bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of ankle-foot orthosis on functional mobility and dynamic balance of patients after stroke
Authors: de Paula Gabriela Vieira , da Silva Taís Regina , de Souza Juli Thomaz , Luvizutto Gustavo José , Bazan Silméia Garcia Zanati , Modolo Gabriel Pinheiro , Winckler Fernanda Cristina , de Oliveira Antunes Letícia Cláudia , Martin Luís Cuadrado , da Costa Rafael Dalle Molle , Bazan Rodrigo
Published: September 2019

Introduction:

Stroke is the principal cause of impairment in the motor function and gait of adults. One of the resources used in rehabilitation to optimize gait is a prescription of ankle-foot orthosis (AFO), and the most prescribed AFOs are Fixed AFO and Articulated AFO; however, it is not known which of these options is more effective for these individuals. The aim of this study is to evaluate the impact of different types of ankle-foot orthosis functional mobility and dynamic balance in stroke patients.

Methods:

Prospective randomized controlled clinical trial with 2 parallel groups will be conducted, and the aim is to recruit 50 patients with stroke diagnosis within 1 year, who indicated that they use both types of orthotics, who had a previous Rankin score less than or equal to 3, and who obtained AFO orthosis through the Hospital Clinics at the Botucatu Medical School (HCBMS) São Paulo, Brazil. After a specific evaluation by a physiotherapist, the patient will receive 1 of the AFO types via randomization. After 30 days, the patient will be reevaluated. The primary outcomes will be balance and mobility, which will be evaluated by the Time Up Go Test (TUG) and Tinetti's Scale of Mobility and Balance (TSMB). The secondary outcomes will be quality of life and the levels of anxiety and depression, which will be evaluated with the European (5D) Quality of Life Scale (Euroqol) and Hospital Anxiety and Depression Scale (HADS). Group allocation will be not concealed because the blinding of participants and of therapists that provide intervention is not possible, and all analyses will be based on an intention-to-treat principle. This study was approved by the Human Research Ethics Committee of the São Paulo State University UNESP, number 2.367.953. The results will be published in relevant journal.

Discussion:

The results of this study will contribute to clinical practice by identifying the type of AFO orthosis that is more suitable for this condition, helping to standardize prescription of these orthoses by professionals, and guiding future research studies on this subject, which is still incompletely defined in the literature.

Trial registration:

RBR-6SF2VV (March 5, 2018).
Adjuvant laser meridian massage in men with opioid use disorder on methadone maintenance treatment
Authors: Hu Wen-Long , Tsai Meng-Chang , Kuo Chun-En , Liu Chun-Ting , Wu Szu-Ying , Wu Tzu-Chan , Hung Yu-Chiang
Published: September 2019

Background:

Heroin addiction remains a significant public health problem worldwide, and relapse to heroin use following cessation of agonist maintenance treatment is common. The problems associated with use of opioid agonists mean that non-opioid therapies need to be developed to ameliorate acute and protracted opioid withdrawal syndromes.

Methods:

Fifteen men with opioid use disorder on methadone maintenance treatment have been enrolled from an addiction treatment center as an experimental group in this case-controlled study. This group is receiving laser meridian massage on the back, including the Bladder meridian and Governor Vessel, 3 times weekly for 4 weeks. An age-matched control group that does not receive laser meridian massage has also been enrolled. Urinary morphine levels are being checked before and after 2 and 4 weeks of treatment. Subjects are requested to self-report their number of episodes or days of heroin use and 0 to 10-point visual analogue scale scores for heroin craving/refusal to use heroin during the previous week before and after 2 and 4 weeks of treatment. Quality of life will be reported using the Short Form-12v2 before and after 4 weeks of treatment. Pulse diagnosis will be recorded and heart rate variability calculated after one single treatment session. The baseline patient characteristics will be compared between the experimental and control groups using the independent t test and Chi-square test. Data are compared between the 2 groups using repeated-measures analysis of variance, generalized estimating equations, and the paired t test.

Objective:

To investigate the effect of adjuvant laser meridian massage in men with opioid use disorder on methadone maintenance treatment.

Trial registration:

ClinicalTrials.gov NCT04003077.
Evaluation of abches and volumetric modulated arc therapy under deep inspiration breath-hold technique for patients with left-sided breast cancer
Authors: Yeh Tien-Chi , Chi Mau-Shin , Chi Kwan-Hwa , Hsu Chung-Hsien
Published: September 2019

Radiotherapy after breast-conserving surgery or mastectomy has clinical benefits including reducing local recurrence and improving overall survival. Deep inspiration breath-hold (DIBH) technique using the Abches system is an easy and practical method to reduce radiation dose to the heart and lungs. This retrospective study was proposed to investigate the dosimetric difference between Abches system and free breathing technique in treating left-sided breast cancer.

Eligible patients underwent computed tomography (CT) scans to acquire both free breathing (FB) and DIBH technique data using the Abches. For each patient, both FB and DIBH image sets were planned based on the volumetric modulated arc therapy (VMAT). Radiation dose to the heart, ipsilateral lung, and contralateral lung was compared between the Abches system and FB.

