bluuebunny/crossref_metadata_2025 huggingface dataset:
Modified Combined Fascia Sheath and Levator Muscle Complex Suspension With Müller Muscle Preservation on Treating Severe Congenital Ptosis
Authors: Xing Yue , Wang Xi , Cao Yuan , Ding Xia , Lin Ming , Li Jin , Fan Xianqun
Published: October 2018

Background

This study aims to evaluate the effect of a modified approach on severe congenital ptosis treatment.

Methods

Through anterior approach, Müller muscle was preserved, meanwhile the upper tarsus was suspended to combined fascia sheath (CFS) and levator muscle (LM) complex. The main outcome measures included marginal reflex distance1 (MRD1), palpebral fissure height (PFH), MRD1 regression, MRD1 improvement, and patient self-satisfaction.

Results

There were 70 patients (90 eyelids) with severe congenital ptosis received treatment of modified operation, including 20 bilateral and 50 unilateral ptosis. The average LF was 2.53 ± 1.06 mm. The preoperative MRD1 and PFH was −0.06 ± 0.76 mm and 4.25 ± 0.85 mm, respectively. The follow-up was at least 6 months with average of 12.67 ± 4.92 months. The immediate postoperative MRD1 and PFH average was 4.52 ± 0.39 mm and 9.24 ± 0.26, respectively. The last follow-up MRD1 and PFH average was 2.43 ± 0.57 mm and 7.16 ± 0.69 mm, respectively, which was improved significantly (P < 0.01). There were variety degrees of MRD1 regression especially in the first month after operation, and the last follow-up MRD1 regression was 2.09 ± 0.67 mm. The lagophthalmos was obvious immediately after operation and regularly released after 6 months. Objective curative effect assessment showed 78 (86.7%) satisfactory eyes, 4 (4.4%) improved eyes, and 8 (8.9%) noneffective eyes. Two noneffective eyes required reoperation of frontalis suspension. Self-satisfaction rate was 93.3%. Parameters analysis showed that LF had positive correlation with last follow-up MRD1 and negative correlation with MRD1 improvement (P < 0.01). Five eyes had levator shorten history, which was associated remarkably with CFS + LM curative effect (P < 0.01). Mean swelling time was 0.53 ± 0.41 months, and no complications were observed until the last visit.

Conclusions

This modified method gives powerful correction and vivid eyelid contour, featured with simple surgical procedures, few complications, and satisfactory effect, which is worth to wide application.
Outcome of Pedicled Thoracodorsal Artery Perforator Flap in the Surgical Treatment of Stage II and III Hidradenitis Suppurativa of Axilla
Authors: Elgohary Hussein , Nawar Ahmed M. , Zidan Ahmed , Shoulah Ahmed A. , Younes Mohamed T. , Hamed Ahmed M.
Published: October 2018

Background

Hidradenitis suppurativa (HS) is a chronic, inflammatory disease affecting the apocrine glands of the axillary, groin, and mammary regions with significant physical and psychosocial sequelae. Surgical excision of the affected tissue is the criterion standard treatment. Advanced cases of axillary HS are associated with high rates of recurrence and require extensive surgical resection with challenging reconstruction associated with risk of postoperative complications. The most effective method for reconstruction of the axilla after excision of HS is yet to be identified.

Objectives

The aim of the study was to evaluate the results of the use of pedicled thoracodorsal artery perforator (TDAP) flap as a method of reconstruction for axillary efect result from wide surgical excision as a line of treatment for stage II and III HS of the axilla.

Patient and Methods

The study included 20 patients with stage II and III (Hurley staging system) HS of the axilla, 18 male and 2 women treated by wide local excision and reconstruction by rotational TDAP flap. At the end of follow-up, outcome is judged by complete remission of disease, comparing preoperative shoulder function (using Constant-Murley shoulder outcome score), and quality of life (using dermatology life quality index) with postoperative results after 1 year, plus durability of reconstruction, donor site morbidity, overall aesthetic outcome, and patient's satisfaction.

Results

The mean ± SD follow-up period was 30 ± 5.2 months (range = 12–60 months). Four patients (20%) were treated for their right side, 8 patients (40%) for their left side, and 8 patients (40%) were treated bilaterally, so we perform 28 operations for 20 patients. The treated patients with stage II disease were 16 (57.14%) and with stage III disease were 12 (42.85%). The size of the defects was usually approximately 10 × 15 cm. By the end of follow-up period, all patient showed complete remission of the disease with improvement in both shoulder function and quality of life, whereas 1 flap (3.57%) was complicated by bleeding treated by reoperation, 2 flaps (7.14%) complicated by wound infection that was treated conservatively, 3 other flaps (10.71%) showed wide scare at insight of the flaps, and 1 flap (3.57%) developed hypertrophic scare at donor site of the flap.

Conclusions

Surgical treatment of stage II and III HS of axilla and reconstruction by rotational TDAP flap provides good aesthetic and functional results with 100% success rate in eradicating and complete remission of the disease during follow-up period and accepted complication rate.
Accuracy of Bladder Scanner for the Assessment of Postvoid Residual Volumes in Women With Pelvic Organ Prolapse
Authors: Taylor Danielle Lynn , Sierra Tania , Duenas-Garcia Omar Felipe , Kim Youngwu , Leung Katherine , Hall Cynthia , Flynn Michael K.
Published: October 2018

Objectives

The aim of the study was to evaluate the accuracy of the bladder scanner in assessing postvoid residual (PVR) volumes in patients with pelvic organ prolapse (POP).

