIPT samples received between January and October 2016 by a commercial laboratory, where the initial blood draw did not yield a result and a second sample was drawn between 5 and 28 days after the initial sampling. We included cases with fetal fraction less than 2.8% (the threshold for “no result” in this laboratory) and those with higher fetal fraction but where the NIPT results could not be interpreted with high confidence.

RESULTS:

For 4,018 cases in which a redraw was recommended, a result was obtained for the second sample in 2,835 cases (70.6%) (95% CI 69.1–72.0%). For the 2,959 cases with insufficient fetal fraction, there was a result for the second sample in 1,861 cases (62.9%) (95% CI 61.1–64.6%). For this subset, the average increase in fetal fraction was 1.2% with an average interval between draws of 14 days. Informative redraw rate was strongly dependent on maternal weight and fetal fraction measured at the first draw. Gestational age was not an important determinant. Informative redraw rate increased rapidly over the first 8 days after the initial draw and more slowly thereafter.

CONCLUSION:

Based on fetal fraction in the initial sample, maternal weight, and interval between blood draws, women can be provided with a personalized estimate of their likelihood of a result on redraw. This should aid in the counseling of women faced with the choice of reattempting NIPT, conventional screening, or an invasive diagnostic test.
Association of Patient Race With Surgical Practice and Perioperative Morbidity After Myomectomy
Authors: Stentz Natalie C. , Cooney Laura G. , Sammel Mary D. , Shah Divya K.
Published: July 2018

OBJECTIVE:

To compare surgical approach, operative time, and perioperative morbidity after myomectomy by patient race.

METHODS:

In this retrospective cohort study, data were abstracted from the American College of Surgeons National Surgical Quality Improvement Program database on 8,438 women undergoing myomectomy between January 1, 2012, and December 31, 2015. Myoma burden and approach to myomectomy were determined based on Current Procedural Terminology coding. Surgical approach and perioperative morbidity were examined in African American, Asian American, and Hispanic American women using non-Hispanic Caucasian women as the referent population. Adjusted means and odds ratios (ORs) with 95% CI were calculated using propensity score matching accounting for age, ethnicity, body mass index (BMI), myoma burden, preoperative anemia, hypertension, smoking, and operative time.

RESULTS:

Data were available for 2,533 Caucasian, 3,359 African American, 664 Asian American, and 700 Hispanic American women. Smoking, BMI, hypertension, myoma burden, and anemia varied by race (P<.001, all comparisons). In adjusted analysis, African American women were twice as likely to undergo abdominal myomectomy (adjusted OR 1.9, 95% CI 1.7–2.0), Asian American women were more than twice as likely (adjusted OR 2.3, 95% CI 1.8–2.8), and Hispanic American women were 50% more likely to undergo abdominal myomectomy (adjusted OR 1.5, 95% CI 1.2–1.9) when compared with Caucasian women. African American women were 50% more likely to experience composite morbidity after abdominal myomectomy (adjusted OR 1.5, 95% CI 1.2–1.7) and Asian American women were more than three times as likely to experience composite morbidity after laparoscopic myomectomy (adjusted OR 3.7, 95% CI 1.7–8.1) compared with Caucasian women. There were no differences in composite morbidity in other racial groups.

CONCLUSION:

Minority women are substantially more likely to undergo abdominal myomectomy when compared with Caucasian women. African American women had 50% increased odds of morbidity after abdominal myomectomy, and Asian American women were more than three times as likely to experience morbidity after laparoscopic myomectomy. Further examination into the etiology and prevention of these racial disparities is needed.
Conditional recurrence-free survival in patients with primary stage I–II cutaneous malignant melanoma – a population-based study
Authors: Lyth Johan
Published: July 2018

Conditional survival in patients with localized primary cutaneous malignant melanoma (CMM) is well described. However, conditional recurrence-free survival (RFS) has not been investigated before. The aim of this study was to determine conditional RFS and test for time dependency in prognostic factors in patients with localized stage I–II CMM. This study included 1437 CMM patients registered in one region of Sweden during 1999–2012 followed up through 31 December 2012. To identify first recurrence of CMM disease, data from a care data warehouse, the pathology and radiology department registries were used. Patients were also followed through a Census Register and the National Cause of Death Register. The time-dependent risk of recurrence was analysed in a Cox’s proportional hazard regression. The 5-year conditional RFS increased from 86% (95% confidence interval: 84–88) at diagnosis to 96% (95% confidence interval: 94–98) at 5 years after diagnosis. Women showed a 60% lower risk of recurrence than men and this effect was stable over time (P=0.39). Patients aged greater than or equal to 65 years had a 40% higher risk of recurrence than patients aged less than 65 years, and this effect was stable over time (P=0.65). Patients with tumour ulceration showed a 70% higher risk of recurrence than nonulcerated patients, but this effect disappeared after 2 years (P=0.04). For patients with T3–T4 CMM, the hazard ratios decreased over time and were similar to hazard ratio of patients with T2 CMM after 2 years and later. The decreasing impact of tumour thickness and ulceration over time could have important implications for CMM patients in terms of counselling and follow-up.
Modification of the Melbourne Method for Total Calvarial Vault Remodeling
Authors: Hughes Christopher D. , Isaac Kathryn V. , Hwang Paul F. , Ganske Ingrid , Proctor Mark R. , Meara John G.
Published: July 2018

