bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Illness Protocol for Urea Cycle Disorders
Authors: Rodan Lance H. , Aldubayan Saud H. , Berry Gerard T. , Levy Harvey L.
Published: November 2017

Inborn errors of metabolism (IEMs) are genetic disorders that disrupt enzyme activity, cellular transport, or energy production. They are individually rare but collectively have an incidence of 1:1000. Most patients with IEMs are followed up by a physician with expertise in biochemical genetics (metabolism), but may present outside this setting. Because IEMs can present acutely with life-threatening crises that require specific interventions, it is critical for the emergency physician, internist, and critical care physician as well as the biochemical geneticist to have information on the initial assessment and management of patients with these disorders. Appropriate early care can be lifesaving. This protocol is not designed to replace the expert consultation of a biochemical geneticist, but rather to improve early care and increase the level of comfort of the acute care physician with initial management of urea cycle disorders until specialty consultation is obtained.
New Oxidative Stress Markers Useful in the Diagnosis of Acute Appendicitis in Children
Authors: Elmas Bahri , Yildiz Turan , Yazar Hayrullah , İlçe Zekeriya , Bal Ceylan , Özbek Betül , Yürümez Yusuf
Published: November 2017

Objectives

The aim of this study was to evaluate 2 new oxidative stress markers, thiol/disulfide homeostasis status and the asymmetric dimethylarginine (ADMA) level, in children with acute appendicitis (AA) and to evaluate their diagnostic utility.

Methods

This case-control study included 45 patients with AA and 35 healthy children. Age, sex, white blood cell count, neutrophil-to-lymphocyte ratio, high-sensitivity C-reactive protein (hs-CRP) level, ultrasonographic findings, thiol/disulfide homeostasis parameters (native and total thiol levels, native thiol/total thiol ratios [antioxidant parameters], and disulfide, disulfide/native thiol, and disulfide/total thiol ratios [oxidant parameters]), and the ADMA level were compared between the 2 groups.

Results

The native and total thiol levels, and the native thiol/total thiol ratio, were significantly lower, and the disulfide level and disulfide/native thiol and disulfide/total thiol ratios significantly higher, in the AA compared with the control group (all P < 0.001). The ADMA level was significantly higher in a perforated versus nonperforated subgroup of AA patients, but the thiol/disulfide homeostasis parameters did not differ significantly between the two subgroups. In addition, the hs-CRP level and appendiceal wall thickness were higher in the perforated subgroup. The thiol/disulfide antioxidant parameters and ADMA level correlated negatively with the white blood cell count, the neutrophil-to-lymphocyte ratio, and the hs-CRP level, in the AA group, but correlated positively with oxidant parameters. The sensitivity and specificity of the disulfide/native thiol and disulfide/total thiol ratios were high when used to diagnose AA, whereas the sensitivity of the ADMA level was high when used to diagnose perforated appendicitis.

Conclusions

Thiol/disulfide homeostasis and the ADMA level, together with certain other parameters, may be useful biomarkers of AA in children.
Micturition Syncope in Childhood
Authors: Marzuillo Pierluigi , Guarino Stefano , Tipo Vincenzo , Apicella Andrea , Grandone Anna , Diplomatico Mario , Polito Cesare , Miraglia del Giudice Emanuele , La Manna Angela , Perrone Laura
Published: November 2017

Frequently, general pediatricians could face a patient with syncope, which represents approximately 1% to 3% of emergency visits. Micturition syncope is a transient loss of consciousness with onset immediately before, during, or after micturition. Literature evidence indicates that healthy young men are a population with major risk for presenting micturition syncope, with a peak of incidence around 40 to 50 years of age. Usually, this syncope occurs in the morning, after wake-up, or, more generally, when the male patients assume the orthostatic position after a period of supine position in a warm bed. No information on micturition syncope clinical presentation and prevalence in childhood is available in the literature, and probably, this kind of syncope is unrecognized in childhood. We describe 4 unreported pediatric patients with a diagnosis of micturition syncope and well-defined clinical presentation. In all patients, the syncope has been presented in the same conditions: in the morning; after wake-up; in an orthostatic position; just before, after, or during urinary bladder voiding; and with spontaneous recovery in few minutes. Interestingly, 1 patient presented with the syncope during urinary bladder voiding by autocatheterization. In our patients, all investigations made as the first approach in the pediatric emergency department did not show any abnormal results, possibly underlying the syncope episodes. By describing our experience, we want to underline the clinical presentation of micturition syncope and give to the clinicians the elements to recognize and manage it easily in children.
Clinical Factors Associated With Pediatric Brain Neoplasms Versus Primary Headache
Authors: Sheridan David C. , Waites Bethany , Lezak Bradley , Coryell Robert J. , Nazemi Kellie J. , Lin Amber L. , Fu Rongwei , Hansen Matthew L.
Published: November 2017

Objective

Pediatric headaches are a common presentation to emergency departments accounting for almost half a million annual visits. Providers are left with the difficult task of deciding who has a secondary headache etiology that warrants neuroimaging.