Methods

We performed a prospective parallel cohort study evaluating the accuracy of the BVI 3000 bladder scanner in patients with POP. Patients with POP to the hymen were offered inclusion. Primary outcome was the absolute difference between bladder scanner and catheterization PVR. We also investigated the effect of prolapse stage on bladder scanner accuracy. A prevoid bladder volume was obtained by bladder scan. Subjects voided volume was then collected. A PVR was obtained by bladder scan, followed by a PVR by catheterization. Descriptive statistics, Wilcoxon signed-rank test, linear regression analysis, and sensitivity/specificity analysis were performed.

Results

We enrolled 87 subjects. There was a statistically significant difference between catheter and bladder scan PVR, with an absolute median difference of 20 mL (SD = 37.7), P < 0.001. Linear regression analysis showed a difference between mild and advanced prolapse groups. The regression coefficients of the mild prolapse group and advanced prolapse were 0.91 (confidence interval = 0.75–1.06) and 0.66 (confidence interval = 0.54–0. 78), P = 0.015, respectively, indicating a deterioration of accuracy of the bladder scanner for advanced prolapse. The sensitivity of the bladder scanner identifying catheterized PVR volumes less than 100 mL was 93.7%. For catheter PVRs greater than 100 mL, the specificity of the bladder scanner was 72.7%.

Conclusions

Bladder scanner PVRs are less accurate in advanced prolapse, and PVRs of greater than 100 mL should be confirmed by catheterization.
Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival
Authors: Cajuso Tatiana , Sulo Päivi , Tanskanen Tomas , Katainen Riku , Taira Aurora , Hänninen Ulrika A. , Kondelin Johanna , Forsström Linda , Välimäki Niko , Aavikko Mervi , Kaasinen Eevi , Ristimäki Ari , Koskensalo Selja , Lepistö Anna , Renkonen-Sinisalo Laura , Seppälä Toni , Kuopio Teijo , Böhm Jan , Mecklin Jukka-Pekka , Kilpivaara Outi , Pitkänen Esa , Palin Kimmo , Aaltonen Lauri A.
Published: October 2018

Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We found highly variable retrotransposon activity among tumors and identified recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identified insertions in APC, likely to be tumor-initiating events. Insertions were positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions was independently associated with poor disease-specific survival.
A membrane-depolarizing toxin substrate of theStaphylococcus aureusType VII secretion system mediates intra-species competition
Authors: Ulhuq Fatima R. , Gomes Margarida C. , Duggan Gina , Guo Manman , Mendonca Chriselle , Buchanan Grant , Chalmers James D. , Cao Zhenping , Kneuper Holger , Murdoch Sarah , Thomson Sarah , Strahl Henrik , Trost Matthias , Mostowy Serge , Palmer Tracy
Published: October 2018

The type VII protein secretion system (T7SS) is conserved acrossStaphylococcus aureusstrains and plays important roles in virulence and interbacterial competition. To date only one T7SS substrate protein, encoded in a subset ofS. aureusgenomes, has been functionally characterized. Here, using an unbiased proteomic approach, we identify TspA as a further T7SS substrate. TspA is encoded distantly from the T7SS gene cluster and is found across allS. aureusstrains as well as inListeriaand Enterococci. Heterologous expression of TspA fromS. aureusstrain RN6390 indicates its C-terminal domain is toxic when targeted to theEscherichia coliperiplasm and that it depolarizes the cytoplasmic membrane. The membrane depolarizing activity is alleviated by co-production of the membrane-bound TsaI immunity protein, which is encoded adjacent totspAon theS. aureuschromosome. Using a zebrafish hindbrain ventricle infection model, we demonstrate that the T7SS of strain RN6390 promotes bacterial replicationin vivo, and deletion oftspAleads to increased bacterial clearance. The toxin domain of TspA is highly polymorphic andS. aureusstrains encode multipletsaIhomologues at thetspAlocus, suggestive of additional roles in intra-species competition. In agreement, we demonstrate TspA-dependent growth inhibition of RN6390 by strain COL in the zebrafish infection model that is alleviated by the presence of TsaI homologues.

Significance statement

Staphylococcus aureus, a human commensal organism that asymptomatically colonizes the nares, is capable of causing serious disease following breach of the mucosal barrier.S. aureusstrains encode a Type VII secretion system (T7SS) that is required for virulence in mouse infection models, and some strains also secrete a nuclease toxin by this route that has antibacterial activity. Here we identify TspA, widely found in Staphylococci and other pathogenic bacteria, as a T7 substrate. We show that TspA has membrane-depolarizing activity and thatS. aureususes TspA to inhibit the growth of a bacterial competitorin vivo.
Bumetanide prevents brain trauma-induced depressive-like behavior
Authors: Emmanuelle Goubert , Marc Altvater , Marie-Noelle Rovira , Ilgam Khalilov , Morgane Mazzarino , Anne Sebastiani , Michael Schaefer , Claudio Rivera , Christophe Pellegrino
Published: October 2018