Background:

Sagittal synostosis is the most common form of single suture synostosis. It often results in characteristic calvarial deformities, including a long, narrow head, frontal bossing, a bullet-shaped occiput, and an anteriorly placed vertex. Several methods for correcting the phenotypic deformities have been described, each with their own advantages and challenges. In this study, we describe a modification of the Melbourne method of total calvarial remodeling for correcting scaphocephaly.

Methods:

We conducted a retrospective review of all consecutive patients who underwent total calvarial remodeling using a modified version of the Melbourne technique from 2011 to 2015. We evaluated clinical photographs, computed tomographic imaging, and cephalic indices both pre- and postoperatively to determine morphologic changes after operation.

Results:

A total of 9 patients underwent the modified Melbourne technique for calvarial vault remodeling during the study period. Intraoperative blood loss was 260 mL (range, 80–400 mL), and mean intraoperative transfusion was 232 mL (range, 0–360 mL). The average length of stay in the hospital was 3.9 days. The mean cephalic indices increased from 0.66 to 0.74 postoperatively (P < 0.01).

Conclusions:

A modified Melbourne method for calvarial vault reconstruction addresses the phenotypic aspects of severe scaphocephaly associated with isolated sagittal synostosis and maintains a homeotopic relationship across the calvaria. It is associated with shorter operative times, lower blood loss, and lower transfusion requirements.
Experiential Learning Enhances Physical Therapist Student Confidence in Management of Neurologically Involved Adults and Children
Authors: Barta Kristen , Flores Megan , Edwards Anna
Published: July 2018

Introduction.

Clinical experiences are an integral part of professional physical therapist (PT) education programs. Hands-on engagement helps foster the critical thinking skills necessary to successfully navigate the complexity of clinical practice during a PT student's final clinical internships. As PT students advance through an entry-level professional program, their clinical decision-making skills improve; however, they lack self-confidence in working with both adult and pediatric patients presenting with neurological impairments. The purpose of this study was to explore the effect of experiential learning using community volunteers (both adults and children) with activity and participation restrictions as a result of neurological insult or developmental delay on PT student perceived self-confidence.

Methods.

A convenience sample of 128 students currently enrolled in a PT education program were recruited. A pretest–posttest survey assessed the students' self-perceived confidence in the evaluation and treatment of a neurologically involved individual across the lifespan. The students completed 4 weeks of experiential learning with one adult and one pediatric community volunteer with a neurological condition in small groups. The four sessions included an initial evaluation, two treatment sessions and one discharge reassessment. An exploratory factor analysis was completed to validate the tool and to determine the factors that make up the survey. Qualitative data (open-ended questions) were analyzed using a grounded theory approach.

Results.

On average, students reported more self-perceived confidence in the posttest survey than in the pretest survey. This difference was significant t(127) = −13.841, P < .001.

Conclusion.

Students expressed that more exposure and increased time spent with neurologically involved adults and children could improve their confidence. This study supports the use of experiential learning in PT education programs.
Maximizing Exposure of the Internal Auditory Canal Via the Retrosigmoid Approach: An Anatomical, Radiological, and Surgical Study
Authors: Cueva Roberto A. , Chole Richard A.
Published: July 2018

Objective:

The purpose of this study was to identify anatomic landmarks and surgical techniques that maximize bone removal for exposure of the distal internal auditory canal (IAC) to avoid labyrinthine injury during retrosigmoid removal of tumors within the IAC.

Study Design:

Anatomic dissection, radiological assessment and retrospective case series.

Setting:

Tertiary referral center.

Methods:

On the basis of previously conducted temporal bone anatomic dissections of the temporal bone, the authors performed intraoperative measurement of the undissected distal IAC, performed pre- and postoperative radiological assessment of vestibular schwannoma (VS) patients. The surgical and anatomic information was used to determine the anatomic limits of labyrinth sparing bone dissection and the landmarks most critical to maximal IAC exposure. The authors describe surgical techniques using these data. An edited video of representative surgery highlights important principles. Review of 251 patients requiring IAC bony dissection for tumor removal from January 2005 through October 2017 is described.

Results:

Achieving complete exposure of the IAC fundus is not possible, without labyrinthine injury, via retrosigmoid approach. Anatomic dissection, intraoperative photography, and postoperative radiographs demonstrate that bone removal within 2 to 3 mm of the fundus is routinely possible. The endolymphatic sac and duct is the optimal landmark for optimizing IAC exposure.