Methods

We conducted a retrospective case-control study. Patients from a pediatric neuro-oncology clinic database with brain cancer and a headache at presentation were identified as cases. Controls were patients from 2 local pediatric tertiary care emergency departments with a final diagnosis of headache after negative neuroimaging. Clinical factors were decided a priori, and logistic regression was used to determine which clinical factors were related to case/control status.

Results

A total of 334 patients (203 controls and 131 cases) were included. Patients with a history of headaches had 0.5 (95% confidence interval [CI]: 0.3–0.9; P = 0.03) times the odds of being a case. Patients with vomiting had increased odds of being a case compared with controls regardless of the time of day (early morning 1.8 [95% CI: 1.0–3.2; P = 0.04] and non–early morning 6.6 [95% CI: 2.0–21.7; P < 0.01]). Patients with neurological signs had 10.3 (95% CI: 5.4–19.4; P < 0.01) times the odds of being a case, and patients with an associated seizure had 10.9 (95% CI: 3.8–30.7; P < 0.01) times the odds of being a case.

Conclusions

This study identified clinical factors associated with pediatric brain neoplasms that may guide acute neuroimaging decisions. This study also provides insight into potential clinical factors to be studied prospectively to derive a clinical decision rule.
Metastatic Endocervical Adenocarcinoma in a Mature Cystic Teratoma: A Case of a Tumor-to-Tumor Metastasis
Authors: Santos Filipa , Oliveira Catarina , Caldeira João P. , Coelho Ana , Félix Ana
Published: November 2017

Tumor-to-tumor metastasis is a rare phenomenon defined as a metastasis in a histologically distinct tumor. We report an unusual case of a 51-yr-old woman who presented with a cervical, bleeding lesion diagnosed as a poorly differentiated adenocarcinoma, HPV18+. Imaging studies revealed an unresectable cervical carcinoma with an associated left ovarian multicystic teratoma. A suspicious solid nodule within the teratoma was also reported. Bilateral salpingo-oophorectomy was performed before the cervical tumor was treated. Pathologic findings showed a multicystic tumor measuring 110×40×30 mm with an area of adenocarcinoma, morphologically similar to the cervical neoplasm. The immunoprofile obtained in the malignant ovarian component (p16+, carcinogenic embryonic antigen+, vimentin−, estrogen receptor−) was similar to the one in the cervix. Moreover, both lesions harbored HPV18. These findings confirmed the presence of a metastatic cervical adenocarcinoma in a mature cystic teratoma. In the differential diagnosis, both somatic malignant transformation of the mature cystic teratomas and the presence of a “collision tumor” were considered and are discussed in this case report.
Clear Cell Renal Cell Carcinoma Metastatic to the Gynecologic Tract: A Clinicopathologic Analysis of 17 Cases
Authors: Fadare Oluwole , Desouki Mohamed M. , Gwin Katja , Hanley Krisztina Z. , Jarboe Elke A. , Liang Sharon X. , Quick Charles M. , Rawish Kojo R. , Roma Andres A. , Zheng Wenxin , Hecht Jonathan L. , Parkash Vinita , Osunkoya Adeboye O.
Published: November 2017

Clear cell renal cell carcinomas (CCRCC) rarely metastasizes to the gynecologic tract. In this study, we analyzed a multi-institutional data set to provide insights into the clinical, morphologic, and immunophenotypic features of this phenomenon. Seventeen metastatic CCRCC involving the gynecologic tract [ovary/fallopian tube (n=9), vulva (n=2), uterine corpus (n=3), cervix (n=2), uterine serosa (n=1)] were analyzed. Mean patient age was 62 yr (range: 45–79 yr). Most cases (15/17) presented as a recurrence 6 to 72 mo postnephrectomy, 1 case was concurrently diagnosed, and 1 case (a cervical metastasis) was diagnosed prenephrectomy. In 10 cases, metastases to other locations were identified within 6 wk of the gynecologic tract lesion. The adnexa were the most common site of metastases and the mean tumor size of adnexal metastases was 3.7 cm; in only 2 of 9 cases were metastases bilateral and only 1 had external surface nodules. The morphologic and immunohistochemical features of metastatic CCRCC were compared with those of 102 müllerian clear cell carcinomas (müllerian CCC: 49 endometrial, 53 ovarian). Although CCRCC and müllerian CCC displayed extensive morphologic overlap, a higher mitotic index and a higher frequency of an alveolar pattern were seen in CCRCC, whereas diffuse hobnail cells, hyaline globules, tubulocystic pattern, or any papillary pattern were more frequently seen in müllerian CCC. CA-IX, CD10, and renal cell carcinoma antigen were more frequently expressed in CCRCC than müllerian CCC, whereas Napsin-A, CK7, and p504S showed the reverse. PAX8 and HNF1β did not significantly distinguish between the 2 groups. In summary, gynecologic tract metastases most often occur as a relapse of a previously resected CCRCC, and these relapses may occur many years postnephrectomy. Gynecologic tract metastases are often accompanied by concurrent metastases to other organs. The gross pathology of metastatic CCRCC in the ovary may potentially overlap with primary neoplasia. However, the expected morphology and immunophenotype of CCRCC are maintained in most gynecologic tract metastases. As such, although metastatic CCRCC and müllerian CCC may display significant overlap in pathologic features, several morphologic and immunophenotypic features are useful in their distinction.
MAGE-A4 and MAGE-A1 Immunohistochemical Expression in High-grade Endometrial Cancer
Authors: Srdelić Sanja , Kuzmić-Prusac Ivana , Spagnoli Giulio C. , Juretić Antonio , Čapkun Vesna
Published: November 2017

