bluuebunny/crossref_metadata_2025 huggingface dataset:
Myoepithelioma-like Hyalinizing Epithelioid Tumors of the Hand With Novel OGT-FOXO3 Fusions
Authors: Lee Jen-Chieh , Chou Hsiu-Chu , Wang Chung-Hsi , Chu Ping-Yuan , Hsieh Tsung-Han , Liu Mei-Ling , Hsieh Shu-Min , Liu Yun-Ru , Kao Yu-Chien
Published: September 2019

Myoepithelial tumors of soft tissue are uncommon neoplasms characterized histologically by spindle to epithelioid cells arranged in cords, nests, and/or reticular pattern with chondromyxoid to hyaline stroma, and genetically by rearrangement involving EWSR1 (among other less common genes) in about half of the cases. The diagnosis often requires immunostaining to confirm myoepithelial differentiation, most importantly the expression of epithelial markers and S100 protein and/or GFAP. However, there are cases wherein the morphology is reminiscent of myoepithelial tumors, while the immunophenotype falls short. Here, we report 2 highly similar myoepithelioma-like tumors arising in the hands of young adults. Both tumors were well-demarcated and composed of alternating cellular areas with palely eosinophilic hyaline stroma and scattered acellular zones of densely eosinophilic collagen deposition. The tumor cells were mainly epithelioid cells and arranged in cords or small nests. Vacuolated cells encircling hyaline matrix globules were focally prominent. A minor component of nonhyaline fibrous nodular areas composed of bland spindle cells and rich vasculature was also observed. Perivascular concentric spindle cell proliferation and perivascular hyalinization were present in some areas. The tumor cells were positive for CD34 and epithelial membrane antigen (focal) by immunostaining, while largely negative for cytokeratin, S100, GFAP, p63, GLUT1, and claudin-1. By RNA sequencing, a novel OGT-FOXO3 fusion gene was identified in case 1 and confirmed by reverse transcription polymerase chain reaction and fluorescence in situ hybridization in both cases. Sharing the unusual clinicopathologic features and the novel fusion, these 2 cases probably represent a distinct tumor entity, whose relationship with myoepithelial tumors and tumorigenic mechanisms exerted by the OGT-FOXO3 fusion remain to be studied.
Integrative Approaches to Stress Management
Authors: Carlson Linda E. , Toivonen Kirsti , Subnis Utkarsh
Published: September 2019

This narrative review provides an overview of the scope of psychosocial distress and stress in cancer patients and survivors and the potential negative consequences of untreated symptoms. Evidence-based interventions to treat these symptoms are reviewed, beginning with a summary of published clinical practice guidelines, followed by more detailed reviews of the specific integrative interventions with the largest empirical support: cognitive-behavioral stress management, yoga, mindfulness-based interventions, and massage. We also comment on use of natural health products because of their popularity. Finally, we conclude with recommendations to improve the quality of research in integrative interventions for stress management.
Integrative Approaches for Sleep Health in Cancer Survivors
Authors: Garland Sheila N. , Mahon Kaitlyn , Irwin Michael R.
Published: September 2019

Sleep disturbance and insomnia are prevalent problems for the more than 15 million cancer survivors in the United States. If not addressed, poor-quality sleep can negatively impact physical and psychological recovery from cancer diagnosis and treatment. Cancer survivors are increasingly turning to integrative therapies to improve sleep and optimize their health. The purpose of this article is to review the evidence for the use of nonpharmacological integrative therapies to improve sleep health in cancer patients. Therapies are grouped into the following categories: cognitive-behavioral, meditative (e.g., mindfulness-based interventions, yoga, qigong/tai chi), and body based (e.g., acupuncture, acupressure, massage, reflexology). Cognitive-behavioral therapy for insomnia, mindfulness-based therapies, qigong/tai chi, and acupuncture have the most evidence for improving sleep and insomnia, whereas yoga, acupressure, massage, and reflexology are still being investigated or building their evidence base. Several areas of strength are identified, gaps in the literature are highlighted, and recommendations for improving future research are provided.
Patient-Reported Outcomes in Integrative Oncology
Authors: Lopez Gabriel , Lacey Judith , Christie Aimee J. , Powers-James Catherine , Narayanan Santhosshi , Liu Wenli , Cohen Lorenzo
Published: September 2019

There is growing interest in the value of routine collection and monitoring of patient-reported outcomes as part of high-quality, patient-centered, oncology care. Integrative oncology, with its focus on providing symptom and lifestyle support for patients throughout the cancer care continuum, serves a diverse patient population with a complex, changing symptom burden. Monitoring of patient-reported outcomes can contribute significantly to the successful comprehensive evaluation and management of patients receiving integrative oncology care. Data collected as part of an integrative oncology evaluation can also support real-world clinical research efforts to help learn more about the effects of integrative oncology interventions on patient symptoms, quality of life, and treatment outcomes.
Maternal and Paternal Well-Being During Nasoalveolar Molding and Primary Surgery Periods
Authors: Nur Yilmaz R. Burcu , Germeç Çakan Derya , Türkyilmaz Uyar Ece
Published: September 2019

Aim:

The aim was to evaluate the anxiety and depression of both the father and mother of an infant with cleft lip and palate (CLP) before, during and after nasoalveolar molding (NAM) therapy and before and after the lip surgery.