No significant differences in the planning target volume (PTV) (674.58 vs 665.88 cm3, P = .29), mean dose (52.28 vs 52.03 Gy, P = .13), and volume received at the prescribed dose (Vpd) (94.66% vs 93.92%, P = .32) of PTV were observed between the FB and DIBH plans. Significant differences were found in mean heart (6.71 Gy vs 4.21 Gy, P < .001), heart V5 (22.73% vs 14.39%, P = .002), heart V20 (10.96% vs. 5.62%, P < .001), mean left lung (11.51 vs 10.07 Gy, P = .01), left lung V20 (22.88% vs 19.53%, P = .02), left lung V30 (18.58 vs 15.27%, P = .005), and mean right lung dose (.89 vs 72 Gy, P = .03).

This is the first report on reduced mean left lung, mean right lung dose, and V20 of left lung using VMAT and Abches. The combination of Abches and VMAT can practically and efficiently reduce extraradiation doses to the heart and lungs.
Klebsiella pneumoniae-induced multiple invasive abscesses
Authors: Wang Bin , Zhang Peng , Li Yuxiang , Wang Yang
Published: September 2019

Rationale:

Klebsiella pneumoniae infection can induce multiple invasive abscesses, and the invasive infection is severe and life-threatening.

Patient concerns:

A 69-year-old previously healthy Chinese male presented with fever, chill, backache, and ocular pain.

Diagnosis:

The blood culture results indicated Klebsiella pneumoniae of the K1 serotype. Multiple invasive abscesses in liver, lung, eye, soft tissue, and central nervous system were identified by imaging examination. Subsequently, the patient experienced right ocular pain accompanied by visual disturbance. Tyndall sign was strongly positive, and lens opacity was observed by the ophthalmologist.

Interventions:

Full-dose and long-term treatment with meropenem was performed. Intraventricular injection of glass and anterior chamber puncture with antibiotics were performed twice. The patient also underwent an evacuation of the brain abscess.

Outcomes:

The patient's headache and lumbar backache were relieved, his ophthalmodynia disappeared, and his vision recovered after nearly 3 months of treatment.

Lessons:

Imaging examination is very important for severe Klebsiella pneumoniae infection. The choice of antibiotics is complex, and the antimicrobial regimen should be adjusted according to the assessment of illness and the therapeutic effect. Surgical intervention must be considered for patients with multiple invasive abscesses.
Clinicopathological characteristics of Epstein-Barr virus-positive gastric cancer in Latvia
Authors: Gasenko Evita , Isajevs Sergejs , Camargo Maria Constanza , Offerhaus George Johan A. , Polaka Inese , Gulley Margaret L. , Skapars Roberts , Sivins Armands , Kojalo Ilona , Kirsners Arnis , Santare Daiga , Pavlova Jelizaveta , Sjomina Olga , Liepina Elina , Tzivian Liliana , Rabkin Charles S. , Leja Marcis
Published: September 2019

Objective

Epstein-Barr virus (EBV)-associated gastric cancer has been proposed to be a distinct gastric cancer molecular subtype. The prognostic significance of EBV infection in gastric cancer remains unclear and needs further investigation. Our study aimed to analyze EBV-positive and EBV-negative gastric cancer patients regarding their personal and tumor-related characteristics, and compare their overall survival.

Methods

Gastric cancer patients consecutively treated at the Riga East University Hospital during 2009–2016 were identified retrospectively. Tumor EBV status was determined by in-situ hybridization for EBV-encoded RNA (EBER). Information about clinicopathological characteristics was obtained from patient questionnaires, hospital records. Overall survival was ascertained through 30 July 2017. Cox proportional hazard regression models adjusted for personal and tumor-related covariates compared survival between EBV-positive and EBV-negative patients.

Results

There were a total of 302 gastric cancer patients (61% males) with mean and SD age 63.6 ± 11.5 years. EBER positivity was present in 8.6% of tumors. EBV-positive gastric cancer patients had better survival at 80 months [adjusted hazard ratio = 0.37, 95% confidence interval (CI) = 0.19–0.72] compared to EBV-negative patients. Worse survival was observed for patients with stage III (hazard ratio = 2.76, 95% CI = 1.67–4.56) and stage IV (hazard ratio = 10.02, 95% CI = 5.72–17.57) compared to stage I gastric cancer, and overlapping and unspecified subsite (hazard ratio = 1.85; 95% CI = 1.14; 3.00) compared to distal tumors.

Conclusion

Tumor EBV positivity is a favorable prognostic factor in gastric cancer.
Expression of SMAD4 is Retained in Most Gynecologic Tumors with Mucinous Differentiation
Authors: Alghamdi Sarah , Alghaashamy Khaled , Pinto Andre
Published: September 2019

SMAD4 is a tumor suppressor gene that plays a role in cancer initiation and progression. A few studies have explored the value of immunohistochemistry for SMAD4 in gynecologic neoplasms, mainly in the ovary. However, literature is sparse when it comes to other sites such as endometrium and cervix, as well as in benign and borderline ovarian mucinous neoplasms. The aim of this study was to assess the expression of SMAD4 in various gynecologic tumors. We selected primary gynecologic tumors comprising a spectrum of neoplasms showing mucinous differentiation. Few cases of metastatic tumors were also included. A total of 103 cases were retrieved, including tumors of ovarian origin (13 mucinous adenocarcinomas, 9 mucinous borderline tumors, 19 mucinous cystadenomas, and 3 mucinous tumors arising from teratomas), 36 of endometrial origin (23 endometrioid adenocarcinomas with mucinous differentiation and 13 mucinous adenocarcinomas), 17 cases of cervical carcinoma (16 of usual type and 1 of gastric type), and 6 metastatic adenocarcinomas to ovary. SMAD4 immunohistochemistry was retained in most primary tumors, except in 3 endocervical adenocarcinomas (2 usual-type, 1 gastric-type) and in one mucinous carcinoma arising from an ovarian teratoma. Of the 6 metastatic cases, 4 showed SMAD4 loss. In summary, retained expression of SMAD4 was seen in 95.8% of primary gynecologic neoplasms. These results can be of utility when dealing with mucinous lesions for which metastatic origin is suspected. Loss of SMAD4 expression virtually excludes primary tumors of endometrial or ovarian origin, but is of less utility when evaluating carcinomas involving the cervix.
Dietary Patterns Vary by Depressive Symptom Severity in Youth With Depressive Disorders
Authors: Perez Leanna F. , Gracious Barbara L. , Miller Carla K.
Published: September 2019