The aim was to investigate MAGE-A4 and MAGE-A1 protein expression in high-grade endometrial cancer and determine its correlation with histologic subtype, FIGO stage, presence of vascular invasion, disease free, and overall survival. Immunohistochemical staining was performed by using 77B (MAGE-A1) and 57B (MAGE-A4) monoclonal antibodies on paraffin-embedded sections from high-grade endometrial cancers diagnosed in University Hospital Split between 1998 and 2011 (n=77). Median follow-up time for survivors was 48 mo. MAGE-A4 was found to be expressed in 33% of endometrioid type endometrial cancers grade 3 and in 27% of serous and clear cell carcinomas. MAGE-A1 was found to be expressed in 93% endometrioid endometrial cancer grade 3 and 86% of serous and clear cell carcinomas. Univariate analysis showed that positive immunohistochemical staining for MAGE-A4 was associated with decreased disease free and overall survival in patients with high-grade endometrial cancer. Multivariate analysis showed an association between MAGE-A4 overexpression and decreased disease free but not overall survival in high-grade endometrial cancer. No correlation was found between MAGE-A1 immunohistochemical expression and patient survival. There was no significant correlation between MAGE-A4 and MAGE-A1 expression and histologic subtype, FIGO stage, lymph node metastasis, muscular infiltration, and lymphovascular invasion. MAGE-A4 immunohistochemical expression is associated with decreased disease free and overall survival in patients with high-grade endometrial cancer. Our findings suggest that MAGE-A1 may be expressed in the epithelial cells of the normal endometrium. MAGE-A1 is highly expressed in high-grade endometrial cancer, with no impact on survival.
PDGFB Rearrangements in Dermatofibrosarcoma Protuberans of the Vulva: A Study of 11 Cases Including Myxoid and Fibrosarcomatous Variants
Authors: Jahanseir Khadijeh , Xing Deyin , Greipp Patricia T. , Sukov William R. , Keeney Gary L. , Howitt Brooke E. , Schoolmeester J. Kenneth
Published: November 2017

Dermatofibrosarcoma protuberans (DFSP) is a low-grade fibroblastic sarcoma that tends to arise in young to middle age adults and involve the trunk and proximal extremities. Rare examples of vulvar DFSP have been reported, including myxoid, myoid, and fibrosarcomatous variants, but detection of the characteristic t(17;22)(q22;q13) that produces COL1A1-PDGFB gene fusion has not been evaluated in a large series of primary vulvar tumors. The clinical, morphologic, immunohistochemical, and molecular cytogenetic features of 11 cases were examined. Patient age ranged from 29 to 75 yr (mean, 46 yr; median, 43 yr). Seven tumors were purely classic DFSP, 1 was purely myxoid DFSP and the remaining 3 had varying quantities of fibrosarcomatous DFSP. All cases of classic DFSP had diffuse expression of CD34 and low-level p53 immunoreactivity. Myxoid variants had strong, but reduced expression of CD34. Fibrosarcomatous DFSP showed focal CD34 expression and increased p53 reactivity. Nine of 11 tumors (82%) had rearrangement of PDGFB by fluorescence in situ hybridization. The 2 nonrearranged tumors were a classic DFSP and a myxoid DFSP with fibrosarcomatous transformation. Follow-up was available for 9 patients (82%) and ranged from 1 to 108 mo (mean, 30 mo; median, 21 mo). Eight patients had tumors with positive margins, one of which developed local recurrence after no further therapy. No patient developed metastasis. The high frequency of PDGFB rearrangement in vulvar DFSP provides a useful exploit in diagnostically challenging cases and genetic evidence of probable clinical response to targeted therapeutics in cases of locally advanced or metastatic tumors.
Bone Mineral Density Declines Twice as Quickly Among HIV-Infected Women Compared With Men
Authors: Erlandson Kristine M. , Lake Jordan E. , Sim Myung , Falutz Julian , Prado Carla M. , Domingues da Silva Ana Rita , Brown Todd T. , Guaraldi Giovanni
Published: November 2017

Background:

Initial declines in bone mineral density (BMD) after antiretroviral therapy initiation in HIV are well described, but data on long-term changes and risk factors for decline, particularly among women, are limited.

Methods:

HIV-infected men and women in the Modena Metabolic Clinic underwent dual-energy X-ray absorptiometry (DXA) scans every 6–12 months for up to 10 years (median 4.6 years). Mixed effect regression models in combined and sex-stratified models determined annual rates of decline and clinical factors associated with BMD. Models included demographics, HIV-specific factors, and bone-specific factors; a final model added a sex × time interaction term.