Subjects and Method:

Forty mothers (age range: 18–36; mean ± SD: 23.6 ± 4.51) and 40 fathers (age range: 19–40; mean ± SD: 26.9 ± 4.69) of infants with CLP were asked to answer the 21-item Beck Depression as well as Anxiety Inventory (BDI and BAI) at 1 week after birth and before any intervention (T1), after impression taking (T2), after 2 months of NAM (T3), immediate before primary surgery (T4) and approximately 1 month of recovery after surgery (T5).

Results:

Maternal and paternal depression levels between T1, T2, T3, T4, and T5 showed significant differences (P < 0.05). The BDI scores decrease from T2 to T3 and T4 to T5. The increases of scores from T3 to T4 were significant (P < 0.05). The maternal depression and anxiety levels were higher than the paternal ones in all time periods. The BDI and BAI levels were lesser in mothers and fathers of babies with unilateral than bilateral CLP (P < 0.05).

Conclusion:

Hence realizing of recovery, being in contact with the cleft team and other families, and having an active role in the therapy, the maternal and parental well-being increase with NAM therapy. However, depression and anxiety levels significantly increase before the lip surgery. It may be recommended that the cleft team deliver information and psychological support especially at birth and before the surgical approaches.
Utilizing a Hospital-based Setting to Increase Organ Donor Registrations
Authors: Sutherland Michael , Moloney Gail , Norton Maddison , Bowling Alison , Walker Iain
Published: September 2019

Background.

Shortages of organs for transplantation are a concern for many countries. In Australia’s “opt-in” system, people register their donation decision on the Australian Organ Donor Register (AODR) in their own time, yet <30% of the population have done so. Consent registrations are honored by the next-of-kin in 90% of cases, so increasing registrations will increase donated organs for transplantation. This study investigated the efficacy of offering an immediate registration opportunity in 2 hospitals, and the role that beliefs about organ donation play in registration behavior.

Methods.

An immediate registration opportunity was offered at a public and a private hospital in New South Wales, Australia. Participants (N = 168) categorized as medical/healthcare (eg, doctor and nurse) and nonhealthcare (eg, teacher and chef) completed a measure of beliefs about organ donation, were encouraged to discuss their fears and concerns about organ donation, and given an immediate opportunity to register on the AODR.

Results.

A total of 81.5% of medical/healthcare participants who were eligible registered, and 71.5% of all eligible participants registered on the spot. Beliefs about the negative consequences of donation and concerns over the medical care given to potential donors predicted (non)registration. Medical/healthcare participants reported lower levels of fears and concerns than nonhealthcare participants. Although both groups reported strong positive beliefs about donation, these did not predict registration.

Conclusions.

Offering an immediate registration opportunity in 2 hospitals notably increased the number of registrations on the AODR, suggesting this is a strategy that could potentially increase registrations in opt-in donation systems.
Association of Clinical Rejection Versus Rejection on Protocol Biopsy With Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients
Authors: Asimacopoulos Eleni P. , Garbern Jessica C. , Gauvreau Kimberlee , Blume Elizabeth D. , Daly Kevin P. , Singh Tajinder P.
Published: September 2019

Background.

Two or more early rejections (<1 y) or any late acute rejection (>1 y) have been associated with coronary artery vasculopathy (CAV) in pediatric heart transplant (HT) recipients. We hypothesized that clinical rejection defined by concurrent new-onset heart failure or left ventricular systolic dysfunction is more strongly associated with future CAV than rejection diagnosed on protocol biopsy.

Methods.

We identified all subjects <21 years old who received first HT at Boston Children’s Hospital during 1986–2015 with at least 1 post-HT coronary angiogram. CAV was diagnosed using 2010 International Society for Heart and Lung Transplantation guidelines. Time to CAV diagnosis was assessed using a Cox model with occurrence of clinical rejection analyzed as a time-varying covariate.

Results.

Of 228 study subjects, 106 remained rejection-free, 77 had rejection diagnosed only on protocol biopsy (≥2R cellular or antibody-mediated), and 45 had a clinical rejection. Subjects with rejection diagnosed only on protocol biopsy were not at higher risk of CAV (hazard ratio [HR] 1.09, 95% confidence interval [CI]: 0.54-2.09). In contrast, clinical rejection was significantly associated with risk of CAV (HR 4.84, 95% CI: 2.99-7.83). Late rejection was associated with a higher risk of CAV (HR 4.27, 95% CI: 2.42-7.51) if it was clinical rejection but not if it was diagnosed on protocol biopsy (HR 0.83, 95% CI: 0.51-1.37).

Conclusions.

Clinical rejection poses a far greater risk for future CAV than rejection on protocol biopsy in pediatric HT recipients. Preventing CAV should therefore become the focus of medical management after initial treatment and resolution of clinical rejection.
Cocaine-induced inheritable epigenetic marks may be altered by changing early postnatal fostering
Authors: Ajonijebu Duyilemi C. , Abboussi Oualid , Mabandla Musa V. , Daniels William M.U.
Published: September 2019