The aim of the study was to characterize dietary patterns by depressive symptom severity in adolescents. Youth aged 13 to 17 years clinically diagnosed with a depressive disorder (n = 30) completed a dietary interview, food frequency questionnaire, and phlebotomy. Rating scales and questionnaires assessed depression severity and comorbid behavioral disorders. Results found that habitual eating patterns varied among participant subgroups by depression severity. In-school versus summer break status further affected eating patterns within subgroups. Results support the need for dietary assessment and monitoring of youth who are depressed. Future clinical interventions should be conducted to determine whether dietary changes could improve nutritional status and psychological outcomes in youth with depression.
The Effect of Zumba Training on Body Composition, Dietary Intake, Sleep Quality, and Duration in Adult Sedentary Women With Overweight
Authors: Muhammad Harry Freitag Luglio , Safika Erri Larene , Wahyuni Fani Cahya , Ermamilia Aviria , Huriyati Emy
Published: September 2019

This study aimed to explore the effect of Zumba training on body composition and its compensatory effect on dietary intake and sleep in sedentary overweight women. This was an experimental study with crossover design conducted in 34 subjects. We showed that Zumba training was associated with the reduction of body fat (P = .023) but not body weight (P = .783). This training was also associated with increased fat intake (P = .004) and sleep duration (P = .043). After compiling the effect of dietary intake, physical activity, and sleep, we found that fat intake during Zumba training was an important determinant of weight changes.
A Quantitative and Narrative Evaluation of Goodman and Gilman’s Pharmacological Basis of Therapeutics
Authors: Piper Brian J. , Alinea Alexandria A. , Wroblewski John R , Graham Sara M. , Chung Daniel Y. , McCutcheon Livia R.M. , Birkett Melissa A , Kheloussi Steven S. , Shah Vicky M. , Zalim Qais K. , Arnott John A. , McLaughlin William A. , Lucchessi Pamela A. , Miller Kimberly A. , Waite Gabi N. , Bordonaro Michael
Published: September 2019

Objective

Goodman and Gilman’s The Pharmacological Basis of Therapeutics (GGPBT) has been a cornerstone in the education of pharmacists, physicians, and pharmacologists for decades. The objectives of this report were to describe and evaluate the 13th edition of GGPBT including: 1) author characteristics; 2) recency of citations; 3) conflict of interest (CoI) disclosure, and 4) expert evaluation of chapters.

Methods

Contributors’ (N = 115) sex, professional degrees, and presence of undisclosed potential CoI as reported by the Center for Medicare and Medicaid’s Open Payments (2013 to 2017) were examined. Year of publication of citations were extracted relative to comparison textbooks (Katzung’s Basic and Clinical Pharmacology (KatBCP), and DiPiro’s Pharmacotherapy: A Pathophysiologic Approach (DiPPAPA). Content experts in pharmacy and pharmacology education provided chapter reviews.

Results

The percent of GGPBT contributors that were female (20.9%) was equivalent to those in KatBCP (17.0%). Citations in GGPBT (11.5 ± 0.2 years) were significantly older than those in KatBCP (10.4 ± 0.2) and DiPPAPA (9.1 ± 0.1, p < .0001). Contributors to GGPBT received three million in undisclosed remuneration from pharmaceutical companies (Maximum author = $743,718). In contrast, DiPPAPA made CoI information available. However, self-reported disclosures were not uniformly congruent with Open Payments reported data. Reviewers noted several strengths but also some areas for improvement.

Conclusion

GGPBT will continue to be an important component of the biomedical curriculum. Areas of improvement include more diverse authorship, improved conflict of interest transparency, and greater inclusion of more recent citations.
Subacute effects of the psychedelic ayahuasca on the salience and default mode networks
Authors: Pasquini Lorenzo , Palhano-Fontes Fernanda , Araujo Draulio B.
Published: September 2019

Background

Neuroimaging studies have just begun to explore the acute effects of psychedelics on large-scale brain networks’ functional organization. Even less is known on the neural correlates of subacute effects taking place days after the psychedelic experience. This study explores the subacute changes of primary sensory brain networks and networks supporting higher-order affective and self-referential functions 24h after a single session with the psychedelic ayahuasca.

Methods

We leveraged task-free functional magnetic resonance imaging data one day before and one day after a randomized placebo-controlled trial exploring the effects of ayahuasca in naïve healthy participants (21 placebo/22 ayahuasca). We derived intra- and inter-network functional connectivity of the salience, default mode, visual, and sensorimotor networks, and assessed post-session connectivity changes between the ayahuasca and placebo groups. Connectivity changes were associated with Hallucinogen Rating Scale scores assessed during the acute effects.