Brain trauma triggers a cascade of deleterious events leading to enhanced incidence of drug resistant epilepsies, depression and cognitive dysfunctions. The underlying mechanisms leading to these alterations are poorly understood and treatment that attenuates those sequels not available. Using controlled-cortical impact (CCI) as experimental model of brain trauma in adult mouse we found a strong suppressive effect of the sodium-potassium-chloride importer (NKCC1) specific antagonist bumetanide on appearance of depression-like behavior. We demonstrate that this alteration in behavior is associated with a block of CCI-induced decrease in parvalbumin-positive interneurons and impairment of post-traumatic secondary neurogenesis within the dentate gyrus of the hippocampus. The mechanism mediating the effect of bumetanide involves early transient changes in expression of chloride regulatory proteins and qualitative changes in GABA(A) mediated transmission after brain trauma. This work opens new perspectives in the early treatment of human post-traumatic induced depression. Our results strongly suggest that bumetanide might constitute an efficient prophylactic treatment to reduce neurological and psychiatric consequences of brain trauma.
Effect of light intensity and nutritional value of food resources on flight response of adult parasitoid, Cotesia plutellae (Kurdjumov) (Hymenoptera: Braconidae)
Authors: Kapinder  , Tarkeshwar  , Singh Ashok Kumar
Published: October 2018

Cotesia plutellae (Kurdjumov) (Hymenoptera: Braconidae) is the major larval parasitoid of Plutella xylostella (L) (Lepidoptera: Plutellidae), which is a serious pest of cruciferous plants throughout the world. We evaluated the influence of light intensities and feeding conditions on the vertical angle of flight in freshly emerged wasps in a cylinder having diameter 15cm and height 30cm. Light intensity was found to directly affects the flight activity. Increase in light intensity causes increase in vertical flight of the female wasps. However, Increase in light intensity did not influence the inclination of vertical flight in males. Feeding condition was also found to affect the vertical flight of the wasps. Honey odour, from below the flight chamber, arrested the flight of unfed or sucrose fed wasps. However, flight of honey fed wasps was not affected by honey odour. Male flight response was also influenced by feeding condition and light intensity but the response was not as higher as shown by females. The present study is useful for selecting suitable food prior to inundative release of parasitoid in the field at suitable time period of the day.
Human neurons from Christianson syndrome iPSCs reveal allele-specific responses to rescue strategies
Authors: Lizarraga Sofia B. , Maguire Abbie M. , Ma Li , van Dyck Laura I. , Wu Qing , Nagda Dipal , Livi Liane L. , Pescosolido Matthew F. , Schmidt Michael , Alabi Shanique , Cowen Mara H. , Brito-Vargas Paul , Hoffman-Kim Diane , Gamsiz Uzun Ece D. , Schlessinger Avner , Jones Richard N. , Morrow Eric M.
Published: October 2018

Human genetic disorders provide a powerful lens to understanding the human brain. Induced pluripotent stem cells (iPSC) represent an important, new resource for mechanistic studies and therapeutic development. Christianson syndrome (CS), an X-linked neurological disorder with attenuation of brain growth postnatally (postnatal microcephaly), is caused by mutations in SLC9A6, the gene encoding endosomal Na+/H+ exchanger 6 (NHE6). We developed CS iPSC lines from patients with a mutational spectrum, as well as robust biologically-related and isogenic controls. We demonstrate that mutations in CS lead to loss of protein function by a variety of mechanisms. Regardless of mutation, all patient-derived neurons demonstrate reduced neurite growth and arborization, likely underlying diminished postnatal brain growth in patients. Additionally, phenotype rescue strategies show allele-specific responses: a gene replacement strategy shows efficacy in nonsense mutations but not in a missense mutation, whereas application of exogenous trophic factors (BDNF or IGF-1) rescues arborization phenotypes across all mutations. Our data emphasize the important principle of personalized medicine whereby success of some therapeutic strategies may be more linked to patient genotype than others.
Electron Microscopy Analysis of hAPP-Induced Neurodegeneration in the Glomerular Network
Authors: Robbins Anastasia E. , Lehmann Katherine S. , Bai Li , Belluscio Leonardo
Published: October 2018

Loss of smell is an early indicator of Alzheimer’s disease (AD), making the olfactory system an accessible model to study the effect of AD related proteins such as Amyloid Precursor Protein (APP). The regenerative capacity of the system further enables studies of circuit recovery after APP-induced degeneration. While the cellular effects of APP are well documented, little is known about its effects on brain circuits at the ultrastructural level. To study circuitry changes, we overexpressed humanized APP with familial AD mutations (hAPP) in olfactory sensory neurons and performed serial electron microscopy on olfactory bulb glomeruli from both control and hAPP expressing mice. We found that hAPP-expressing mice showed a striking decrease in glomerular connectivity along with widespread changes of subcellular structures. By then turning off hAPP expression for 6 weeks we tested the capacity of glomerular circuits to recover and found clear restoration of both connectivity and subcellular features, including an increase in post-synaptic density to above the control level. These data provide an important ultrastructural view of olfactory regions associated with AD and suggest that circuit recovery is possible in brain tissue that has experienced APP-induced neurodegeneration.
Maximum Caliber can build and infer models of oscillation in a three-gene feedback network
Authors: Firman Taylor , Amgalan Anar , Ghosh Kingshuk
Published: October 2018