Conclusion:

The course of the endolymphatic sac and duct in the posterior petrous bone is the most important landmark determining the lateral limit of bony removal during IAC exposure for tumor resection. Surgical techniques based on these anatomic findings facilitate tumor resection while preserving the labyrinth.
Validation of Posturographic Measurements in Adolescents
Authors: Christensen Ida Kolind , Deilami Seyedeh Shadi Javadian , Amiri Sahar , Nissen Monika Holm , Devantier Louise , Ovesen Therese
Published: July 2018

Objective:

The objectives of the present study were to validate the test–retest reliability of static posturography in healthy adolescents aged 13 to 16 years, to identify the most reliable and least variable measurements.

Patients:

Thirty-two healthy pupils from Skåde Skole participated in this study.

Intervention:

Static posturography.

Outcome Measures:

Subjects were tested for 32 seconds in eight trials (eyes open/eyes closed, on stable ground/foam pads, head neutral/head turned) by using a Tetrax platform. Testing included two rounds of trials and postural regulation was assessed by measuring sway during the eight trials.

Results:

We found statistically significant lower sway scores during round two in position NO; a similar trend was seen for position NC, PO, HR, HL, and HB, but was not statistically significant. For position PC and HF an increase was seen, but not statistically significant.

Conclusion:

The most reliable and least variable measurements include position NO, NC, PO, and PC. Influence of all three systems involved in maintaining balance is tested in these positions. Static posturography can easily be implemented in a clinical setting as the equipment does not take up much space and is easy to use and instruct the test subjects about. Finally, the costs related to the static posturography are considerably lower compared with dynamic posturography equipment. However, static posturography might not be challenging enough when testing athletic individuals.
A case of diencephalic syndrome presenting with isolated lipodystrophy
Authors: McDermott John H. , Harris Julie , Fédée Joanne , Skae Mars , Semple Robert , Douzgou Sofia
Published: July 2018

Diencephalic syndrome is a disorder characterized by severe emaciation during childhood. The rarity of the disorder coupled with nonspecific symptomology means that there is often a protracted diagnostic journey. Here, we report a child who was referred to a clinical genetics service for investigation of lipodystrophy and failure to thrive. A broad range of genetic differential diagnoses were considered and investigated before a mass lesion was identified in the hypothalamus, confirming diencephalic syndrome. In the context of this case, we consider the relevant differentials and appropriate workup of a child with lipodystrophy presenting to a genetics service. This report also highlights the importance of considering diencephalic syndrome in cases such as this.
Risk of Diffuse Infiltrative Lymphocytosis Syndrome in HIV-Infected Patients: A Nationwide Population-Based Cohort Study
Authors: Chen Marcelo , Yen Yung-Feng , Lan Yu-Ching , Jen I-An , Chuang Pei-Hung , Lee Chun-Yuan , Lee Yun , Lin Yu-An , Arthur Chen Yi-Ming
Published: July 2018

Objective:

Diffuse infiltrative lymphocytosis syndrome (DILS) is the term used for sicca syndrome in HIV patients and has similar clinical manifestations as Sjögren syndrome. In this nationwide population-based study, we aimed to determine the association between HIV infection and DILS in the Taiwanese population.

Methods:

The National Health Insurance Research Database was searched for cases of DILS in HIV-infected individuals diagnosed between January 1, 2000, and December 31, 2012. The incidence of DILS and the factors associated with DILS in people living with HIV/AIDS (PLWHA) were determined.

Results:

A total of 20,364 PLWHA were followed, and 57 (0.28%) individuals had new-onset DILS. The incidence rate of DILS in PLWHA was 0.56/1000 person-years. One (0.11%) female HIV patient with highly active antiretroviral therapy (HAART) and 24 (2.99%) without HAART had incident DILS, whereas 22 (0.17%) male HIV patients with HAART and 10 (0.17%) without HAART had incident DILS. Hypertension increased the risk of incident DILS. HAART decreased the risk of DILS, but this relationship somewhat attenuated in an adjusted model. None of the patients taking emtricitabine, raltegravir, darunavir, enfuvirtide, or tipranavir developed DILS. Lopinavir was associated with a decreased risk of DILS (adjusted hazard ratio = 0.10, 95% confidence interval: 0.01 to 0.84), whereas zalcitabine was associated with an increased risk of DILS (adjusted hazard ratio = 13.7, 95% confidence interval: 2.18 to 85.9).

Conclusions:

DILS is a rare disease found in PLWHA. Hypertension is a risk factor for incident DILS, and HAART could affect the pathogenesis of DILS. Zalcitabine was the only antiretroviral agent found to increase the risk of DILS.
Securing the Appendiceal Stump During Emergency Appendicectomy: Options and Influencing Factors in Current UK Surgical Practice
Authors: Wilson Michael S.J. , Knight Stephen R. , Vaughan-Shaw Peter
Published: July 2018

Introduction:

The aim of our study was to identify the most commonly employed methods and influencing factors for securing the appendiceal stump in current NHS practice.

Methods:

An electronic survey of the Scottish Surgical Research Group network, invitation extended to the UK National Research Collaborative.