Here, we explored the hypothesis that parental cocaine exposure could alter epigenetic machinery in their drug-naive offspring while early postnatal fostering may further modify the accompanied neurochemical and functional components. Variant drug-naive pups were produced from cocaine-exposed or unexposed C57BL/6 female mice that were matched with their male counterparts for mating. Within 3 days of birth, half of the pups were cross-fostered and nurtured by non-biological lactating dams. The pups were initially examined for locomotor activity and memory performance and subsequently for changes in DNA methylation in promoter regions of cAMP response element modulator (Crem) and Fosb in the prefrontal cortex at 48 days postnatum. The impact of postnatal fostering on these parameters was also investigated. Our results showed that cocaine exposure significantly decreased both Crem and Fosb methylation in the prefrontal cortex of progenitor mice, while similar patterns of methylation were replicated in the brains of drug-naive non-fostered offspring mice but reversed by postnatal fostering. Furthermore, offspring raised by cocaine-exposed dams were impaired in discriminative learning and exhibited memory decline, whereas locomotor activity remains unaltered in all groups of mice. Our data provide some evidence that indirect exposure to cocaine may cause marked epigenetic changes within the cortical networks of drug-naive descendants and that mediation by Crem/Fosb signalling in this brain region may be beneficial, while early postnatal fostering may further engineer molecular switching that may predispose the individual to future risky behaviours as well as accumulative potential to developing cognitive impairment later in life.
Photo-Disassembly of Membrane Microdomains Revives Conventional Antibiotics against MRSA
Authors: Hui Jie , Dong Pu-Ting , Liang Lijia , Mandal Taraknath , Li Junjie , Ulloa Erilinda R. , Zhan Yuewei , Jusuf Sebastian , Zong Cheng , Seleem Mohamed N. , Liu George Y. , Cui Qiang , Cheng Ji-Xin
Published: September 2019

Confronted with the rapid evolution and dissemination of antibiotic resistance, there is an urgent need to develop alternative treatment strategies for drug-resistant pathogens. Here, we present an unconventional approach to restore the susceptibility of methicillin-resistantS. aureus(MRSA) to a broad spectrum of conventional antibiotics via photo-disassembly of functional membrane microdomains. The photo-disassembly of microdomains is based on effective photolysis of staphyloxanthin, the golden carotenoid pigment that gives its name. Upon pulsed laser treatment, cell membranes are found severely disorganized and malfunctioned to defense antibiotics, as unveiled by membrane permeabilization, membrane fluidification, and detachment of membrane protein, PBP2a. Consequently, our photolysis approach increases susceptibility and inhibits development of resistance to a broad spectrum of antibiotics including penicillins, quinolones, tetracyclines, aminoglycosides, lipopeptides, and oxazolidinones.

One Sentence Summary

Using photons to crashS. aureuscell membrane and its formidable defense against a broad spectrum of antibiotics.
Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling
Authors: Gopallawa Indiwari , Freund Jenna R. , Lee Robert J.
Published: September 2019

Bitter taste receptors (T2Rs) are GPCRs involved in detection of bitter compounds by type 2 taste cells of the tongue, but are also expressed in other tissues throughout the body, including the airways, gastrointestinal tract, and brain. These T2Rs can be activated by several bacterial products and regulate innate immune responses in several cell types. Expression of T2Rs has been demonstrated in immune cells like neutrophils; however, the molecular details of their signaling are unknown. We examined mechanisms of T2R signaling in primary human monocyte-derived unprimed (M0) macrophages (MΦs) using live cell imaging techniques. Known bitter compounds and bacterial T2R agonists activated low-level calcium signals through a pertussis toxin (PTX)-sensitive, phospholipase C-dependent, and inositol trisphosphate receptor-dependent calcium release pathway. These calcium signals activated low-level nitric oxide (NO) production via endothelial and neuronal NO synthase (NOS) isoforms. NO production increased cellular cGMP and enhanced acute phagocytosis ∼3-fold over 30-60 min via protein kinase G. In parallel with calcium elevation, T2R activation lowered cAMP, also through a PTX-sensitive pathway. The cAMP decrease also contributed to enhanced phagocytosis. Moreover, a co-culture model with airway epithelial cells demonstrated that NO produced by epithelial cells can also acutely enhance MΦ phagocytosis. Together, these data define MΦ T2R signal transduction and support an immune recognition role for T2Rs in MΦ cell physiology.
Structure-based identification and characterisation of novel inhibitors of KNa1.1 potassium channels, a stratified target for KCNT1-related epilepsy
Authors: Cole Bethan A. , Johnson Rachel M. , Dejakaisaya Hattapark , Pilati Nadia , Fishwick Colin W.G. , Muench Stephen P. , Lippiat Jonathan D.
Published: September 2019

Several types of drug-resistant epileptic encephalopathies of infancy have been associated with mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel subunit KNa1.1. These mutations are commonly gain-of-function, increasing channel activity, therefore inhibition by drugs is proposed as a stratified approach to treat disorders. To date, quinidine therapy has been trialled with several patients, but mostly with unsuccessful outcomes, which has been linked to its low potency and lack of specificity. Here we describe the use of a cryo-electron microscopy-derived KNa1.1 structure and mutational analysis to identify the quinidine biding site and identified novel inhibitors that target this site using computational methods. We describe six compounds that inhibit KNa1.1 channels with low- and sub-micromolar potencies, likely through binding in the intracellular pore vestibule. In preliminary hERG inhibition and cytotoxicity assays, two compounds showed little effect. These compounds may provide starting points for the development of novel pharmacophores for KNa1.1 inhibition, with the view to treating KCNT1-associated epilepsy and, with their potencies higher than quinidine, could become key tool compounds to further study this channel. Furthermore, this study illustrates the potential for utilising cryo-electron microscopy in ion channel drug discovery.
Maternal high-fat diet induces sex-specific changes to glucocorticoid and inflammatory signaling in response to corticosterone and lipopolysaccharide challenge in adult rat offspring
Authors: Wijenayake Sanoji , Rahman Mouly F. , Lum Christine M.W. , De Vega Wilfred C. , Sasaki Aya , McGowan Patrick O.
Published: September 2019