Single-cell protein expression time trajectories provide rich temporal data quantifying cellular variability and its role in dictating fitness. However, theoretical models to analyze and fully extract information from these measurements remain limited for three reasons: i) gene expression profiles are noisy, rendering models of averages inapplicable, ii) experiments typically measure only a few protein species while leaving other molecular actors – necessary to build traditional bottom-up models – unnoticed, and iii) measured data is in fluorescence, not particle number. We have recently addressed these challenges in an alternate top-down approach using the principle of Maximum Caliber (MaxCal) to model genetic switches with one and two protein species. In the present work we address scalability and broader applicability of MaxCal by extending to a three-gene (A, B, C) feedback network that exhibits oscillation, commonly known as the repressilator. We test MaxCal’s inferential power by using synthetic data of noisy protein number time traces – serving as a proxy for experimental data – generated from a known underlying model. We notice that the minimal MaxCal model – accounting for production, degradation, and only one type of symmetric coupling between all three species – reasonably infers several underlying features of the circuit such as the effective production rate, degradation rate, frequency of oscillation, and protein number distribution. Next, we build models of higher complexity including different levels of coupling between A, B, and C and rigorously assess their relative performance. While the minimal model (with four parameters) performs remarkably well, we note that the most complex model (with six parameters) allowing all possible forms of crosstalk between A, B, and C slightly improves prediction of rates, but avoids ad-hoc assumption of all the other models. It is also the model of choice based on Bayesian Information Criteria. We further analyzed time trajectories in arbitrary fluorescence (using synthetic trajectories) to mimic realistic data. We conclude that even with a three-protein system including both fluorescence noise and intrinsic gene expression fluctuations, MaxCal can faithfully infer underlying details of the network, opening up future directions to model other network motifs with many species.
High resolution atlas of the venous brain vasculature from 7 T quantitative susceptibility maps
Authors: Huck Julia , Wanner Yvonne , Fan Audrey P. , Jäger Anna-Thekla , Grahl Sophia , Schneider Uta , Villringer Arno , Steele Christopher J. , Tardif Christine L. , Bazin Pierre-Louis , Gauthier Claudine J.
Published: October 2018

The vascular organization of the human brain can determine neurological and neurophysiological functions, yet thus far it has not been comprehensively mapped. Aging and diseases such as dementia are known to be associated with changes to the vasculature and normative data could help detect these vascular changes in neuroimaging studies. Furthermore, given the well-known impact of venous vessels on the blood oxygen level dependent (BOLD) signal, information about the common location of veins could help detect biases in existing datasets. In this work, a quantitative atlas of the venous vasculature using quantitative susceptibility maps (QSM) acquired with a 0.6 mm isotropic resolution is presented. The Venous Neuroanatomy (VENAT) atlas was created from 5 repeated 7 Tesla MRI measurements in young and healthy volunteers (n = 20, 10 females, mean age = 25.1 ± 2.5 years) using a two-step registration method on 3D segmentations of the venous vasculature. This cerebral vein atlas includes the average vessel location, diameter (mean: 0.84 ± 0.33 mm) and curvature (0.11 ± 0.05 mm−1) from all participants and provides an in vivo measure of the angio-architectonic organization of the human brain and its variability. This atlas can be used as a basis to understand changes in the vasculature during aging and neurodegeneration, as well as vascular and physiological effects in neuroimaging.
Subtraction and division of visual cortical population responses by the serotonergic system
Authors: Azimi Zohre , Spoida Katharina , Barzan Ruxandra , Wollenweber Patric , Mark Melanie D. , Herlitze Stefan , Jancke Dirk
Published: October 2018

Normalization is a fundamental operation throughout neuronal systems to adjust dynamic range. In the visual cortex various cell circuits have been identified that provide the substrate for such a canonical function, but how these circuits are orchestrated remains unclear. Here we suggest the serotonergic (5-HT) system as another player involved in normalization. 5-HT receptors of different classes are co-distributed across different cortical cell types, but their individual contribution to cortical population responses is unknown. We combined wide-field calcium imaging of primary visual cortex (V1) with optogenetic stimulation of 5-HT neurons in mice dorsal raphe nucleus (DRN) — the major hub for widespread release of serotonin across cortex — in combination with selective 5-HT receptor blockers. While inhibitory (5-HT1A) receptors accounted for subtractive suppression of spontaneous activity, depolarizing (5-HT2A) receptors promoted divisive suppression of response gain. Added linearly, these components led to normalization of population responses over a range of visual contrasts.
Actomyosin-mediated nanostructural remodeling of the presynaptic vesicle pool by cannabinoids induces long-term depression
Authors: McFadden Maureen H. , Xu Hao , Cui Yihui , Piskorowski Rebecca A. , Leterrier Christophe , Zala Diana , Venance Laurent , Chevaleyre Vivien , Lenkei Zsolt
Published: October 2018