Results:

A total of 111 responses were received from 32 surgical centers; 28 (25.2%) consultants, 66 (59.5%) specialty trainees and 12 (10.8%) core trainees. Endoscopic ligatures were the preferred method in 96 (86.5%) with no difference in those with the greatest operative experience (P=0.79), 12 (10.8%) preferred polymeric clips. Ease of application (70.3%) and severity of stump inflammation (65.8%) had the greatest influence on the method chosen. Cost was a factor in 36.0%.

Conclusions:

The preferred method for securing the appendiceal stump in UK practice is endoscopic ligatures regardless of operative experience. Factors with the greatest influence on the method employed include the ease of application and severity of stump inflammation. Our findings are likely to be representative of current NHS practice in Scotland.
Introduction to redundancy rules: the continuous wavelet transform comes of age
Authors: Addison Paul S.
Published: July 2018

Redundancy: it is a word heavy with connotations of lacking usefulness. I often hear that the rationale for not using the continuous wavelet transform (CWT)—even when it appears most appropriate for the problem at hand—is that it is ‘redundant’. Sometimes the conversation ends there, as if self-explanatory. However, in the context of the CWT, ‘redundant’ is not a pejorative term, it simply refers to a less compact form used to represent the information within the signal. The benefit of this new form—the CWT—is that it allows for intricate structural characteristics of the signal information to be made manifest within the transform space, where it can be more amenable to study: resolution over redundancy. Once the signal information is in CWT form, a range of powerful analysis methods can then be employed for its extraction, interpretation and/or manipulation. This theme issue is intended to provide the reader with an overview of the current state of the art of CWT analysis methods from across a wide range of numerate disciplines, including fluid dynamics, structural mechanics, geophysics, medicine, astronomy and finance.

This article is part of the theme issue ‘Redundancy rules: the continuous wavelet transform comes of age’.
A non-coding genetic variant maximally associated with serum urate levels is functionally linked to HNF4A-dependent PDZK1 expression
Authors: Ketharnathan Sarada , Leask Megan , Boocock James , Phipps-Green Amanda J. , Antony Jisha , O’Sullivan Justin M. , Merriman Tony R. , Horsfield Julia A.
Published: July 2018

Several dozen genetic variants associate with serum urate levels, but the precise molecular mechanisms by which they affect serum urate are unknown. Here we tested for functional linkage of the maximally-associated genetic variant rs1967017 at the PDZK1 locus to elevated PDZK1 expression.

We performed expression quantitative trait locus (eQTL) and likelihood analyses followed by gene expression assays. Zebrafish were used to determine the ability of rs1967017 to direct tissue-specific gene expression. Luciferase assays in HEK293 and HepG2 cells measured the effect of rs1967017 on transcription amplitude.

PAINTOR analysis revealed rs1967017 as most likely to be causal and rs1967017 was an eQTL for PDZK1 in the intestine. The region harboring rs1967017 was capable of directly driving green fluorescent protein expression in the kidney, liver and intestine of zebrafish embryos, consistent with a conserved ability to confer tissue-specific expression. The urate-increasing T-allele of rs1967017 strengthens a binding site for the transcription factor HNF4A. siRNA depletion of HNF4A reduced endogenous PDZK1 expression in HepG2 cells. Luciferase assays showed that the T-allele of rs1967017 gains enhancer activity relative to the urate-decreasing C-allele, with T-allele enhancer activity abrogated by HNF4A depletion. HNF4A physically binds the rs1967017 region, suggesting direct transcriptional regulation of PDZK1 by HNF4A.

With other reports our data predict that the urate-raising T-allele of rs1967017 enhances HNF4A binding to the PDZK1 promoter, thereby increasing PDZK1 expression. As PDZK1 is a scaffold protein for many ion channel transporters, increased expression can be predicted to increase activity of urate transporters and alter excretion of urate.
Representation Learning of Genomic Sequence Motifs with Convolutional Neural Networks
Authors: Koo Peter K. , Eddy Sean R.
Published: July 2018

Although convolutional neural networks (CNNs) have been applied to a variety of computational genomics problems, there remains a large gap in our understanding of how they build representations of regulatory genomic sequences. Here we perform systematic experiments on synthetic sequences to reveal how CNN architecture, specifically convolutional filter size and max-pooling, influences the extent that sequence motif representations are learned by first layer filters. We find that CNNs designed to foster hierarchical representation learning of sequence motifs - assembling partial features into whole features in deeper layers - tend to learn distributed representations, i.e. partial motifs. On the other hand, CNNs that are designed to limit the ability to hierarchically build sequence motif representations in deeper layers tend to learn more interpretable localist representations, i.e. whole motifs. We then validate that this representation learning principle established from synthetic sequences generalizes to in vivo sequences.
Predictors of Malaria Rapid Diagnostic Tests’ Utilisation Among Healthcare Workers in Zamfara State
Authors: Rabi Usman , Umar Ahmad A. , Gidado Saheed , Gobir A.A , Obi Izuchukwu F. , Ajayi IkeOluwapo , Ajumobi Olufemi
Published: July 2018

Introduction

Early diagnosis and prompt and effective treatment is one of the pillars of malaria control Malaria case management guidelines recommend diagnostic testing before treatment using malaria Rapid Diagnostic Test (mRDT) or microscopy and this was adopted in Nigeria in 2010. However, despite the deployment of mRDT, the use of mRDTs by health workers varies by settings. This study set out to assess factors influencing utilisation of mRDT among healthcare workers in Zamfara State, Nigeria.