Results:

A total of 839 women and 1759 men contributed ≥2 DXA scans. The majority (82%) were 50 years and younger; 76% had HIV-1 RNA <50 copies per milliliter at baseline; 15% of women were postmenopausal and 7% of men had hypogonadism; and 30% and 27%, respectively, had hepatitis C virus (HCV) coinfection. The adjusted slopes in BMD among women and men were significantly different at both the femoral neck (women −0.00897 versus men −0.00422 g/cm2 per year; P < 0.001) and L-spine (women −0.0127 versus men −0.00763 g/cm2 per year; P < 0.001). Modifiable risks associated with BMD decline included antiretroviral therapy exposure (greater decline with tenofovir disoproxil fumarate and less decline with integrase strand transfer inhibitor therapy), HCV, physical activity, and vitamin D insufficiency.

Conclusions:

Among HIV-infected individuals, bone density at the femoral neck, a significant predictor of fracture risk, declined twice as quickly among women compared with men. Female sex was independently associated with both lower femoral neck and lumbar BMD over time in adjusted models.
Platelet Function Changes in a Time-Dependent Manner Following Traumatic Brain Injury in a Murine Model
Authors: Martin Grace E. , Xia Brent , Kim Young , Johnson Mark D. , Veile Rosalie , Friend Lou Ann , Makley Amy T. , Caldwell Charles C. , Goodman Michael D.
Published: November 2017

Traumatic brain injury (TBI) results in systemic changes in coagulation and inflammation that contribute to post-traumatic morbidity and mortality. The potential interaction of platelets and pro-inflammatory cytokines in the modulation of coagulation, microthrombosis, and venous thromboembolic events after moderate TBI has not been determined. Using a murine model, we hypothesized that the degree of platelet-induced coagulation varies depending on the platelet aggregation agonist platelet-induced coagulation changes in a time-dependent manner following TBI, and changes in platelet-induced coagulation are mirrored by changes in the levels of circulating pro-inflammatory cytokines. An established weight-drop model was used to induce TBI in anesthetized mice. Blood samples were collected at intervals after injury for measurements of platelet count, serum fibrinogen, pro-inflammatory cytokines, and determination of soluble P-selectin levels. Thromboelastometry was used to evaluate changes in hemostasis. Platelet function was determined using whole blood impedance aggregometry. Ten minutes following TBI, adenosine diphosphate-induced platelet aggregation decreased as measured by platelet aggregometry. Despite no changes in platelet counts and serum fibrinogen, platelet aggregation, pro-inflammatory cytokines, and soluble P-selectin were increased at 6 h after TBI. Rotation thromboelastometry demonstrated increased maximal clot firmness at 6 h. Platelet function and coagulability returned to baseline levels 24 h following head injury. Our data demonstrate that after TBI, acute platelet dysfunction occurs followed by rebound platelet hyperaggregation. Alterations in post-TBI platelet aggregation are reflected in whole blood thromboelastometry and are temporally associated with the systemic pro-inflammatory response.
Relative Efficacies of HBOC-201 and Polyheme to Increase Oxygen Transport Compared to Blood and Crystalloids
Authors: Dubé Gregory P. , Pitman Arkadiy N. , Mackenzie Colin F.
Published: November 2017

Background:

Because total hemoglobin in circulation ([THb]) is an established predictor of clinical outcomes in anemic individuals, the relative efficacies of resuscitation fluids to increase [THb] can be used to design better hemoglobin-based oxygen carrier (HBOC) clinical trials.

Methods:

Expected efficacies of HBOC-201 (13 g Hb/dL) and packed red blood cells (RBCs) (packed red blood cells [pRBCs], 24 g Hb/dL) to increase [THb] were calculated and interpreted in the context of severe adverse events (SAEs) in the HEM-0115 phase III clinical trial.

The PolyHeme phase III clinical trial compared the HBOC, PolyHeme (10 g Hb/dL), with crystalloid control prehospital and packed RBCs in hospital. The comparative abilities of these resuscitation fluids to maintain [THb] were interpreted in the context of mortality.

Results:

In HEM-0115, infusion of HBOC-201 increased [THb] by 0.18 ± 0.03 g/dL (N=121) compared with 0.87 ± 0.07 g/dL (n = 115) following one unit of pRBCs. These observed increases in [THb] were similar to expected increases for these fluids. Use of HBOC-201 was associated with 0.34 SAEs per patient compared with 0.25 SAEs per patient in the pRBC arm (P = 0.016).

Hemoglobin Deficit was greater in HBOC-201-treated patients than in pRBC controls and emerged as a predictor of SAEs in a logistics model. Randomization to HBOC-201 had no power to predict SAEs.

PolyHeme more effectively maintained [THb] than did crystalloid prior to arrival at hospital, associated with initially higher survival in the PolyHeme arm. Thereafter, PolyHeme subjects sustained lower [THb] and higher mortality than controls.