Endo- and exocannabinoids, such as the psychoactive component of marijuana, exert their effects on brain function by inducing several forms of synaptic plasticity through the modulation of presynaptic vesicle release1-3. However, the molecular mechanisms underlying the widely expressed endocannabinoid-mediated long-term depression3 (eCB-LTD), are poorly understood. Here, we reveal that eCB-LTD depends on the contractile properties of the pre-synaptic actomyosin cytoskeleton. Preventing this contractility, both directly by inhibiting non-muscle myosin II NMII ATPase and indirectly by inhibiting the upstream Rho-associated kinase ROCK, abolished long-term, but not short-term forms of cannabinoid-induced functional plasticity in both inhibitory hippocampal and excitatory cortico-striatal synapses. Furthermore, using 3D superresolution microscopy, we find an actomyosin contractility-dependent redistribution of synaptic vesicle pools within the presynaptic compartment following cannabinoid receptor activation, leading to vesicle clustering and depletion from the pre-synaptic active zone. These results suggest that cannabinoid-induced functional plasticity is mediated by a nanoscale structural reorganization of the presynaptic compartment produced by actomyosin contraction. By introducing the contractile NMII as an important actin binding/structuring protein in the dynamic regulation of synaptic function, our results open new perspectives in the understanding of mechanisms of synaptic and cognitive function, marijuana intoxication and psychiatric pathogenesis.
Reduced visual and frontal cortex activation during visual working memory in grapheme-colour synaesthetes relative to young and older adults
Authors: Pfeifer Gaby , Ward Jamie , Sigala Natasha
Published: October 2018

The sensory recruitment model envisages visual working memory (VWM) as an emergent property that is encoded and maintained in sensory (visual) regions. The model implies that enhanced sensory-perceptual functions, as in synaesthesia, entail a dedicated VWM-system, showing reduced visual cortex activity as a result of neural specificity. By contrast, sensory-perceptual decline, as in old age, is expected to show enhanced visual cortex activity as a result of neural broadening. To test this model, young grapheme-colour synaesthetes, older adults and young controls engaged in a delayed pair-associative retrieval and a delayed matching-to-sample task, consisting of achromatic fractal stimuli that do not induce synaesthesia. While a previous analysis of this dataset (Pfeifer et al., 2016) has focused on cued retrieval and recognition of pair-associates (i.e. long-term memory), the current study focuses on visual working memory and considers, for the first time, the crucial delay period in which no visual stimuli are present, but working memory processes are engaged. Participants were trained to criterion and demonstrated comparable behavioural performance on VWM tasks. Whole-brain and region-of-interest-analyses revealed significantly lower activity in synaesthetes’ middle frontal gyrus and visual regions (cuneus, inferior temporal cortex) respectively, suggesting greater neural efficiency relative to young and older adults in both tasks. The results support the sensory recruitment model and can explain age and individual WM-differences based on neural specificity in visual cortex.
Two-component systems regulate swarming inPseudomonas aeruginosaPA14
Authors: Joge Shubham , Kollaran Ameen M. , Kotian Harshitha S. , Badal Divakar , Prakash Deep , Mishra Ayushi , Varma Manoj , Singh Varsha
Published: October 2018

Swarming inPseudomonas aeruginosais a quorum-dependant motility over semi-solid surfaces. On soft agar,P. aeruginosaexhibits a dendritic swarm pattern, with multiple levels of branching. Swarm patterns vary considerably depending upon the experimental design. In the present study, we show that the swarm pattern is plastic and media dependent. We define several quantifiable, macroscale features of the swarm to study the plasticity observed across media. Further, through a targeted screen of 113 genes encoding two-component system (TCS) components, we show that 44 TCS genes regulate PA14 swarming in a contextual fashion. However, only four TCS genes are essential for swarming. Many swarming-defective TCS mutants are highly efficient in biofilm formation indicating an antagonistic relationship between swarming and biofilm states inP. aeruginosa.
ChiCMaxima: a robust and simple pipeline for detection and visualization of chromatin looping in Capture Hi-C
Authors: Ben Zouari Yousra , Molitor Anne M , Sikorska Natalia , Pancaldi Vera , Sexton Tom
Published: October 2018

Capture Hi-C (CHi-C) is a new technique for assessing genome organization, based on chromosome conformation capture coupled to oligonucleotide capture of regions of interest such as gene promoters. Chromatin loop detection is challenging, since existing Hi-C/4C-like analyses, which make different assumptions about the technical biases presented, are often unsuitable. We describe a new approach, ChiCMaxima, which uses local maxima combined with a background model to detect DNA looping interactions, integrating information from biological replicates. ChiCMaxima shows more stringency and robustness compared to previously developed tools. The tool includes a GUI browser for flexible visualization of CHi-C profiles alongside epigenomic tracks.
Substantial Batch Effects in TCGA Exome Sequences Undermine Pan-Cancer Analysis of Germline Variants
Authors: Rasnic Roni , Brandes Nadav , Zuk Or , Linial Michal
Published: October 2018

Background

In recent years, research on cancer predisposition germline variants has emerged as a prominent field. The identity of somatic mutations is based on a reliable mapping of the patient germline variants. In addition, the statistics of germline variants frequencies in healthy individuals and cancer patients is the basis for seeking candidates for cancer predisposition genes. The Cancer Genome Atlas (TCGA) is one of the main sources of such data, providing a diverse collection of molecular data including deep sequencing for more than 30 types of cancer from >10,000 patients.

Methods

Our hypothesis in this study is that whole exome sequences from healthy blood samples of cancer patients are not expected to show systematic differences among cancer types. To test this hypothesis, we analyzed common and rare germline variants across six cancer types, covering 2,241 samples from TCGA. In our analysis we accounted for inherent variables in the data including the different variant calling protocols, sequencing platforms, and ethnicity.

Results

We report on substantial batch effects in germline variants associated with cancer types. We attribute the effect to the specific sequencing centers that produced the data. Specifically, we measured 30% variability in the number of reported germline variants per sample across sequencing centers. The batch effect is further expressed in nucleotide composition and variant frequencies. Importantly, the batch effect causes substantial differences in germline variant distribution patterns across numerous genes, including prominent cancer predisposition genes such as BRCA1, RET, MAX, and KRAS. For most of known cancer predisposition genes, we found a distinct batch-dependent difference in germline variants.