Methods

A cross-sectional study was carried out among 306 healthcare workers selected using multistage sampling from six Local Government Areas between January and February 2017. Mixed method was used for data collection. A pre-tested self-administered questionnaire was used to collect information on knowledge, use of mRDT and factors influencing utilization. An observational checklist was used to assess the availability of mRDT in the six months prior to this study. Data were analyzed using descriptive statistics such as means and proportions. Association between mRDT use and independent variables was tested using Chi square while multiple regression was used to determine predictors of use at 5% level of significance.

Results

Mean age of respondents was 36.0 ± 9.4years. Overall, 198 (64.7%) of health workers had good knowledge of mRDT; malaria RDT was available in 33 (61.1%) facilities. Routine use of mRDT was reported by 253 (82.7%) healthcare workers. This comprised 89 (35.2%) laboratory scientists/technicians, 89 (35.2%) community health extension workers/community health officers; 59 (23.3%) nurses and 16 (6.3%) doctors. Predictors of mRDT utilisation were good knowledge of mRDT (adjusted OR (aOR):3.3, CI: 1.6-6.7), trust in mRDT results (aOR: 4.0, CI: 1.9 - 8.2), having being trained on mRDT (aOR: 2.7, CI: 1.2 - 6.6), and provision of free mRDT (aOR: 2.3, CI: 1.0 - 5.0).

Conclusion

This study demonstrated that healthcare worker utilisation of mRDT was associated with health worker and health system-related factors that are potentially modifiable. There is need to sustain training of healthcare workers on benefits of using mRDT and provision of free mRDT in health facilities.
Help-seeking behavior for problematic substance uses in Bahir Dar town, North-West Ethiopia
Authors: Belete Habte , Mekonen Tesfa , Fekadu Wubalem , Legas Getasew , Getnet Asmamaw
Published: July 2018

Background

Mental, neurological and substance use disorders are common, but 76% to 85% of people with those disorders in low and middle-income countries did not receive treatment.

Objective

Our objective was to assess the level of help seeking behavior and associated factors among residents with problematic substance uses (alcohol, khat, tobacco and hashish).

Methods

Community based cross sectional study was conducted in Bahir Dar town among total of 548 participants with problematic substance users. We had interviewed for help seeking behavior by pre-tested modified General Help Seeking Questionnaire. Logistic regression was done and p-value < 0.05 was used for declaration of significant level. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) have been used.

Results

Among five hundred and forty-eight participants with problematic substance users, only one hundred and sixty-eight (30.7%) sought help for their substance related problems. Participants’ age above 35 years [AOR = .47 95% CI (.25, .90)], positively screened for common mental disorders [AOR = 4.12, 95% CI (2.7, 6.3)], comorbid medical [AOR = 3.0, 95% CI (1.7, 5.3)], and grand-families’ history of substance user [AOR = 2.18, 95% CI (1.4, 3.4)] found significantly associated with help seeking.

Conclusion

There was low proportion of help seeking behavior among participants with problematic substance users. Advanced age was a barrier to seek help while medical illnesses, common mental disorders and history of substance use in grand families were found to enforce to seek help.
Identification of substrates for the conserved prolyl hydroxylase Ofd1 using quantitative proteomics in fission yeast
Authors: Gu He , Hughes Bridget T. , Espenshade Peter J.
Published: July 2018

Prolyl hydroxylation functions in diverse cellular pathways, such as collagen biogenesis, oxygen sensing, and translation termination. Prolyl hydroxylation is catalyzed by 2-oxoglutarate (2-OG) oxygenases. The fission yeast 2-OG oxygenase Ofd1 dihydroxylates the 40S ribosomal protein Rps23 and regulates the hypoxic response by controlling activity and stability of the sterol regulatory element-binding protein Sre1. Multiple substrates have been found for 2-OG oxygenases, yet the only known substrate of Ofd1 and its homologs is Rps23. Here, we report the first fission yeast prolyl hydroxylome and demonstrate that hydroxylation is more prevalent than previously known. Using quantitative mass spectrometry, we identify Rpb10, a shared subunit in RNA polymerase I, II, and III, as a novel Ofd1 substrate. In addition, we discovered six Ofd1 binding partners and 16 additional Ofd1 candidate substrates. Although Ofd1 promotes Sre1 degradation, proteomic analysis revealed that Ofd1 does not broadly regulate protein degradation. Instead, the effect of Ofd1 on the proteome is through negative regulation of Sre1N. Finally, we show that the interaction between Ofd1 and the Sre1 bHLH region is conserved across Sre1 homologs suggesting that Ofd1-dependent regulation of SREBPs may be conserved in other fungi. Collectively, these studies provide a new dataset of post-translational modifications and expand the biological functions for a conserved prolyl hydroxylase.
Filamentous calcareous alga provides a substrate for coral-competitive macroalgae in the degraded lagoon of Dongsha Atoll, Taiwan
Authors: Nieder Carolin , Chen Chaolun Allen , Liu Shao-Lun
Published: July 2018