Background

Acute elevations in endogenous corticosterone (CORT) with psychosocial stress or exogenous administration potentiate inflammatory gene expression. Maternal obesity as a result of high-fat diet (HFD) consumption has been linked to higher basal levels of neuroinflammation, including increased expression of pro-inflammatory genes in the amygdala. These findings suggest that exposure to maternal HFD may elicit pro-inflammatory responses in the presence of an immune stressor such as lipopolysaccharide (LPS), a component of gram-negative bacteria, as well as acute elevated CORT.

Methods

Rat offspring were exposed to maternal HFD or control diet (CHD) throughout pre and postnatal development until weaning, when all offspring were provided CHD until adulthood. In adulthood, offspring were ‘challenged’ with administration of exogenous CORT, to simulate an acute physiological stress, LPS, to induce an immune stress, or both. qPCR was used to measure transcript abundance of CORT receptors and downstream inflammatory genes in the amygdala, hippocampus and prefrontal cortex, brain regions that mediate neuroendocrine and behavioral responses to stress.

Results

HFD female offspring exhibited elevations in anti-inflammatory transcripts, whereas HFD male offspring responded with greater pro-inflammatory gene expression to simultaneous CORT and LPS administration.

Conclusions

These findings suggest that exposure to maternal HFD leads to sex-specific alterations that may alter inflammatory responses in the brain, possibly as an adaptive response to basal inflammation.
Risk factors associated with Avian Influenza subtype H9 outbreaks on poultry farms in Kathmandu valley, Nepal
Authors: Gompo Tulsi Ram , Shah Bikash Raj , Karki Surendra , Koirala Pragya , Maharjan Manju , Bhatt Diker Dev
Published: September 2019

Poultry sector contributes to four percent in national GDP of Nepal. However, this sector is under threat with periodic outbreaks of Avian Influenza (AI) subtypes H5 and H9 since 2009. This has been both a both public health threat and an economic issue. Since last three years, outbreaks of AI subtype H9 has caused huge economic losses in major poultry producing areas of Nepal. However, the risk factors associated with these outbreaks have not been assessed. A retrospective case-control study was conducted from April 2018 to May 2019 in Kathmandu Valley to understand the risk factors associated with AI subtype H9 outbreaks. Out of 100 farms selected, 50 were “case” farms, confirmed positive to H9 at Central Veterinary Laboratory, Kathmandu, and other 50 farms were “control” farms, matched for farm size and locality within a radius of three km from the case farm. Each farm was visited to collect information using semi-structured questionnaire. Nineteen potential risk factors were included in the questionnaire under the broad categories: birds and farm characteristics, management aspects and biosecurity status of the farms. Univariable and multivariable logistic regression analysis were conducted to calculate corresponding odds ratios. Identified risk factors associated with AI subtype H9 outbreaks in Kathmandu valley were: “Birds of age 31-40 days” (OR= 11.31, 95% CI: 1.31-98.02, p=0.028), “Older farms operating for >5 years” (OR= 10.9, 95% CI: 1.76-66.93, p=0.01), “Commercial layers farms” (OR=36.0, 95% CI: 0.97-1332.40, p=0.052), “Used stream water to water birds (OR= 5.7, 95% CI: 1.10-30.13, p=0.039)”, “Farms without practice of fumigation after each batch of poultry (OR= 4, 95% CI: 1.44-13.13, p=0.009)., “Farm with previous history of AI (OR= 13.8, 95% CI: 1.34-143.63, p = 0.028), “Did not applied farm boots (OR= 2.58, 95% CI: 0.98-6.80, p= 0.055), “Visitors allowed to enter the farms (OR= 2.5, 95% CI: 1.011-6.17, p = 0.047) and “No foot bath at entry of farms (OR= 3.3, 95% CI: 1.29-8.38, p = 0.013). This study depicts that outbreaks of AI subtype H9 in Kathmandu valley was related to poor management practices and biosecurity in the poultry farms. We suggest improving management practices and increase biosecurity in the farms to reduce incidences of AI subtype H9 outbreaks in Kathmandu valley.
Say what I mean – Expectancy effects in the EEG during joint and spontaneous word-by-word sentence production
Authors: Goregliad Fjaellingsdal Tatiana , Schwenke Diana , Scherbaum Stefan , Kuhlen Anna K. , Bögels Sara , Meekes Joost , Bleichner Martin G.
Published: September 2019