Conclusion

TCGA germline data is exposed to strong batch effects with substantial variabilities among TCGA sequencing centers. We claim that those batch effects are consequential for numerous TCGA pan-cancer studies. In particular, these effects may compromise the reliability and the potency to detect new cancer predisposition genes. Furthermore, interpretation of pan-cancer analyses should be revisited in view of the source of the genomic data after accounting for the reported batch effects.
Evolutionary stasis of the pseudoautosomal boundary in strepsirrhine primates
Authors: Shearn Rylan , Wright Alison E. , Mousset Sylvain , Régis Corinne , Penel Simon , Lemaitre Jean-François , Douay Guillaume , Crouau-Roy Brigitte , Lecompte Emilie , Marais Gabriel A.B.
Published: October 2018

Abstract

Sex chromosomes are typically comprised of a non-recombining region and a recombining pseudoautosomal region. Accurately quantifying the relative size of these regions is critical for sex chromosome biology both from a functional (i.e. number of sex-linked genes) and evolutionary perspective (i.e. extent of Y degeneration and X-Y heteromorphy). The evolution of the pseudoautosomal boundary (PAB) - the limit between the recombining and the non-recombining regions of the sex chromosomes - is well documented in haplorrhines (apes and monkeys) but not in strepsirrhines (lemurs and lorises), which represent almost 30% of all primates. Here we studied the PAB of seven species representing the main strepsirrhine lineages by sequencing a male and a female genome in each species and using sex differences in coverage to identify the PAB. We found that during primate evolution, the PAB has remained unchanged in strepsirrhines whereas several recombination suppression events moved the PAB and shortened the pseudoautosomal region in haplorrhines. Strepsirrhines are well known to have much lower sexual dimorphism than haplorrhines. We suggest that mutations with antagonistic effects between males and females have driven recombination suppression and PAB evolution in haplorrhines. Our work supports the view that sexually antagonistic mutations have influenced the evolution of sex chromosomes in primates.
Double-digest RAD-sequencing: do wet and dry protocol parameters impact biological results?
Authors: Cumer Tristan , Pouchon Charles , Boyer Frédéric , Yannic Glenn , Rioux Delphine , Bonin Aurélie , Capblancq Thibaut
Published: October 2018

Next-generation sequencing technologies have opened a new era of research in genomics. Among these, restriction enzyme-based techniques such as restriction-site associated DNA sequencing (RADseq) or double-digest RAD-sequencing (ddRADseq) are now widely used in many population genomics fields. From DNA sampling to SNP calling, both wet and dry protocols have been discussed in the literature to identify key parameters for an optimal loci reconstruction.

The impact of these parameters on downstream analyses and biological results drawn from RADseq or ddRADseq data has however not been fully explored yet. In this study, we tackled this issue by investigating the effects of ddRADseq laboratory (i.e. wet protocol) and bioinformatics (i.e. dry protocol) settings on loci reconstruction and inferred biological signal at two evolutionary scale using two systems: a complex of butterfly species (Coenonympha sp.) and populations of Common beech (Fagus sylvatica).

Results suggest an impact of wet protocol parameters (DNA quantity, number of PCR cycles during library preparation) on the number of recovered reads and SNPs, the number of unique alleles and individual heterozygosity. We also found that bioinformatic settings (i.e. clustering and minimum coverage thresholds) impact loci reconstruction (e.g. number of loci, mean coverage) and SNP calling (e.g. number of SNPs, heterozygosity). We however do not detect an impact of parameter settings on three types of analysis performed with ddRADseq data: measure of genetic differentiation, estimation of individual admixture, and demographic inferences. In addition, our work demonstrates the high reproducibility and low rate of genotyping inconsistencies of the ddRADseq protocol.

Thus, our study highlights the impact of wet parameters on ddRADseq protocol with strong consequences on experimental success and biological conclusions. Dry parameters affects loci reconstruction and descriptive statistics but not biological conclusion for the two studied systems. Overall, this study illustrates, with others, the relevance of ddRADseq for population and evolutionary genomics at the inter- or intraspecific scales.
Insulin Receptor Deletion in S100a4-lineage cells accelerates age-related bone loss
Authors: Studentsova Valentina , Knapp Emma , Loiselle Alayna E.
Published: October 2018

Type I and Type II Diabetes dramatically impair skeletal health. Altered Insulin Receptor (IR) signaling is a common feature of both diseases, and insulin has potent bone anabolic functions. Several previous studies have demonstrated that loss of IR in bone cells results in disrupted bone homeostasis during early post-natal growth. Here we have deleted IR in S100a4-lineage cells (IRcKOS100a4) and assessed the effects on bone homeostasis at both young (15 weeks) and older adult (48 weeks) mice. S100a4-cre has previously been shown to target the perichondrium during bone development, and here we show that S100a4 is expressed by adult trabecular and cortical bone cells, and that S100a4-Cre effectively targets adult bone, resulting in efficient deletion of IR. Deletion of IR in S100a4-lineage cells does effect initial bone acquisition or homeostasis with no changes in cortical, trabecular or mechanical properties at 15-weeks of age, relative to wild type (WT) littermates. However, by 48-weeks of age, IRcKOS100a4 mice display substantial declines in trabecular bone volume, bone volume fraction and torsional rigidity, relative to age-matched WT controls. This work establishes the utility of using S100a4-cre to target bone and demonstrates that IR in S100a4-lineage cells is required for maintenance of bone homeostasis in adult mice.
A Sparse Additive Model for High-Dimensional Interactions with an Exposure Variable
Authors: Bhatnagar Sahir R , Lu Tianyuan , Lovato Amanda , Olds David L , Kobor Michael S , Meaney Michael J , O’Donnell Kieran , Yang Yi , Greenwood Celia MT
Published: October 2018