Background

The chemically-rich seaweed Galaxaura is not only highly competitive with corals, but also provides substrate for other macroalgae. Its ecology and associated epiphytes remain largely unexplored. To fill this knowledge gap, we herein undertook an ecological assessment to explore the spatial variation, temporal dynamics, and epiphytic macroalgae of G. divaricata on patch reefs in the lagoon of Dongsha Atoll, a shallow coral reef ecosystem in the northern South China Sea, repeatedly impacted by mass coral bleaching events.

Methods

Twelve spatially independent patch reefs in the Dongsha lagoon were first surveyed to assess the benthic composition in April 2016, and then revisited to determine G. divaricata percent cover in September 2017, with one additional Galaxaura-dominated reef (site 9). Four surveys over a period of 17 months were carried out on a degraded patch reef (site 7) to assess the temporal variation in G. divaricata cover. Epiphytic macroalgae associated with G. divaricata were quantified and identified through the aid of DNA barcoding.

Results

Patch reefs in the Dongsha lagoon were degraded, exhibiting relatively low live coral cover (5-43%), but high proportions of macroalgae (13-58%) and other substrates (rubble and dead corals; 23-69%). The distribution of G. divaricata was heterogeneous across the lagoon, with highest abundance (16-41%) in the southeast area. Temporal surveys from site 7 and photo-evidence from site 9 suggested that an overgrowth by G. divaricata was still present to a similar extend after 17 months and 3.5 years. Yet, G. divaricata provides a suitable substrate some allelopathic macroalgae (e.g., Lobophora sp.).

Conclusions

Our study demonstrates that an allelopathic seaweed, such as G. divaricata, can overgrow degraded coral reefs for extended periods of time. By providing habitat for harmful macroalgae, a prolonged Galaxaura overgrowth could strengthen negative feedback loops on degraded coral reefs, further decreasing their recovery potential.
Disparate expression specificities coded by a shared Hox-C enhancer
Authors: Miller Steven W. , Posakony James W.
Published: July 2018

Can a single regulatory sequence be shared by two genes undergoing functional divergence? Here we describe a single promiscuous enhancer within theDrosophilaAntennapedia Complex, EO053, that directs aspects of the expression of two adjacent genes,pb(aHox2ortholog) andzen2(a divergentHox3paralog), with disparate spatial and temporal expression patterns. We were unable to separate thepb-like andzen2-like specificities within EO053, and we identify sequences affecting both expression patterns. Importantly, deletion of EO053 affects expression of both genes as well, despite each gene having additional enhancers. We examine sequence conservation of EO053 within the Schizophora, and show that patterns of synteny between theHox2andHox3orthologs in Arthropods are consistent with a shared regulatory relationship extending prior to theHox3/zendivergence. Thus, EO053 represents an example of two genes having evolved disparate outputs while utilizing this shared regulatory region.
A smartphone-based tool for rapid, portable, and automated wide-field retinal imaging
Authors: Kim Tyson N. , Myers Frank , Reber Clay , Loury PJ , Loumou Panagiota , Webster Doug , Echanique Chris , Li Patrick , Davila Jose R. , Maamari Robi N. , Switz Neil A. , Keenan Jeremy , Woodward Maria A. , Paulus Yannis M. , Margolis Todd , Fletcher Daniel A.
Published: July 2018

Purpose

High-quality, wide-field retinal imaging is a valuable method to screen preventable, vision-threatening diseases of the retina. Smartphone-based retinal cameras hold promise for increasing access to retinal imaging, but variable image quality and restricted field of view can limit their utility. We developed and clinically tested a smartphone-based system that addresses these challenges with automation-assisted imaging.

Methods

The system was designed to improve smartphone retinal imaging by combining automated fixation guidance, photomontage, and multi-colored illumination with optimized optics, user-tested ergonomics, and touch-screen interface. System performance was evaluated from images of ophthalmic patients taken by non-ophthalmic personnel. Two masked ophthalmologists evaluated images for abnormalities and disease severity.

Results

The system automatically generated 100-degree retinal photomontages from five overlapping images in under 1 minute at full resolution (52.3 pixels per retinal degree) fully on-phone, revealing numerous retinal abnormalities. Feasibility of the system for DR screening using the retinal photomontages was performed in 71 diabetics by masked graders. DR grade matched perfectly with dilated clinical examination in 55.1% of eyes and within 1 severity level for 85.2% of eyes. For referral-warranted DR, average sensitivity was 93.3% and specificity 56.8%.