Our aim in the present study is to measure neural correlates during spontaneous interactive sentence production. We present a novel approach using the word-by-word technique from improvisational theatre, in which two speakers jointly produce one sentence. This paradigm allows the assessment of behavioural aspects, such as turn-times, and electrophysiological responses, such as event-related-potentials (ERPs). Twenty-five participants constructed a cued but spontaneous four-word German sentence together with a confederate, taking turns for each word of the sentence. In 30% of the trials, an unexpected gender-marked article was uttered by the confederate. To complete the sentence in a meaningful way, the participant had to detect the violation, (possibly) inhibit a prepared response, and retrieve and utter a new fitting response. We found significant increases in response times after unexpected words and – despite allowing unscripted language production and naturally varying speech material – successfully detected significant N400 and P600 ERP effects for the unexpected word. The N400 EEG activity further significantly predicted the response time of the subsequent turn. Our results show that combining behavioural and neuroscientific measures of verbal interactions while retaining sufficient experimental control is possible, and that this combination provides promising insights into the mechanisms of spontaneous spoken dialogue.
Molecular patterning during the development ofPhoronopsis harmerireveals similarities to rhynchonelliform brachiopods
Authors: Andrikou Carmen , Passamaneck Yale J. , Lowe Chris J. , Martindale Mark Q. , Hejnol Andreas
Published: September 2019

Background

Answering the question how conserved patterning systems are across evolutionary lineages requires a broad taxon sampling. Phoronid development has previously been studied using fate mapping and morphogenesis, yet molecular descriptions are missing. Here we report the expression patterns of the evolutionarily conserved anterior (otx, gsc, six3/6, nk2.1), posterior (cdx, bra) and endomesodermal (foxA, gata4/5/6, twist) markers in the phoronidPhoronopsis harmeri.

Results

The transcription factorsfoxA, gata4/5/6andcdxshow conserved expression in patterning the development and regionalization of the phoronid embryonic gut, withfoxAexpressed in the presumptive foregut,gata4/5/6demarcating the midgut andcdxconfined to the hindgut. Surprisingly,brachyury, an evolutionary conserved transcription factor often associated with gastrulation movements and patterning of the mouth and hindgut, seems to be unrelated with gastrulation and mouth patterning in phoronids. Furthermore,six3/6, a well-conserved anterior marker, shows a remarkably dynamic expression, demarcating not only the apical organ and the oral ectoderm, but also clusters of cells of the developing midgut and the anterior mesoderm, similar to what has been reported for brachiopods, bryozoans and some deuterostome Bilateria.

Conclusions

Our comparison of gene expression patterns with other studied Bilateria reveals that the timing of axis determination and cell fate distribution of the phoronid shows highest similarities to rhynchonelliform brachiopods. Despite these similarities, the phoronidP. harmerishows also particularities in its development, which hint to divergences in the arrangement of gene regulatory networks responsible for germ layer formation and axis specification.
Rapid evolution at the Drosophila telomere: transposable element dynamics at an intrinsically unstable locus
Authors: McGurk Michael P , Dion-Côté Anne-Marie , Barbash Daniel A
Published: September 2019

Drosophila telomeres have been maintained by three families of active transposable elements (TEs),HeT-A, TAHREandTART, collectively referred to as HTTs, for tens of millions of years, which contrasts with an unusually high degree of HTT interspecific variation. While the impacts of conflict and domestication are often invoked to explain HTT variation, the telomeres are unstable structures such that neutral mutational processes and evolutionary tradeoffs may also drive HTT evolution. We leveraged population genomic data to analyze nearly 10,000 HTT insertions in 85D. melanogastergenomes and compared their variation to other more typical TE families. We observe that occasional large-scale copy number expansions of both HTTs and other TE families occur, highlighting that the HTTs are, like their feral cousins, typically repressed but primed to take over given the opportunity. However, large expansions of HTTs are not caused by the runaway activity of any particular HTT subfamilies or even associated with telomere-specific TE activity, as might be expected if HTTs are in strong genetic conflict with their hosts. Rather than conflict, we suggest instead that distinctive aspects of HTT copy number variation and sequence diversity largely reflect telomere instability, with HTT insertions being lost at much higher rates than other TEs elsewhere in the genome. We extend previous observations that telomere deletions occur at a high rate, and surprisingly discover that more than a third do not appear to have been healed with an HTT insertion. We also report that some HTT families may be preferentially activated by the erosion of whole telomeres, implying the existence of HTT-specific host control mechanisms. We further suggest that the persistent telomere localization of HTTs may reflect a highly successful evolutionary strategy that trades away a stable insertion site in order to have reduced impact on the host genome. We propose that HTT evolution is driven by multiple processes with niche specialization and telomere instability being previously underappreciated and likely predominant.
Two parallel arms of the heterochronic pathway direct coordinated juvenile-to-adult transition through distinct LIN-29 isoforms
Authors: Azzi Chiara , Aeschimann Florian , Neagu Anca , Großhans Helge
Published: September 2019

Robust organismal development relies on temporal coordination of disparate physiological processes. InCaenorhabditis elegans, the timely transition from juvenile to adult is controlled by the heterochronic pathway, a regulatory cascade of conserved proteins and small RNAs. The heterochronic pathway culminates in accumulation of the transcription factor LIN-29, which triggers coordinated execution of juvenile-to-adult (J/A) transition events. Here, we reveal that two LIN-29 isoforms fulfill distinct functions during the J/A transition. We show that the functional differences between the isoforms do not stem from differences in their sequences, but from their distinct spatiotemporal expression, and we propose that distinct LIN-29 dose sensitivities of the individual J/A transition events help to ensure their temporal ordering. We demonstrate that uniquelin-29isoform expression patterns are generated by the RNA-binding protein LIN-41 forlin-29a, and the transcription factor HBL-1 forlin-29b. By regulating both HBL-1 and LIN-41, the RNA-binding protein LIN-28 coordinates LIN-29 isoform activity. Thus, our findings reveal that a coordinated transition from juvenile to adult involves branching of a linear pathway to achieve timely control of multiple events.
In silico analysis of long non-coding RNAs in medulloblastoma and its subgroups
Authors: Joshi Piyush , Perera Ranjan J.
Published: September 2019