A conceptual paradigm for onset of a new disease is often considered to be the result of changes in entire biological networks whose states are affected by a complex interaction of genetic and environmental factors. However, when modelling a relevant phenotype as a function of high dimensional measurements, power to estimate interactions is low, the number of possible interactions could be enormous and their effects may be non-linear. In this work, we introduce a method calledsailfor detecting non-linear interactions with a key environmental or exposure variable in high-dimensional settings which respects the strong or weak heredity constraints. We prove that asymptotically, our method possesses the oracle property, i.e., it performs as well as if the true model were known in advance. We develop a computationally efficient fitting algorithm with automatic tuning parameter selection, which scales to high-dimensional datasets. Through an extensive simulation study, we show thatsailoutperforms existing penalized regression methods in terms of prediction accuracy and support recovery when there are non-linear interactions with an exposure variable. We applysailto detect non-linear interactions between genes and a prenatal psychosocial intervention program on cognitive performance in children at 4 years of age. Results show that individuals who are genetically predisposed to lower educational attainment are those who stand to benefit the most from the intervention. Our algorithms are implemented in an R package available on CRAN (https://cran.r-project.org/package=sail).
Baseline human gut microbiota profile in healthy people and standard reporting template
Authors: King Charles Hadley , Desai Hiral , Sylvetsky Allison C. , LoTempio Jonathan , Ayanyan Shant , Carrie Jill , Crandall Keith , Fochtman Brian , Gasparyan Lusine , Gulzar Naila , Howell Paul , Issa Najy , Krampis Konstantinos , Mishra Lopa , Morizono Hiroki , Pisegna Joseph R. , Rao Shuyun , Ren Yao , Simonyan Vahan , Smith Krista , VedBrat Sharanjit , Yao Michael , Mazumder Raja
Published: October 2018

A comprehensive knowledge of the types and ratios of microbes that inhabit the healthy human gut is necessary before any kind of pre-clinical or clinical study can be performed that attempts to alter the microbiome to treat a condition or improve therapy outcome. To address this need we present an innovative scalable comprehensive analysis workflow, a healthy human reference microbiome list and abundance profile (GutFeelingKB), and a novel Fecal Biome Population Report (FecalBiome) with clinical applicability. GutFeelingKB provides a list of 157 organisms (8 phyla, 18 classes, 23 orders, 38 families, 59 genera and 109 species) that forms the baseline biome and therefore can be used as healthy controls for studies related to dysbiosis. The incorporation of microbiome science into routine clinical practice necessitates a standard report for comparison of an individual’s microbiome to the growing knowledgebase of “normal” microbiome data. The FecalBiome and the underlying technology of GutFeelingKB address this need. The knowledgebase can be useful to regulatory agencies for the assessment of fecal transplant and other microbiome products, as it contains a list of organisms from healthy individuals. In addition to the list of organisms and abundances the study also generated a list of contigs of metagenomics dark matter. In this study, metagenomic dark matter represents sequences that cannot be mapped to any known sequence but can be assembled into contigs of 10,000 nucleotides or higher. These sequences can be used to create primers to study potential novel organisms. All data is freely available from https://hive.biochemistry.gwu.edu/gfkb and NCBI’s Short Read Archive.
Exploratory and prospective model of stent restenosis after Percutaneous Coronary Intervention using Multivariate Gaussian Subspatial Regression
Authors: Vicente-Palacios Victor , Vicente-Tavera Santiago , Dorado-Díaz P. Ignacio , Sanchez-Puente Antonio , Sampedro-Gómez Jesús , Galindo Purificación , Gómez Itziar , San Román José A. , Fernández-Avilés Francisco , Sánchez Pedro L.
Published: October 2018

A new statistical analysis methodology, “Multivariate Gaussian Subspatial Regression” (MGSR), has been applied to randomized clinical trial data collected from percutaneous coronary intervention (PCI) patients, which combines the descriptive quality of Factorial Techniques and the predictive power of Gaussian Processes.

This model has been built from 3 different quantitative coronary angiographic core-lab measures of the same lesion from 2 separate angiograms (at baseline before PCI, at baseline immediately after PCI and at 12 months follow-up). Measurements of the pre-PCI variables of a patient are mapped to the factorial plane and predictions are visualized as regions of interest in this plane.

MGSR makes it possible to detect patients at risk of coronary stent restenosis or patients in whom ruling out the disease, in a graphical way; avoiding unnecessary, costly and possibly risky treatments for patients with no complications predicted; and advising to closely follow patients at risk. In addition, the model recovers missing values regardless of the variables, and once fitted, it corrects itself when more dependent variables are included.