Conclusion:

Greater anemia in subjects randomized to HBOC-201 was consistent with the relative efficacies of HBOC-201 and pRBCs to increase [THb] and may have contributed to more SAEs in the HBOC arm of HEM-0115 and greater long-term mortality in the PolyHeme trial.
Definition of Recurrent Urinary Tract Infections in Women: Which One to Adopt?
Authors: Malik Rena D. , Wu Yuefeng (Rose) , Zimmern Philippe E.
Published: November 2017

Objectives

The aim of this study was to systematically review the various definitions of recurrent urinary tract infection (RUTI) recommended by experts and specialty societies cited in biomedical literature.

Methods

A systematic review of RUTI in women was conducted using MEDLINE, EMBASE, and PubMed between 1966 and 2016 according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Statement. Twenty-five publications were selected for inclusion in this analysis.

Results

From review of included publications, 14 definitions of RUTI were obtained. Each source was searched for a textual definition of RUTI as well as presence or absence of specific key elements including urinary symptoms, colony forming unit count, bacterial species, number of UTIs per year, interval time between infections and a negative intervening culture. All data were reviewed by 2 separate investigators. The definition of RUTI was found highly variable in the literature. The tallying of key elements in included definitions suggests that a minimum RUTI definition should include urinary symptoms, urine culture colony forming unit/mL threshold, differentiation of bacterial persistence versus reinfection by bacterial species, and number of UTIs per year.

Conclusions

This review of major RUTI definition recommendations by expert individuals and specialty societies underlines the lack of uniformity and the need for a more robust and generally agreeable RUTI definition for use in clinical and academic practice.
The Relationship Between Intra-Abdominal Pressure and Body Acceleration During Exercise
Authors: de Gennaro Johanna Day , de Gennaro Claire K. , Shaw Janet M. , Petelenz Tomasz J. , Nygaard Ingrid E. , Hitchcock Robert W.
Published: November 2017

Objectives

High intra-abdominal pressure (IAP) may influence the development of pelvic floor disorders. We and others have used intravaginal pressure transducers to measure IAP in women during exercise and daily activities, but utilizing the transducer for long-term measurements creates compliance issues. Waist-worn accelerometers are prominent in research and may be a reliable alternative for approximating IAP. We hypothesized that there are pair-wise positive correlations between the mean maximal accelerometer vector magnitude and 2 IAP measurements: mean maximal IAP and area under the curve (AUC).

Methods

Twenty-five women who regularly participated in exercise performed 13 activities. Intra-abdominal pressure was measured with an intravaginal transducer and acceleration with a waist-worn accelerometer. We determined the mean maximal IAP, AUC for IAP, and mean maximal accelerometer vector magnitude for each activity and participant. The relationship between IAP and acceleration was determined by computing the Pearson correlation coefficient (R) and the 95% confidence interval for mean maximal accelerometer vector magnitude versus mean maximal IAP and mean maximal accelerometer vector magnitude versus AUC for IAP.

Results

The R values were 0.7353 for mean maximal accelerometer vector magnitude versus mean maximal IAP (including walking) and 0.5059 for mean maximal accelerometer vector magnitude versus AUC for IAP (excluding walking). Walking at 3 speeds, analyzed separately, presented R values of 0.72208 for mean maximal IAP and 0.21678 for AUC.

Conclusion

Waist-worn accelerometers may provide a viable method for approximating mean maximal IAP in a population of women during most activities.
The thermodynamic efficiency of computations made in cells across the range of life
Authors: Kempes Christopher P. , Wolpert David , Cohen Zachary , Pérez-Mercader Juan
Published: November 2017

Biological organisms must perform computation as they grow, reproduce and evolve. Moreover, ever since Landauer’s bound was proposed, it has been known that all computation has some thermodynamic cost—and that the same computation can be achieved with greater or smaller thermodynamic cost depending on how it is implemented. Accordingly an important issue concerning the evolution of life is assessing the thermodynamic efficiency of the computations performed by organisms. This issue is interesting both from the perspective of how close life has come to maximally efficient computation (presumably under the pressure of natural selection), and from the practical perspective of what efficiencies we might hope that engineered biological computers might achieve, especially in comparison with current computational systems. Here we show that the computational efficiency of translation, defined as free energy expended per amino acid operation, outperforms the best supercomputers by several orders of magnitude, and is only about an order of magnitude worse than the Landauer bound. However, this efficiency depends strongly on the size and architecture of the cell in question. In particular, we show that the
useful
efficiency of an amino acid operation, defined as the bulk energy per amino acid polymerization, decreases for increasing bacterial size and converges to the polymerization cost of the ribosome. This cost of the largest bacteria does not change in cells as we progress through the major evolutionary shifts to both single- and multicellular eukaryotes. However, the rates of total computation per unit mass are non-monotonic in bacteria with increasing cell size, and also change across different biological architectures, including the shift from unicellular to multicellular eukaryotes.