Medulloblastoma is the most common malignant pediatric brain tumor with high fatality rate. Recent large-scale studies utilizing genome-wide technologies have sub-grouped medulloblastomas into four major subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. However, there has yet to be a global analysis of long non-coding RNAs, a crucial part of the regulatory transcriptome, in medulloblastoma. Here, we performed bioinformatic analysis of RNA-seq data from 175 medulloblastoma patients. Differential lncRNA expression sub-grouped medulloblastomas into the four main molecular subgroups. Some of these lncRNAs were subgroup-specific, with a random forest-based machine-learning algorithm identifying an 11-lncRNA diagnostic signature. We also validated the diagnostic signature in patient derived xenograft (PDX) models. We further identified a 17-lncRNA prognostic model using LASSO based penalized Cox’ PH model (Score HR= 13.6301, 95% CI= 8.857-20.98, logrank p-value=< 2e-16). Our analysis represents the first global lncRNA analysis in medulloblastoma. Our results identify putative candidate lncRNAs that could be evaluated for their functional role in medulloblastoma genesis and progression or as diagnostic and prognostic biomarkers.
Hedgehog pathway activation through conformational blockade of the Patched sterol conduit
Authors: Zhang Yunxiao , Lu Wan-Jin , Bulkley David P. , Liang Jiahao , Ralko Arthur , Roberts Kelsey J. , Li Anping , Cho Wonhwa , Cheng Yifan , Manglik Aashish , Beachy Philip A.
Published: September 2019

Activation of the Hedgehog pathway may have therapeutic value for improved bone healing, taste receptor cell regeneration, and alleviation of colitis or other conditions. Systemic pathway activation, however, may be detrimental and therapeutic application has been difficult for lack of agents amenable to tissue targeting. We have developed a novel agonist, a conformation-specific nanobody against the Hedgehog receptor Patched1. This nanobody potently activates the Hedgehog pathway in vitro and in vivo by stabilizing an alternative conformation of a Patched1 “switch helix”, as revealed by cryo-EM structure determination. Although this conformation likely constitutes part of the transport cycle, nanobody-trapping disrupts the cycle and prevents substrate movement through the Patched1 sterol conduit. Our conformation-selective nanobody approach provides a new route to the development of transporter-related pharmacologic agents and may be generally applicable to the study of other transporters.
Adaptive Tree Proposals for Bayesian Phylogenetic Inference
Authors: Meyer X.
Published: September 2019

Bayesian inference of phylogenies with MCMC is without a doubt a staple in the study of evolution. Yet, this method still suffers from a practical challenge identified more than two decades ago: designing tree topology proposals that efficiently sample the tree space. In this article, I introduce the concept of tree topology proposals that adapt to the posterior distribution as it is estimated. I use this concept to elaborate two adaptive variants of existing proposals and an adaptive proposal based on a novel design philosophy in which the structure of the proposal is informed by the posterior distribution of trees. I investigate the performance of these proposals by first presenting a metric that captures the performance of each proposals within a mixture. Using this metric, I then compare the adaptive proposals performance to the performance of standard and parsimony-guided proposals on 11 empirical datasets. Using adaptive proposals led to consistent performance gains and resulted in up to 18-fold increases in mixing efficiency and 6-fold increases in converge rate without increasing the computational cost of these analyses. [Bayesian inference; Adaptive tree proposals; Markov chain Monte Carlo; phylogenetics; posterior probability distribution.]
A native prokaryotic voltage-dependent calcium channel with a novel selectivity filter sequence
Authors: Shimomura Takushi , Yonekawa Yoshiki , Nagura Hitoshi , Tateyama Michihiro , Fujiyoshi Yoshinori , Irie Katsumasa
Published: September 2019

Voltage-dependent Ca2+ channels (Cavs) are indispensable for coupling action potentials with Ca2+ signaling in living organisms. The structure of Cavs is similar to that of voltage-dependent Na+ channels (Navs). It is known that prokaryotic Navs can obtain Ca2+ selectivity by negative charge mutations of the selectivity filter, but native prokaryotic Cavs had not yet been identified.

Here, we report the first identification of a native prokaryotic Cav, CavMr, and its relative, NavPp. Although CavMr contains a smaller number of negatively charged residues in the selectivity filter than artificial prokaryotic Cavs, CavMr exhibits high Ca2+ selectivity. In contrast, NavPp, which has similar filter sequence to artificial Cavs, mainly allows Na+ to permeate. Interestingly, a NavPp mutant whose selectivity filter was replaced with that of CavMr exhibits high Ca2+ selectivity. Mutational analyses revealed that the glycine residue of the CavMr selectivity filter is a determinant for Ca2+ selectivity. This glycine residue is well conserved among subdomains I and III of eukaryotic Cavs.