MGSR software is freely available online at https://github.com/victorvicpal/MGSR.
Synthesis, structural characterization and fluorescence enhancement of chromophore-modified polyoxometalates
Authors: Fura Gizaw D. , Long Yong , Yan Jun , Chen Wei , Lin Chang-Gen , Song Yu-Fei
Published: October 2018

Intramolecular charge transfers between π-conjugated molecules and polyoxometalate (POM) clusters have been observed in donor–acceptor systems based on organic donors and inorganic POM acceptors, which unfortunately results in a general quenching of the chromophore luminescence. The development of POM–chromophore dyads that are capable of tackling the quenching process and enhancing the fluorescence intensity of such systems remains a highly challenging area of study. A family of organic–inorganic polyoxometalate hybrids, {[(n-C4H9)4N]3[(MnMo6O24){(CH2)3CR}2]} [1, R = –NHCH2C14H9, namely (anthracen-9-ylmethyl)amino; 2, R = –NHCH2C13H9, (9H-fluoren-2-ylmethyl)amino; 3, R = –NHCH2C10H7, (naphthalen-2-ylmethyl)amino; 4, R = –NHCH2C16H9, (pyren-2-ylmethyl)amino], were synthesized by covalently tethering π-conjugated molecules onto an Anderson cluster. The resulting POM–chromophore dyads were fully characterized by various spectroscopic techniques, single-crystal X-ray diffraction analysis and ESI–MS. The fluorescence features of these dyads were studied in detail to verify a dramatic emission enhancement that can be achieved by fine-tuning the microenvironment in solution and suppressing the intrinsic photo-induced electron-transfer process.
Iron(II) and copper(II) paratungstates B: a single-crystal X-ray diffraction study
Authors: Gumerova Nadiia I. , Dobrov Anatolie , Roller Alexander , Rompel Annette
Published: October 2018

Paratungstate B is a common isopolytungstate (IPOT) built of the [W12O40(OH)2]10− anion and exhibits a cluster-like construction of 12 W-centred distorted octahedra. Due to a high surface charge density, the paratungstate anion acts as a multidentate ligand forming high-dimensional extended structures, which exhibit unique catalytic and magnetic properties. Two new paradodecatungstate B compounds decorated by iron(II) or copper(II), namely Na5Fe2.5[W12O40(OH)2]·36H2O (Na5Fe2.5paraB) and Na4Cu3[W12O40(OH)2]·28H2O (Na4Cu3paraB), have been synthesized by a convenient aqueous solution method, and structurally characterized by single-crystal and powder X-ray diffraction, IR spectroscopy, elemental analysis and thermogravimetric analysis. Both compounds crystallize in the triclinic P\overline{1} space group. In both compounds, the [W12O40(OH)2]10− polyanion acts as a multidentate ligand that links transition-metal and sodium cations, forming a three-dimensional framework.
Characterization and structure determination of a llama-derived nanobody targeting the J-base binding protein 1
Authors: van Beusekom Bart , Heidebrecht Tatjana , Adamopoulos Athanassios , Fish Alexander , Pardon Els , Steyaert Jan , Joosten Robbie P. , Perrakis Anastassis
Published: October 2018

J-base binding protein 1 (JBP1) contributes to the biosynthesis and maintenance of base J (β-D-glucosylhydroxymethyluracil), a modification of thymidine confined to some protozoa. Camelid (llama) single-domain antibody fragments (nanobodies) targeting JBP1 were produced for use as crystallization chaperones. Surface plasmon resonance screening identified Nb6 as a strong binder, recognizing JBP1 with a 1:1 stoichiometry and high affinity (K
d = 30 nM). Crystallization trials of JBP1 in complex with Nb6 yielded crystals that diffracted to 1.47 Å resolution. However, the dimensions of the asymmetric unit and molecular replacement with a nanobody structure clearly showed that the crystals of the expected complex with JBP1 were of the nanobody alone. Nb6 crystallizes in space group P31 with two molecules in the asymmetric unit; its crystal structure was refined to a final resolution of 1.64 Å. Ensemble refinement suggests that in the ligand-free state one of the complementarity-determining regions (CDRs) is flexible, while the other two adopt well defined conformations.
Crystal structure and optical spectroscopic analyses of (E)-3-(1H-indol-2-yl)-1-(4-nitrophenyl)prop-2-en-1-one hemihydrate
Authors: Zaini Muhamad Fikri , Razak Ibrahim Abdul , Khairul Wan Mohd , Arshad Suhana
Published: October 2018

The asymmetric unit of the title compound, 2C17H12N2O3·H2O comprises two molecules of (E)-3-(1H-indol-2-yl)-1-(4-nitrophenyl)prop-2-en-1-one and a water molecule. The main molecule adopts an s-cis configuration with respect to the C=O and C=C bonds. The dihedral angle between the indole ring system and the nitro-substituted benzene ring is 37.64 (16)°. In the crystal, molecules are linked by O—-H...O and N—H...O hydrogen bonds, forming chains along [010]. In addition, weak C—H...O, C—H...π and π–π interactions further link the structure into a three-dimensional network. The optimized structure was generated theoretically via a density functional theory (DFT) approach at the B3LYP/6–311 G++(d,p) basis level and the HOMO–LUMO behaviour was elucidated to determine the energy gap. The obtained values of 2.70 eV (experimental) and 2.80 eV (DFT) are desirable for optoelectronic applications. The intermolecular interactions were quantified and analysed using Hirshfeld surface analysis.