Results

Our findings revealed increased anterior cingulate cortex connectivity within the salience network, decreased posterior cingulate cortex connectivity within the default mode network, and increased connectivity between the salience and default mode networks one day after the session in the ayahuasca group compared to placebo. Connectivity of primary sensory networks did not differ between-groups. Salience network connectivity increases correlated with altered somesthesia scores, decreased default mode network connectivity correlated with altered volition scores, and increased salience-default mode network connectivity correlated with altered affect scores.

Conclusion

These findings provide preliminary evidence for subacute functional changes induced by the psychedelic ayahuasca on higher-order cognitive brain networks that support interoceptive, affective, and self-referential functions.
First Complete Genome Sequence of the Novel Lineage G-IX (BD-18) of FMDV Serotype Asia1
Authors: Rubayet Ul Alam A. S. M. , Rahmat Ali M. , Amin Md. Al , Siddique Mohammad Anwar , Sultana Munawar , Hossain M. Anwar
Published: September 2019

Foot-and-Mouth Disease (FMD) has been a major threat to livestock worldwide, and is caused by FMD Virus (FMDV) existing as seven serotypes (A, O, C, Asia1 and SAT 1-3), each having variability into topotypes, genetic lineages, sublineages, and strains. Three serotypes are circulating in Indian subcontinent with the widespread distribution of serotype O, whereas serotype A and Asia1 are restricted to certain geographical regions. During 2017-2018, the Sindh-08 lineages of Asia1 serotype was reported from Pakistan, however, in 2018, a novel circulatory foot-and-mouth disease virus serotype Asia1 BD-18 (G-IX) lineage containing a unique mutation has emerged in Bangladesh. The first complete genome of the Asia1/ASIA/G-IX novel lineage strain, isolated from Bangladesh, is reported here. Amino acid substitutions at critical antigenic sites of capsid were identified compared to genome of existing vaccine strain (IND/63/72), and contemporary FMDV serotype A isolate of Bangladesh.
Tximeta: reference sequence checksums for provenance identification in RNA-seq
Authors: Love Michael I. , Soneson Charlotte , Hickey Peter F. , Johnson Lisa K. , Pierce N. Tessa , Shepherd Lori , Morgan Martin , Patro Rob
Published: September 2019

Correct annotation metadata is critical for reproducible and accurate RNA-seq analysis. When files are shared publicly or among collaborators with incorrect or missing annotation metadata, it becomes difficult or impossible to reproduce bioinformatic analyses from raw data. It also makes it more difficult to locate the transcriptomic features, such as transcripts or genes, in their proper genomic context, which is necessary for overlapping expression data with other datasets. We provide a solution in the form of an R/Bioconductor package tximeta that performs numerous annotation and metadata gathering tasks automatically on behalf of users during the import of transcript quantification files. The correct reference transcriptome is identified via a hashed checksum stored in the quantification output, and key transcript databases are downloaded and cached locally. The computational paradigm of automatically adding annotation metadata based on reference sequence checksums can greatly facilitate genomic workflows, by helping to reduce overhead during bioinformatic analyses, preventing costly bioinformatic mistakes, and promoting computational reproducibility. The tximeta package is available athttps://bioconductor.org/packages/tximeta.
UVB mutagenesis differs in NRAS- and BRAF-mutant mouse models of melanoma
Authors: Bowman Robert L. , Hennessey Rebecca C. , Tallman David A. , Weiss Tirzah J. , Crawford Emma R. , Murphy Brandon M. , Webb Amy , Zhang Souhui , La Perle Krista M. D. , Burd Craig J. , Levine Ross L. , Shain A. Hunter , Burd Christin E.
Published: September 2019

BRAF-mutant melanomas are more likely than NRAS-mutant melanomas to arise in anatomical locations protected from chronic sun damage. We hypothesized that this discrepancy in tumor location is a consequence of the differential sensitivity of BRAF and NRAS-mutant melanocytes to ultraviolet light (UV)-mediated carcinogenesis. We tested this hypothesis by comparing the mutagenic consequences of a single, narrow band ultraviolet-A (UVA; 320-400nm) or ultraviolet-B (UVB; 280-320nm) exposure in mouse models predisposed to Braf- or Nras-mutant melanoma. Exposures approximated the amount of UVA or UVB energy contained in ~40 minutes of summer sunlight. Tumor onset was accelerated in all UVB-, but only half of UVA- irradiated mice as compared to unirradiated controls. Melanomas from both mouse models, harbored recurrent mutations affecting the RING domain of MAP3K1 and Actin-binding domain of Filamin A irrespective of UV status. Melanomas from UVB-irradiated, Braf-mutant mice averaged twice as many SNVs (1,025 vs. 435) and five times as many dipyrimidine variants (33.3 vs. 5.7) than tumors from similarly irradiated Nras-mutant mice. We identified a mutational signature enriched in UVB-accelerated tumors which mirrored COSMIC signatures associated with human skin cancer. Notably, this signature was enriched to a greater extent in Braf- than Nras-mutant murine melanomas. These data suggest that oncogenic BRAF may enhance UVB carcinogenesis to promote melanoma formation at anatomic sites with low or intermittent sun exposure.
Structural insights into the mammalian late-stage initiation complexes
Authors: Simonetti Angelita , Guca Ewelina , Bochler Anthony , Kuhn Lauriane , Hashem Yaser
Published: September 2019