This article is part of the themed issue ‘Reconceptualizing the origins of life’.
A Cell type-specific Class of Chromatin Loops Anchored at Large DNA Methylation Nadirs
Authors: Jeong Mira , Huang Xingfan , Zhang Xiaotian , Su Jianzhong , Shamim Muhammad S. , Bochkov Ivan D. , Reyes Jaime , Jung Haiyoung , Heikamp Emily , Aiden Aviva Presser , Li Wei , Aiden Erez Lieberman , Goodell Margaret A.
Published: November 2017

Higher order chromatin structure and DNA methylation are implicated in multiple developmental processes, but their relationship to cell state is unknown. Here, we found that large (~10kb) DNA methylation nadirs can form long loops connecting anchor loci that may be dozens of megabases apart, as well as interchromosomal links. The interacting loci comprise ~3.5Mb of the human genome. The data are more consistent with the formation of these loops by phase separation of the interacting loci to form a genomic subcompartment, rather than with CTCF-mediated extrusion. Interestingly, unlike previously characterized genomic subcompartments, this subcompartment is only present in particular cell types, such as stem and progenitor cells. Further, we identify one particular loop anchor that is functionally associated with maintenance of the hematopoietic stem cell state. Our work reveals that H3K27me3-marked large DNA methylation nadirs represent a novel set of very long-range loops and links associated with cellular identity.

Hi-C and DNA methylation analyses reveal novel chromatin loops between distant sites implicated in stem and progenitor cell function.
Removing unwanted variation between samples in Hi-C experiments
Authors: Fletez-Brant Kipper , Qiu Yunjiang , Gorkin David U. , Hu Ming , Hansen Kasper D.
Published: November 2017

Hi-C data is commonly normalized using single sample processing methods, with focus on comparisons between regions within a given contact map. Here, we aim to compare contact maps across different samples. We demonstrate that unwanted variation, of likely technical origin, is present in Hi-C data with replicates from different individuals, and that properties of this unwanted variation changes across the contact map. We present BNBC, a method for normalization and batch correction of Hi-C data and show that it substantially improves comparisons across samples, including in a QTL analysis as well as differential enrichment across cell types.
Quantitative methods to investigate the 4D dynamics of heterochromatic repair sites in Drosophila cells
Authors: Caridi Christopher P. , Delabaere Laetitia , Tjong Harianto , Hopp Hannah , Das Devika , Alber Frank , Chiolo Irene
Published: November 2017

Heterochromatin is mostly composed of long stretches of repeated DNA sequences prone to ectopic recombination during double-strand break (DSB) repair. In Drosophila, ‘safe’ homologous recombination (HR) repair of heterochromatic DSBs relies on a striking relocalization of repair sites to the nuclear periphery. Central to understanding heterochromatin repair is the ability to investigate the 4D dynamics (movement in space and time) of repair sites. A specific challenge of these studies is preventing phototoxicity and photobleaching effects while imaging the sample over long periods of time, and with sufficient time points and Z-stacks to track repair foci over time. Here we describe an optimized approach for high-resolution live imaging of heterochromatic DSBs in Drosophila cells, with a specific emphasis on the fluorescent markers and imaging setup used to capture the motion of repair foci over long time periods. We detail approaches that minimize photobleaching and phototoxicity with a DeltaVision widefield deconvolution microscope, and image-processing techniques for signal recovery post-imaging using SoftWorX and Imaris software. We present a method to derive mean square displacement (MSD) curves revealing some of the biophysical properties of the motion. Finally, describe a method in R to identify tracts of directed motions in mixed trajectories. These approaches enable a deeper understanding of the mechanisms of heterochromatin dynamics and genome stability in the three-dimensional context of the nucleus, and have broad applicability in the field of nuclear dynamics.
Identification of residue pairing in interacting β-strands from a predicted residue contact map
Authors: Mao Wenzhi , Wang Tong , Zhang Wenxuan , Gong Haipeng
Published: November 2017

Despite the rapid progress of protein residue contact prediction, predicted residue contact maps frequently contain many errors. However, information of residue pairing in β strands could be extracted from a noisy contact map, due to the presence of characteristic contact patterns in β-β interactions. This information may benefit the tertiary structure prediction of mainly β proteins. In this work, we introduce a novel ridge-detection-based β-β contact predictor, RDb2C, to identify residue pairing in β strands from any predicted residue contact map. The algorithm adopts ridge detection, a well-developed technique in computer image processing, to capture consecutive residue contacts, and then utilizes a novel multi-stage random forest framework to integrate the ridge information and additional features for prediction. Starting from the predicted contact map of CCMpred, RDb2C remarkably outperforms all state-of-the-art methods on two conventional test sets of β proteins (BetaSheet916 and BetaSheet1452), and achieves F1-scores of ~62% and ~76% at the residue level and strand level, respectively. Taking the prediction of the more advanced RaptorX-Contact as input, RDb2C achieves impressively higher performance, with F1-scores reaching ~76% and ~86% at the residue level and strand level, respectively. According to our tests on 61 mainly β proteins, improvement in the β-β contact prediction can further ameliorate the structural prediction.

Availability: All source data and codes are available athttp://166.111.152.91/Downloads.htmlor at the GitHub address ofhttps://github.com/wzmao/RDb2C.