Conclusions

Automation-assisted imaging produced high-quality, wide-field retinal images that demonstrate the potential of smartphone-based retinal cameras to be used for retinal disease screening.

Translational Relevance

Enhancement of smartphone-based retinal imaging through automation and software intelligence holds great promise for increasing the accessibility of retinal screening.
The Human Kinesin Kif18A’s Neck Linker Permits Navigation of Microtubule Bound Obstacles within the Mitotic Spindle
Authors: Malaby Heidi L. H. , Lessard Dominique V. , Berger Christopher L. , Stumpff Jason
Published: July 2018

Mitotic chromosome alignment is essential for the robust separation of genetic material into daughter cells. In mammalian cells, this process requires the function of Kif18A, a kinesin-8 motor protein. Kif18A confines chromosome movement to the mitotic spindle equator by accumulating at the plus-ends of kinetochore microtubule bundles (K-fibers), where it functions to suppress K-fiber dynamics. It is not understood how the motor accumulates at K-fiber plus-ends, a difficult feat requiring the motor to navigate protein dense microtubule tracks. Our data indicate that Kif18A’s relatively long (17 amino acid) neck linker is required for the motor’s accumulation at K-fiber plus-ends. Shorter neck linker (sNL) variants of Kif18A display a deficiency in K-fiber accumulation, especially on K-fibers near the center of the spindle. This pattern correlates with the more uniform concentration of the microtubule bundling protein HURP on central K-fibers compared to peripheral K-fibers. Depletion of HURP permits Kif18A sNL to accumulate on central K-fibers, while HURP overexpression reduces wild-type Kif18A’s ability to accumulate on this same K-fiber subset. Furthermore, single molecule assays indicate that Kif18A sNL motors are less proficient at navigating microtubules coated with the microtubule associated protein tau. Taken together, these results support a model in which Kif18A’s neck linker length permits efficient navigation of obstacles such as HURP to reach K-fiber ends during mitosis.

Signficiance Statement

Kinesin motor proteins play key roles in controlling chromosome alignment and segregation during cell division. The kinesin Kif18A confines chromosomes to the middle of the spindle by accumulating at the ends of microtubules attached to chromosomes. We show here that Kif18A’s ability to accumulate at the end of these microtubules requires navigation of microtubule-associated protein obstacles, and that this activity is imparted by a relatively long neck linker region. These findings demonstrate a molecular mechanism for navigation of densely populated microtubules inside a cell.
Cascading regime shifts within and across scales
Authors: Rocha Juan C. , Peterson Garry , Bodin Örjan , Levin Simon A.
Published: July 2018

Regime shifts are large, abrupt and persistent critical transitions in the function and structure of systems (1,2). Yet it is largely unknown how these transitions will interact, whether the occurrence of one will increase the likelihood of another, or simply correlate at distant places. Here we explore two types of cascading effects: domino effects create one-way dependencies, while hidden feedbacks produce two-way interactions; and compare them with the control case of driver sharing which can induce correlations. Using 30 regime shifts described as networks, we show that 45% of the pair-wise combinations of regime shifts present at least one plausible structural interdependence. Driver sharing is more common in aquatic systems, while hidden feedbacks are more commonly found in terrestrial and Earth systems tipping points. The likelihood of cascading effects depends on cross-scale interactions, but differs for each cascading effect type. Regime shifts should not be studied in isolation: instead, methods and data collection should account for potential teleconnections.
Elucidation of ion effects on the Thermodynamics of RNA Folding
Authors: Denesyuk Natalia A. , Thirumalai D.
Published: July 2018

How ions affect RNA folding thermodynamics and kinetics is an important but a vexing problem that remains unsolved. Experiments have shown that the free energy change, ΔG(c), of RNA upon folding varies with the salt concentration (c) as, ΔG(c) = kc ln c + const, where the coefficient kc is proportional to the difference in the uptake of ions (ion preferential coefficient), ΔΓ, between the folded and unfolded states. We performed simulations of a coarse-grained model, by modeling electrostatic interactions implicitly and with explicit representation of ions, to elucidate the molecular underpinnings of the relationship between folding free energy and ion preferential coefficient. Without any input from experiments, the simulations quantitatively reproduce the heat capacity for the −1 frame shifting pseudoknot (PK) from Beet Western Yellow Virus, thus validating the model. We show that ΔG(c) calculated directly from ΔΓ varies linearly with ln c (c < 0.2M), for a hairpin and the PK, thus demonstrating a molecular link between the two quantities for RNA molecules that undergo substantial conformational changes during folding. Explicit ion simulations also show the linear dependence of ΔG(c) on ln c at all c with kc = 2kBT, except that ΔG(c) values are shifted by about 2 kcal/mol higher than experiments at all salt concentrations. The discrepancy is due to an underestimate the Γ values for both the folded and unfolded states, while giving accurate values for ΔΓ. The predictions for the salt dependence of ΔΓ are amenable to test using single molecule pulling experiments. Our simulations, representing a significant advance in quantitatively describing ion effects in RNA, show that the framework provided here can be used to obtain accurate thermodynamics of RNA folding.
YBX2 Dysregulation in Maturation Arrest NOA YBX2 Dysregulation is a Potential Cause for Late Maturation Arrest in Men with Non-Obstructive Azoospermia
Authors: Flannigan Ryan , Mielnik Anna , Robinson Brian D. , Khani Francesca , Bolyakov Alex , Schlegel Peter N. , Paduch Darius A
Published: July 2018