In higher eukaryotes, the mRNA sequence in direct vicinity of the start codon, called the Kozak sequence (CRCCaugG, where R is a purine), is known to influence the rate of the initiation process. However, the molecular basis underlying its role remains poorly understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of mammalian late-stage 48S initiation complexes (LS48S IC) in the presence of two different native mRNA sequences, β-globin and histone 4 (H4) at overall resolution of 3Å and 3.5Å, respectively. Our high-resolution structures unravel key interactions from the mRNA to eukaryotic initiation factors (eIF): 1A, 2, 3, 18S rRNA, and several 40S ribosomal proteins. In addition, we were able to study the structural role of ABCE1 in the formation of native 48S ICs. Our results reveal a comprehensive map of the ribosome/eIFs –mRNA and –tRNA interactions and suggest the impact of mRNA sequence on the structure of the LS48S IC.
Aging, computation, and the evolution of neural regeneration processes
Authors: Ollé-Vila Aina , Seoane Luís F , Solé Ricard
Published: September 2019

Metazoans gather information from their environments and respond in predictable ways. These computational tasks are achieved with neural networks of varying complexity. Their performance must be reliable over an individual’s lifetime while dealing with the shorter lifespan of cells and connection failure – thus rendering aging a relevant feature. How do computations degrade over an organism’s lifespan? How reliable can they remain throughout? We tackle these questions with a multiobjective optimization approach. We demand that digital organisms equipped with neural networks solve a computational task reliably over an extended lifespan. Neural connections are costly (as an associated metabolism in living beings). They also degrade over time, but can be regenerated at some expense. We investigate the simultaneous minimization of both these costs and the computational error. Pareto optimal tradeoffs emerge with designs displaying a broad range of solutions: from small networks with high regeneration rate, to large, redundant circuits that regenerate slowly. The organism’s lifespan and the external damage act as evolutionary pressures. They improve the exploration of the space of solutions and impose tighter optimality constraints. Large damage rates can also constrain the space of possibilities, forcing the commitment of organisms to unique strategies for neural systems maintenance.
Gene duplications trace mitochondria to the onset of eukaryote complexity
Authors: Tria Fernando D. K. , Brückner Julia , Skejo Josip , Xavier Joana C. , Zimorski Verena , Gould Sven B. , Garg Sriram G. , Martin William F.
Published: September 2019

The last eukaryote common ancestor (LECA) lived 1.6 billion years ago1,2. It possessed nuclei, sex, an endomembrane system, mitochondria, and all key traits that make eukaryotic cells more complex than their prokaryotic ancestors2–6. The closest known relatives of the host lineage that acquired the mitochondrion are, however, small obligately symbiotic archaea that lack any semblance of eukaryotic cell complexity7. Although the steep evolutionary grade separating prokaryotes from eukaryotes increasingly implicates mitochondrial symbiosis at eukaryote origin4,7, the timing and evolutionary significance of mitochondrial origin remains debated. Gradualist theories contend that eukaryotes arose from archaea by slow accumulation of eukaryotic traits8–10 with mitochondria arriving late11, while symbiotic theories have it that mitochondria initiated the onset of eukaryote complexity in a non-nucleated archaeal host7 by gene transfers from the organelle4,12–14. The evolutionary process leading to LECA should be recorded in its gene duplications. Among 163,545 duplications in 24,571 gene trees spanning 150 sequenced eukaryotic genomes we identified 713 gene duplication events that occurred in LECA. LECA’s bacterially derived genes were duplicated more frequently than archaeal derived or eukaryote specific genes, reflecting the serial copying15,16 of genes from the mitochondrial endosymbiont to the archaeal host’s chromosomes prior to the onset of eukaryote genome complexity. Bacterial derived genes for mitochondrial functions, lipid synthesis, biosynthesis, as well as core carbon and energy metabolism in LECA were duplicated more often than archaeal derived genes and even more often than eukaryote-specific inventions for endomembrane, cytoskeletal or cell cycle functions. Gene duplications record the sequence of events at LECA’s origin and indicate that recurrent gene transfer from a resident mitochondrial endosymbiont preceded the onset of eukaryotic cellular complexity.
Massive gene presence/absence variation in the mussel genome as an adaptive strategy: first evidence of a pan-genome in Metazoa
Authors: Gerdol Marco , Moreira Rebeca , Cruz Fernando , Gómez-Garrido Jessica , Vlasova Anna , Rosani Umberto , Venier Paola , Naranjo-Ortiz Miguel A. , Murgarella Maria , Balseiro Pablo , Corvelo André , Frias Leonor , Gut Marta , Gabaldón Toni , Pallavicini Alberto , Canchaya Carlos , Novoa Beatriz , Alioto Tyler S. , Posada David , Figueras Antonio
Published: September 2019

Mussels are ecologically and economically relevant edible marine bivalves, highly invasive and resilient to biotic and abiotic stressors causing recurrent massive mortalities in other species. Here we show that the Mediterranean mussel Mytilus galloprovincialis has a complex pan-genomic architecture, which includes a core set of 45,000 genes shared by all individuals plus a surprisingly high number of dispensable genes (∼15,000). The latter are subject to presence/absence variation (PAV), i.e., they may be entirely missing in a given individual and, when present, they are frequently found as a single copy. The enrichment of dispensable genes in survival functions suggests an adaptive value for PAV, which might be the key to explain the extraordinary capabilities of adaptation and invasiveness of this species. Our study underpins a unique metazoan pan-genome architecture only previously described in prokaryotes and in a few non-metazoan eukaryotes, but that might also characterize other marine invertebrates.