These findings provide new insight into the Ca2+ selectivity mechanism conserved from prokaryotes to eukaryotes.
Tuning Intermediate Filament Mechanics by Variation of pH and Ion Charges
Authors: Schepers Anna V. , Lorenz Charlotta , Köster Sarah
Published: September 2019

The cytoskeleton is formed by three types of filamentous proteins – microtubules, actin filaments, and intermediate filaments (IFs) – and enables cells to withstand external and internal forces. Vimentin is the most abundant IF protein in humans and assembles into 10 nm diameter filaments with remarkable mechanical properties, such as high extensibility and stability. It is, however, unclear to which extent these properties are influenced by the electrostatic environment. Here, we study the mechanical properties of single vimentin filaments by employing optical trapping combined with microfluidics. Force-strain curves, recorded at varying ion concentrations and pH values, reveal that the mechanical properties of single vimentin IFs are influenced by pH and ion concentration. By combination with Monte Carlo simulations, we relate these altered mechanics to electrostatic interactions of subunits within the filaments. We thus suggest possible mechanisms that allow cells to locally tune their stiffness without remodeling the entire cytoskeleton.
Effects of active dry yeast on growth performance, rumen fermentation characteristics and slaughter performance in beef cattle
Authors: Liu Siqiang , Yuan Mei , Kang Kun , Wang Zhisheng , Wang Lizhi , Xue Bai , Tian Gang , Zou Huawei , Shah Ali Mujtaba , Zhang Xiangfei , Yu Peiqiang , Wang Hongze , Peng Quanhui
Published: September 2019

This study aimed to investigate the effects of active dry yeast (ADY) on rumen microbial composition and slaughter performance of beef cattle. Thirty-two finishing beef cattle (simmental crossbred cattle ♂ × cattle-yaks ♀), with an average body weight of 110 ± 12.85 kg, were randomly assigned to one of four treatments: the low plane of nutrition group (Control), low plane of nutrition group + ADY 2 g/head/d (ADY2), low plane of nutrition group + ADY 4 g/head/d (ADY4) and high plane of nutrition group (HPN). ADY supplementation increased average daily gain (P<0.001), and the carcass weight of ADY4 group had no significant difference with HPN group (P>0.05). The serum glutamic-pyruvic transaminase activity in control and ADY4 group was higher than HPN group (P=0.001). The neutral detergent fiber (P=0.022) and acid detergent fiber (P=0.043) digestibility in HPN group was greater than control, but no difference was obtained among ADY2, ADY4 and HPN group (P>0.05). The rumen ammonium nitrogen content in control was greater than ADY2 and ADY4 group (P=0.003), and no difference was obtained ADY2, ADY4 and HPN group (P>0.05). The propionic acid content in the rumen in ADY2, ADY4, and HPN group were greater than control group (P<0.001). The simpson (P=0.014) and shannon (P=0.045) indexes in control and HPN group were greater than ADY4 group. At the phylum level, the relative abundance of Firmicutes in the HPN group was higher than ADY4 group (P=0.015). At the genus level, HPN and ADY4 were clustered together, and the relative abundance of Ruminococcaceae UCG-002 in ADY4 group was higher than control and HPN group (P=0.004). In conclusion, supplementation ADY 4 g/head/d shift the rumen microbial composition of beef cattle fed low plane of nutrition to a more similar level with cattle fed with HPN diet, produced comparable carcass weight with HPN diet.
Chilling induces unidirectional solute leak through the locust gut epithelia
Authors: Brzezinski Kaylen , MacMillan Heath A.
Published: September 2019

Chill-susceptible insects, like the migratory locust, often die when exposed to low temperatures from an accumulation of tissue damage that is unrelated to freezing (chilling injuries). Chilling injury is consistently associated with ion imbalance across the gut epithelia. It has recently been suggested that this imbalance is at least partly caused by a cold-induced disruption of epithelial barrier function. Here, we aim to test this hypothesis in the migratory locust (L. migratoria). First, chill tolerance was quantified by exposing locusts to −2°C for various durations and monitored for chill coma recovery time and survival 24h post-cold exposure. Longer exposure times significantly increased recovery time and caused injury and death. Ion-selective microelectrodes were also used to determine the presence of cold-induced ion imbalance. We found a significant increase and decrease of hemolymph K+and Na+concentrations over time, respectively. Next, barrier failure along the gut was tested by monitoring the movement of an epithelial barrier marker (FITC-dextran) across the gut epithelia during exposure to −2°C. We found minimal marker movement across the epithelia in the serosal to mucosal direction, suggesting that locust gut barrier function remains generally conserved during chilling. However, when tested in the mucosal to serosal direction, we saw significant increases of FITC-dextran with chilling. This instead suggests that while cold-induced barrier disruption is present, it is likely unidirectional. It is important to note that these data reveal only the phenomenon itself. The location of this leak as well as the underlying mechanisms remain unclear and require further investigation.