Introduction

YBX2 protein binds to Y-box promotors and to mRNAs in the cytoplasm of pachytene spermatocytes and round spermatids in rodents. Knock-out of YBX2 leads to maturation arrest in animal models. YBX2 binds PRM1 and 2 mRNA, which is transcribed early and sequestrated for translation during late spermatogenesis.

Objective

This study aimed to determine if the loss of YBX2 is associated with MA arrest due to the loss of sequestration of protamines in the human testis. As a second aim, we examined the expression of YBX2, and its transcription factors in maturation arrest (MA)(early and late) and normal controls in men.

Methods

RNAseq was performed using RNA extracted from human testis samples from 44 men with non-obstructive azoospermia and ten from healthy controls. Differential expression was performed using JMPgenomics, FDR<0.001. FANTOM5 was used to predict enhancers and inhibitors of YBX2 expression. Immunofluorescence (IF) was used to stain testis tissue sections with antibodies against YBX2, SYCP3, and PRM2 in normal and MA samples. Flow cytometry was utilized to characterize YBX2 positive cells.

Results

Expression ofYBX2mRNA was significantly downregulated in early and late MA compared to controls. Surprisingly, PRM1&2 mRNAs were also depleted in men with MA. Multifactorial regression analysis demonstrated a decrease in YBX2 expression in MA is due to decrease in COMP levels (p<0.0001). IF localized YBX2 protein in spermatocytes and round spermatids among fertile men, with rare YBX2 positive spermatocytes stained in LMA. PRM1&2 proteins were absent or abnormally sequestrated within spermatocytes.

Conclusions

Decrease in YBX2 protein expression in men with LMA leads to loss of translational suppression and lack of PRM1 and PRM2 necessary to complete spermatogenesis.
Do below-ground genotypes influence above-ground microbiomes of grafted tomato plants?
Authors: Toju Hirokazu , Okayasu Koji , Notaguchi Michitaka
Published: July 2018

Bacteria and fungi form complex communities (microbiomes) in the phyllosphere and rhizosphere of plants, contributing to hosts’ growth and survival in various ways. Recent studies have suggested that host plant genotypes control, at least partly, microbial community compositions in the phyllosphere. However, we still have limited knowledge of how microbiome structures are determined in/on grafted crop plants, whose above-ground (scion) and below-ground (rootstock) genotypes are different with each other. By using eight varieties of grafted tomato plants, we examined how rootstock genotypes determine phyllosphere microbial assembly in field conditions. An Illumina sequencing analysis showed that both bacterial and fungal community structures did not significantly differ among tomato plants with different rootstock genotypes. Nonetheless, a further statistical analysis targeting respective microbial taxa suggested that some bacteria and fungi were preferentially associated with particular rootstock treatments. Specifically, a bacterium in the genus Deinococcus was found disproportionately from ungrafted tomato individuals. In addition, yeasts in the genus Hannaella were preferentially associated with the tomato individuals whose rootstock genotype was “Ganbarune”. Overall, this study suggests to what extent phyllosphere microbiome structures can be affected/unaffected by rootstock genotypes in grafted crop plants.
Glutamic acid is a carrier for hydrazine during the biosyntheses of fosfazinomycin and kinamycin
Authors: Wang Kwo-Kwang Abraham , Ng Tai L. , Wang Peng , Huang Zedu , Balskus Emily P. , van der Donk Wilfred A.
Published: July 2018

Fosfazinomycin and kinamycin are natural products that contain nitrogen-nitrogen (N-N) bonds but that are otherwise structurally unrelated. Despite their considerable structural differences, their biosynthetic gene clusters share a set of genes predicted to facilitate N-N bond formation. In this study, we show that for both compounds, one of the nitrogen atoms in the N-N bond originates from nitrous acid. Furthermore, we show that for both compounds, an acetylhydrazine biosynthetic synthon is generated first and then funneled via a glutamyl carrier into the respective biosynthetic pathways. Therefore, unlike other pathways to NN bond-containing natural products wherein the N-N bond is formed directly on a biosynthetic intermediate, during the biosyntheses of fosfazinomycin, kinamycin, and related compounds, the N-N bond is made in an independent pathway that forms a branch of a convergent route to structurally complex natural products.