Significance statement

In animals, intraspecific genomic diversity is generally thought to derive from relatively small-scale variants, such as single nucleotide polymorphisms, small indels, duplications, inversions and translocations. On the other hand, large-scale structural variations which involve the loss of genomic regions encoding protein-coding genes in some individuals (i.e. presence/absence variation, PAV) have been so far only described in bacteria and, occasionally, in plants and fungi. Here we report the first evidence of a pan-genome in the animal kingdom, revealing that 25% of the genes of the Mediterranean mussel are subject to PAV. We show that this unique feature might have an adaptive value, due to the involvement of dispensable genes in functions related with defense and survival.
Mechanism underlying starvation-dependent modulation of olfactory behavior in Drosophila larva
Authors: Slankster Eryn , Kollala Sai , Baria Dominique , Dailey-Krempel Brianna , Jain Roshni , Odell Seth R. , Mathew Dennis
Published: September 2019

Starvation enhances olfactory sensitivity that encourage animals to search for food. The molecular mechanisms that enable sensory neurons to remain flexible and adapt to a particular internal state remain poorly understood. Here, we study the roles of GABA and insulin signaling in starvation-dependent modulation of olfactory sensory neuron (OSN) function in the Drosophila larva. We show that GABAB-receptor and insulin-receptor are necessary for OSN modulation. Using a novel OSN-specific gene expression analysis, we explore downstream targets of insulin signaling in OSNs. Our results strongly suggest that insulin and GABA signaling pathways interact within OSNs and modulate OSN function by impacting olfactory information processing and neurotransmission. We further show that manipulating these signaling pathways specifically in the OSNs impact larval feeding behavior and its body weight. These results challenge the prevailing model of OSN modulation and highlight opportunities to better understand OSN modulation mechanisms and their relationship to animal physiology.
A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis
Authors: Mohanty Atish , Nam Arin , Pozhitkov Alex , Bhattacharya Supriyo , Yang Lu , Nathan Anusha , Wu Xiwei , Srivastava Saumya , Mambetsariev Isa , Nelson Michael , Pangeni Rajendra , Raz Dan , Chen Yihong , He Yanan , Orban John , Subbalakshmi A. R. , Guo Linlin , Nasser Mohd W. , Koczywas Marianna , Batra Surinder K. , Jolly Mohit Kumar , Kulkarni Prakash , Massarelli Erminia , Salgia Ravi
Published: September 2019

Tumor heterogeneity and cisplatin resistance are a major cause of tumor relapse and poor survival. Here we show that in lung adenocarcinoma (LUAD), paxillin (PXN) and integrin beta 4 (ITGB4) are associated with tumor progression, and cisplatin resistance. Silencing PXN and ITGB4 render cisplatin tolerant cells sensitive, and immunologically neutralizing ITGB4 improves sensitivity. The N-terminal half of PXN is intrinsically disordered and interacts with ITGB4 to regulate expression of USP1 and VDAC1 which are required for maintaining genomic stability and mitochondrial function in LUAD. By virtual screening an FDA-approved compound library, we identified compounds that interact with PXNin silicoand attenuate cisplatin resistance in LUAD cells. RNAseq analysis identified a double negative feedback loop between ITGB4 and microRNA miR-1-3p, suggesting that bistability could lead to stochastic switching between cisplatin-sensitive and resistant states in these cells. The data highlight an alternate, non-genetic, mechanism underlying chemoresistance in lung cancer.
H3K9me2 protects lifespan against the transgenerational burden of germline transcription in C. elegans
Authors: Lee Teresa W. , David Heidi S. , Engstrom Amanda K. , Carpenter Brandon S. , Katz David J.
Published: September 2019

During active transcription, the COMPASS complex methylates histone H3 at lysine 4 (H3K4me). In Caenorhabditis elegans, mutations in COMPASS subunits, including WDR-5, extend lifespan and enable the inheritance of increased lifespan in wild-type descendants. Here we show that the increased lifespan of wdr-5 mutants is itself a transgenerational trait that manifests after eighteen generations and correlates with changes in the heterochromatin factor H3K9me2. Additionally, we find that wdr-5 mutant longevity and its inheritance requires the H3K9me2 methyltransferase MET-2 and can be recapitulated by a mutation in the putative H3K9me2 demethylase JHDM-1. These data suggest that lifespan is constrained by reduced H3K9me2 due to transcription-coupled H3K4me. wdr-5 mutants alleviate this burden, extending lifespan and enabling the inheritance of increased lifespan. Thus, H3K9me2 functions in the epigenetic establishment and inheritance of a complex trait. Based on this model, we propose that lifespan is limited by the germline in part because germline transcription reduces heterochromatin.
Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway
Authors: Zonderland Jip , Rezzola Silvia , Moroni Lorenzo
Published: September 2019