Author summary

Due to the topological complexity, mainly β proteins are challenging targets in protein structure prediction. Knowledge of the pairing between β strands, especially the residue pairing pattern, can greatly facilitate the tertiary structure prediction of mainly β proteins. In this work, we developed a novel algorithm to identify the residue pairing in β strands from a predicted residue contact map. This method adopts the ridge detection technique to capture the characteristic pattern of β-β interactions from the map and then utilizes a multi-stage random forest framework to predict β-β contacts at the residue level. According to our tests, our method could effectively improve the prediction of β-β contacts even from a highly noisy contact map. Moreover, the refined β-β contact information could effectively improve the structural modeling of mainly β proteins.
A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure
Authors: Frayling Timothy M. , Beaumont Robin N. , Jones Samuel E. , Yaghootkar Hanieh , Tuke Marcus A. , Ruth Katherine S. , Casanova Francesco , West Ben , Locke Jonathan , Sharp Seth , Ji Yingjie , Thompson William , Harrison Jamie , Lindgren Cecilia M. , Grarup Niels , Murray Anna , Freathy Rachel M. , Weedon Michael N. , Tyrrell Jessica , Wood Andrew R.
Published: November 2017

Fibroblast Growth Factor 21 (FGF21) is a hormone that induces weight loss in model organisms. These findings have led to trials in humans of FGF21 analogues with some showing weight loss and lipid lowering effects. Recent genetic studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with body fat distribution, with less fat in the lower body, and higher blood pressure, than it is with BMI, where there is only nominal evidence of an effect. These human phenotypes of naturally occurring variation in the FGF21 gene will inform decisions about FGF21’s therapeutic potential.
Wnt/β-Catenin Signaling Controls Spatio-Temporal Elasticity Patterns in Extracellular Matrix duringHydraMorphogenesis
Authors: Veschgini Mariam , Petersen Hendrik O. , Kaufmann Stefan , Abuillan Wasim , Suzuki Ryo , Burghammer Manfred , Özbek Suat , Holstein Thomas W. , Tanaka Motomu
Published: November 2017

Albeit ample evidence has suggested the remodeling of extracellular matrix (ECM) in animals plays crucial roles in development and diseases, little is understood how ECM mechanics correlates with tissue morphogenesis. In this study, we quantitatively determined how spatio-temporal elasticity patterns in ECM change during the asexual reproduction of freshwater polypHydra. We first determined the mesoscopic protein arrangement inHydraECM (mesoglea) by grazing-incidence small-angle X-ray scattering with nano-beam (nano-GISAXS). Our data unraveled fibrillar type I collagen inHydramesoglea (Hcol-I) takes an anisotropic, more strongly distorted hexagonal lattice compared to those in vertebrates that could be attributed to the lower proline content and lack of lysin-crosslinks in Hcol-1 fibers. Then, we “mapped” the spatio-temporal changes in ECM stiffnessex vivowith aid of nano-indentation. We identified three representative elasticity patterns during tissue growth along the oral-aboral body axis of the animals. Our complementary proteome analysis demonstrated that the elasticity patterns of the ECM correlate with a gradient like distribution of proteases. Perturbations of the oral Wnt/β-catenin signaling center further indicated that ECM elasticity patterns are governed by Wnt/β-catenin signaling. Theex vivobiomechanical phenotyping ofHydramesoglea established in this study will help us gain comprehensive insights into the spatio-temporal coordination of biochemical and biomechanical cues in tissue morphogenesisin vivo.
QUETZAL - an open source C++ template library for coalescence-based environmental demogenetic models inference
Authors: Becheler Arnaud , Coron Camille , Dupas Stéphane
Published: November 2017

1

The purpose of this article is to introduce an implementation framework enabling us, using available genetic samples, to understand and foresee the behavior of species living in a fragmented and temporally changing environment. To this aim, we first present a model of coalescence which is conditioned to environment, through an explicit modeling of population growth and migration. The parameters of this model can be infered using Approximate Bayesian Computation techniques, which supposes that the considered model can be efficiently simulated. We next present Quetzal, a C++ library composed of reusable generic components and designed to efficiently implement a wide range of coalescence-based environmental demogenetic models.
Multivariate pattern analysis of fMRI data for imaginary and real colours in grapheme-colour synaesthesia
Authors: Ruiz Mathieu J. , Dojat Michel , Hupé Jean-Michel
Published: November 2017