Summary statement

In this study, we provide the first evidence for the presence of cold-induced paracellular leak along the gut of the migratory locust, and that this leak is strongest in the mucosal to serosal direction.
During environmental change, cooperation can promote rescue or lead to evolutionary suicide
Authors: Henriques Gil J. B. , Osmond Matthew M.
Published: September 2019

The adaptation of populations to changing conditions may be affected by interactions between individuals. For example, cooperative interactions may allow populations to maintain high densities, and thus keep track of moving environmental optima. At the same time, changes in population density alter the marginal benefits of cooperative investments, creating a feedback loop between population dynamics and the evolution of cooperation. Here we model how the evolution of cooperation is affected by, and in turn affects, adaptation to a changing environment. We hypothesize that changes in the environment lower population size and thus promote the evolution of cooperation, and that this in turn helps the population keep up with the moving optimum. However, we find that the evolution of cooperation can have qualitatively different effects, depending on which fitness component is reduced by the costs of cooperation. If the costs decrease fecundity, cooperation indeed speeds adaptation by increasing population density; if, in contrast, the costs decrease viability, cooperation may in fact slow adaptation by lowering the effective population size, leading to evolutionary suicide. Thus, we show that cooperation can either promote or—counter-intuitively—hinder adaptation to a changing environment.
Identification of four unconventional kinetoplastid kinetochore proteins KKT22–25 in Trypanosoma brucei
Authors: Nerusheva Olga O. , Ludzia Patryk , Akiyoshi Bungo
Published: September 2019

The kinetochore is a multi-protein complex that drives chromosome segregation in eukaryotes. It assembles onto centromere DNA and interacts with spindle microtubules during mitosis and meiosis. Although most eukaryotes have canonical kinetochore proteins, kinetochores of evolutionarily divergent kinetoplastid species consist of at least 20 unconventional kinetochore proteins (KKT1–20). In addition, twelve proteins (KKIP1–12) are known to localize at kinetochore regions during mitosis. It remains unclear whether KKIP proteins interact with KKT proteins. Here, we report the identification of four additional kinetochore proteins, KKT22–25, in Trypanosoma brucei. KKT22 and KKT23 constitutively localize at kinetochores, while KKT24 and KKT25 localize from S phase to anaphase. KKT23 has a Gcn5-related N-acetyltransferase (GNAT) domain, which is not found in any kinetochore protein known to date. We also show that KKIP1 co-purifies with KKT proteins, but not with KKIP proteins. Finally, our affinity purification of KKIP2/3/4/6 identifies a number of proteins as their potential interaction partners, many of which are implicated in RNA binding or processing. These findings further support the idea that kinetoplastid kinetochores are unconventional.
Hippo pathway deletion in adult resting cardiac fibroblasts initiates a cell state transition with spontaneous and self-sustaining fibrosis
Authors: Xiao Yang , Hill Matthew C. , Li Lele , Deshmukh Vaibhav , Martin Thomas J. , Wang Jun , Martin James F.
Published: September 2019

Cardiac fibroblasts (CFs) respond to injury by transitioning through multiple cell states, including resting CFs, activated CFs, and myofibroblasts. We report here that Hippo signaling cell-autonomously regulates CF fate transitions and proliferation, and non-cell-autonomously regulates both myeloid and CF activation in the heart. Conditional deletion of Hippo pathway kinases, Lats1 and Lats2, in uninjured CFs initiated a self-perpetuating fibrotic response in the adult heart that was exacerbated by myocardial infarction (MI). Single cell transcriptomics showed that uninjured Lats1/2 mutant CFs spontaneously transitioned to a myofibroblast cell state. Through gene regulatory network reconstruction, we found that Hippo-deficient myofibroblasts deployed a network of transcriptional regulators of endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) consistent with elevated secretory activity. We observed an expansion of myeloid cell heterogeneity in uninjured Lats1/2 CKO hearts with similarity to cells recovered from control hearts post-MI. Integrated genome-wide analysis of Yap chromatin occupancy revealed that Yap directly activates myofibroblast cell identity genes, the proto-oncogene Myc, and an array of genes encoding pro-inflammatory factors through enhancer–promoter looping. Our data indicate that Lats1/2 maintain the resting CF cell state through restricting the Yap-induced injury response.
Crystal structure and Hirshfeld surface analysis of 3-amino-5-phenylthiazolidin-2-iminium bromide
Authors: Duruskari Gulnara Sh. , Khalilov Ali N. , Akkurt Mehmet , Mammadova Gunay Z. , Chyrka Taras , Maharramov Abel M.
Published: September 2019

In the cation of the title salt, C9H12N3S+·Br−, the thiazolidine ring adopts an envelope conformation with the C atom adjacent to the phenyl ring as the flap. In the crystal, N—H...Br hydrogen bonds link the components into a three-dimensional network. Weak π–π stacking interactions between the phenyl rings of adjacent cations also contribute to the molecular packing. A Hirshfeld surface analysis was conducted to quantify the contributions of the different intermolecular interactions and contacts.
Is integrated reporting associated with corporate financing decisions? Some empirical evidence
Authors: Lemma Tesfaye T. , Khan Arifur , Muttakin Mohammad Badrul , Mihret Dessalegn Getie
Published: September 2019

Purpose

The emerging practice of integrated reporting (IR) has raised curiosity regarding how it impacts on firms and their stakeholders. The purpose of this paper is to examine whether a firm’s decision to provide integrated reports is associated with its financing decisions and whether financial reporting quality mediates the relationship.

Design/methodology/approach

A usable sample of 832 firm-year observations was employed based on a dataset drawn from companies listed on the Johannesburg Securities Exchange (JSE) for the period between 2009 and 2015.

Findings

The findings show that firms that provide integrated reports tend to have lower levels of leverage, and this effect is partially mediated through financial reporting quality. We further document that the partial effect of financial reporting quality on leverage is stronger for firms that provide integrated reports than is the case for other firms. The findings suggest that IR enables firms to employ equity financing, which is a more informationally-sensitive source of capital than debt financing.

Originality/value

This study is the first to document evidence suggesting that management can draw on IR in devising optimal financing strategy.