Controlling basic fibroblast growth factor (bFGF) signaling is important for both tissue-engineering purposes, controlling proliferation and differentiation potential, and for cancer biology, influencing tumor progression and metastasis. Here, we observed that human mesenchymal stromal cells (hMSCs) no longer responded to soluble or covalently bound bFGF when cultured on microfibrillar substrates, while fibroblasts did. This correlated with a downregulation of FGF receptor 1 (FGFR1) expression of hMSCs on microfibrillar substrates, compared to hMSCs on conventional tissue culture plastic (TCP). hMSCs also expressed less SRF on ESP scaffolds, compared to TCP, while fibroblasts maintained high FGFR1 and SRF expression. Inhibition of actin-myosin tension or the MRTF/SRF pathway decreased FGFR1 expression in hMSCs, fibroblasts and MG63 osteosarcoma cells. This downregulation was functional, as hMSCs became irresponsive to bFGF in the presence of MRTF/SRF inhibitor. Together, our data show that hMSCs, but not fibroblasts, are irresponsive to bFGF when cultured on microfibrillar susbtrates by downregulation of FGFR1 through the MRTF/SRF pathway. This is the first time FGFR1 expression has been shown to be mechanosensitive and adds to the sparse literature on FGFR1 regulation. These results could open up new targets for cancer treatments and could aid designing tissue engineering constructs that better control cell proliferation.
Learning with naturalistic odor representations in a dynamic model of the Drosophila olfactory system
Authors: Kennedy Ann
Published: September 2019

Many odor receptors in the insect olfactory system are broadly tuned, yet insects can form associative memories that are odor-specific. The key site of associative olfactory learning in insects, the mushroom body, contains a population of Kenyon Cells (KCs) that form sparse representations of odor identity and enable associative learning of odors by mushroom body output neurons (MBONs). This architecture is well suited to odor-specific associative learning if KC responses to odors are uncorrelated with each other, however it is unclear whether this hold for actual KC representations of natural odors. We introduce a dynamic model of the Drosophila olfactory system that predicts the responses of KCs to a panel of 110 natural and monomolecular odors, and examine the generalization properties of associative learning in model MBONs. While model KC representations of odors are often quite correlated, we identify mechanisms by which odor-specific associative learning is still possible.
Assessment of enzyme active site positioning and tests of catalytic mechanisms through X-ray-derived conformational ensembles
Authors: Yabukarski Filip , Biel Justin T , Pinney Margaux M , Doukov Tzanko , Powers Alexander S , Fraser James S , Herschlag Daniel
Published: September 2019

How enzymes achieve their enormous rate enhancements remains a central question in biology, and our understanding to date has impacted drug development, influenced enzyme design, and deepened our appreciation of evolutionary processes. While enzymes position catalytic and reactant groups in active sites, physics requires that atoms undergo constant motion. Numerous proposals have invoked positioning or motions as central for enzyme function, but a scarcity of experimental data has limited our understanding of positioning and motion, their relative importance, and their changes through the enzyme’s reaction cycle. To examine positioning and motions and test catalytic proposals, we collected “room temperature” X-ray crystallography data forP. putidaketosteroid isomerase (KSI), and we obtained conformational ensembles for this and a homologous KSI from multiple PDB crystal structures. Ensemble analyses indicated limited change through KSI’s reaction cycle. Active site positioning was on the 1-1.5 Å scale, and was not exceptional compared to non-catalytic groups. The KSI ensembles provided evidence against catalytic proposals invoking oxyanion hole geometric discrimination between the ground state and transition state or highly precise general base positioning. Instead, increasingordecreasing positioning of KSI’s general base reduced catalysis, suggesting optimized Ångstrom-scale conformational heterogeneity that allows KSI to efficiently catalyze multiple reaction steps. Ensemble analyses of surrounding groups for WT and mutant KSIs provided insights into the forces and interactions that allow and limit active site motions. Most generally, this ensemble perspective extends traditional structure–function relationships, providing the basis for a new era of “ensemble–function” interrogation of enzymes.
A pentylenetetrazole-induced kindling zebrafish larval model for evoked recurrent seizures
Authors: Sun Sha , Zhu Chenyanwen , Ma Manxiu , Ni Bing , Chen Lin , Zhu Hongwei , Zuxiang Liu
Published: September 2019

Background

Transient pentylenetetrazol (PTZ) treatment on zebrafish larvae has been widely accepted a promising animal model for human epilepsy. However, this model is not ideal due to its acuteness and lack of recurrent seizures, which are the key feature of epilepsy in human disease. It is important to develop a more sensitive zebrafish model for epilepsy with well-controlled, predictable, recurrent seizures.

New Method

The new method includes an experimental setup and a treatment protocol. The setup tracks the locomotion activity of up to 48 larvae simultaneously, while a visual stimulus can be presented to each of the 48 animals individually. The protocol treated the larvae through a water bath in 5 mM PTZ while being stimulated with rotating grating stimuli for 1 hour/day from 5 to 7 days postfertilization.

Results

The setup captured the locomotion activity of zebrafish larvae during visual stimulation. The new protocol generated recurrent responses after flashing lights 4 hours post PTZ treatment. The effects could be suppressed by the anti-epileptic drug valproic acid. The characteristics of the visual stimulus play a major role in this kindling model.

Comparisons with Existing Methods

We compared the proposed method with the transient PTZ model and confirmed that the flashing-light-evoked recurrent seizure is a new feature in addition to the transient changes.

Conclusions

The new method generated non-drug-triggered predictable recurrent seizures in response to intermittent photic stimulation in zebrafish larvae and may serve as a sensitive method for anti-epileptic drug screening or a new research protocol in epilepsy research.
PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS
Authors: Barber Amanda C , Evans Rachel S , Nieuwenhuis Bart , Pearson Craig S , Fuchs Joachim , MacQueen Amy R , Erp Susan van , Haenzi Barabara , Hulshof Lianne A , Osborne Andrew , Conceicao Raquel , Deshpande Sarita S , Cave Joshua , ffrench-Constant Charles , Smith Patrice D , Okkenhaug Klaus , Eickholt Britta J , Martin Keith R , Fawcett James W , Eva Richard
Published: September 2019

Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol(3,4,5)-trisphosphate (PIP3). We found that neuronal PIP3 decreases with maturity in line with regenerative competence, firstly in the cell body and subsequently in the axon. We show that adult PNS neurons utilise two catalytic subunits of PI3K for efficient regeneration: p110α and p110δ. Overexpressing p110α in CNS neurons had no effect, however expression of p110δ restored axonal PIP3 and enhanced CNS regeneration in rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings demonstrate a deficit of axonal PIP3 as a reason for intrinsic regeneration failure and show that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.
A novel constrained optimization-build method for precision assembly of aircraft engine
Authors: Sun Chuanzhi , Chen Danyang , Li Chengtian , Liu Yongmeng , Liu Zewei , Hu Ming , Tan Jiubin
Published: September 2019

Purpose

This paper aims to provide a precision assembly method to improve the aircraft engine quality of initial unbalance with the purpose of founding the process for mass eccentricity propagation and demonstration of assembly process. The proposed method can be used for assembly guidance, tolerance allocation and so on, especially for the assembly with a large number of rotors and the assembly requirements of initial unbalance and coaxiality in high precision.

Design/methodology/approach

This paper proposes a constrained optimization-build method to minimize initial unbalance of aircraft engine assembly, which takes amount of unbalance and concentricity of each rotor into account. A constrained nonlinear programming model is extracted by choosing the initial unbalance as the objective function, and choosing the coaxiality and assembly orientations as the nonlinear constraints. The initial unbalance is reduced stage-by-stage by controlling the assembly angle of each rotor.

Findings

The validity and accuracy of the proposed method is verified by the multistage rotors assembly through experiments run with the measuring instruments. Compared with the direct-build method, the initial unbalance of final assembly using proposed method is reduced by 22.2% in four rotors assembly.

Originality/value

Different from the geometric eccentricity propagation control methods to reduce the initial unbalance indirectly, this paper establishes mass eccentric propagation model in multistage rotors assembly of aircraft engine for the first time. It provides a new idea to establish the relationship between the amount of unbalance of each rotor and the initial unbalance of multistage rotors.
Leveraging service design as a multidisciplinary approach to service innovation
Authors: Prestes Joly Maíra , Teixeira Jorge Grenha , Patrício Lia , Sangiorgi Daniela
Published: September 2019

Purpose

Service design is a multidisciplinary approach that plays a key role in fostering service innovation. However, the lack of a comprehensive understanding of its multiple perspectives hampers this potential to be realized. Through an activity theory lens, the purpose of this paper is to examine core areas that inform service design, identifying shared concerns and complementary contributions.

Design/methodology/approach

The study involved a literature review in two stages, followed by a qualitative study based on selected focus groups. The first literature review identified core areas that contribute to service design. Based on this identification, the second literature review examined 135 references suggested by 13 world-leading researchers in this field. These references were qualitatively analyzed using the NVivo software. Results were validated and complemented by six multidisciplinary focus groups with service research centers in five countries.

Findings

Six core areas were identified and characterized as contributing to service design: service research, design, marketing, operations management, information systems and interaction design. Data analysis shows the various goals, objects, approaches and outcomes that multidisciplinary perspectives bring to service design, supporting them to enable service innovation.

Practical implications

This paper supports service design teams to better communicate and collaborate by providing an in-depth understanding of the multiple contributions they can integrate to create the conditions for new service.

Originality/value

This paper identifies and examines the core areas that inform service design, their shared concerns, complementarities and how they contribute to foster new forms of value co-creation, building a common ground to advance this approach and leverage its impact on service innovation.
Impacts of tourism and the generation of employment in Mexico
Authors: Gómez López Claudia Susana , Barrón Arreola Karla Susana
Published: September 2019

Purpose

This paper aims to study the relationship between employment and tourism activities as well as economic variables for the 32 states of Mexico for the period 1999-2014.

Design/methodology/approach

To study the case of Mexico, the authors use panel data and cointegration panel data. They also use geographic information systems to observe changes over time between the variables, which is useful in the empirical evidence.

Findings

The main results obtained by the models are as following: domestic tourism is the variable with the greatest impact on the generation of direct employment in the tourism sector, a finding supported by both methodologies; economic growth (measured by state gross domestic product) also directly impacts the generation of employment; and the cointegration of the panels causes a long-term equilibrium among the states and some variables.

Research limitations/implications

The model used leaves out other variables that may influence the performance of the tourist activity. In addition, given the availability of official and homogeneous information, it only covers what has been documented up to 2014.

Social implications

The aim is to measure the impact of tourism on the variables at the state level, where the economic activities could be based on public policies, as well as the importance of tourism activities in generating employment. In this sense, the impact would be in channeling efforts to support the main economic activities and could serve as a starting point for the evaluation of programs to promote domestic tourism.

Originality/value

This paper reviews the relationship that exists between tourism activity and its effect on other variables, especially employment. It is the first time that these topics are studied for the Mexican economy.