Grapheme-colour synaesthesia is a subjective phenomenon related to perception and imagination, in which some people involuntarily but systematically associate specific, idiosyncratic colours to achromatic letters or digits. Its investigation is relevant to unravel the neural correlates of colour perception in isolation from low-level neural processing of spectral components, as well as the neural correlates of imagination by being able to reliably trigger imaginary colour experiences. However, functional MRI studies using univariate analyses failed to provide univocal evidence of the activation of the ‘colour network’ by synaesthesia. Applying Multivariate (multivoxel) Pattern Analysis (MVPA) on 20 synaesthetes and 20 control participants, we tested whether the neural processing of real colours (concentric rings) and synaesthetic colours (black graphemes) shared patterns of activations. Region of interest analyses in retinotopically and anatomically defined visual regions revealed neither evidence of shared circuits for real and synaesthetic colour processing, nor processing difference between synaesthetes and controls. We also found no correlation with individual experiences, characterised by measuring the strength of synaesthetic associations. The whole brain, searchlight, analysis led to similar results. We conclude that identifying the neural correlates of the synaesthetic experience of colours may still be beyond the reach of present technology and data analysis techniques.
Integrated molecular, clinical, and ontological analysis identifies overlooked disease relationships
Authors: Haynes Winston A. , Vashisht Rohit , Vallania Francesco , Liu Charles , Gaskin Gregory L. , Bongen Erika , Lofgren Shane , Sweeney Timothy E. , Utz Paul J. , Shah Nigam H. , Khatri Purvesh
Published: November 2017

Existing knowledge of human disease relationships is incomplete. To establish a comprehensive understanding of disease, we integrated transcriptome profiles of 41,000 human samples with clinical profiles of 2 million patients, across 89 diseases. Based on transcriptome data, autoimmune diseases clustered with their specific infectious triggers, and brain disorders clustered by disease class. Clinical profiles clustered diseases according to the similarity of their initial manifestation and later complications, identifying disease relationships absent in prior co-occurrence analyses. Our integrated analysis of transcriptome and clinical profiles identified overlooked, therapeutically actionable disease relationships, such as between myositis and interstitial cystitis. Our improved understanding of disease relationships will identify disease mechanisms, offer novel therapeutic targets, and create synergistic research opportunities.
Meiosis leads to pervasive segregation distortion and copy-number variation in accessory chromosomes of the wheat pathogenZymoseptoria tritici
Authors: Fouché Simone , Plissonneau Clémence , McDonald Bruce A. , Croll Daniel
Published: November 2017

Meiosis is one of the most conserved molecular processes in eukaryotes. The fidelity of pairing and segregation of homologous chromosomes has a major impact on the proper transmission of genetic information. Aberrant chromosomal transmission can have major phenotypic consequences, yet the mechanisms are poorly understood. Fungi are excellent models to investigate processes of chromosomal transmission, because many species have highly polymorphic genomes that include accessory chromosomes. Inheritance of accessory chromosomes is often unstable and chromosomal losses have little impact on fitness. We analyzed chromosomal inheritance in 477 progeny coming from two crosses of the fungal wheat pathogenZymoseptoria tritici. For this, we developed a high-throughput screening method based on restriction site associated DNA sequencing (RAD-seq) that generated dense coverage of genetic markers along each chromosome. We identified rare instances of chromosomal duplications (disomy) in core chromosomes. Accessory chromosomes showed high overall frequencies of disomy. Chromosomal rearrangements were found exclusively on accessory chromosomes and were more frequent than disomy. Accessory chromosomes present in only one of the parents in an analyzed cross were inherited at significantly higher rates than the expected 1:1 segregation ratio. Both the chromosome and the parental background had significant impacts on the rates of disomy, losses, rearrangements and segregation distortion. We found that chromosomes with higher sequence similarity and lower repeat content were inherited more faithfully. The large number of rearranged progeny chromosomes identified in this species will enable detailed analyses of the mechanisms underlying chromosomal rearrangement.
Streptococcus pyogenesinfection and the human proteome with a special focus on the IgG-cleaving enzyme IdeS
Authors: Karlsson Christofer A. Q. , Järnum Sofia , Winstedt Lena , Kjellman Christian , Björck Lars , Linder Adam , Malmström Johan A.
Published: November 2017

Infectious diseases are characterized by a complex interplay between host and pathogen, but how these interactions impact the host proteome is unclear. Here we applied a novel mass spectrometry based proteomics strategy to investigate how the human proteome is transiently modified by the pathogenStreptococcus pyogenes, with a particular focus on bacterial cleavage of IgGin vivo. In invasive diseases,S. pyogenesevokes a massive host response in blood, whereas superficial diseases are characterized by a local leakage of several blood plasma proteins at the site of infection including IgG.S. pyogenesproduces IdeS, a protease cleaving IgG in the lower hinge region and we find highly effective IdeS-cleavage of IgG in samples from local IgG poor microenvironments. The results show that IdeS contributes to the adaptation ofS. pyogenesto its normal ecological niches. Additionally, the work identifies novel clinical opportunities forin vivopathogen detection.
ReprDB and panDB: minimalist databases with maximal microbial representation
Authors: Zhou Wei , Gay Nicole , Oh Julia
Published: November 2017

Background

Profiling of shotgun metagenomic samples is hindered by a lack of unified microbial reference genome databases that i) assemble genomic information from all open access microbial genomes, ii) have relatively small sizes, and iii) are compatible to various metagenomic read mapping tools. Moreover, computational tools to rapidly compile and update such databases to accommodate the rapid increase in new reference genomes do not exist. As a result, database-guided analyses often fail to profile a substantial fraction of metagenomic shotgun sequencing reads from complex microbiomes.

Results

We report pipelines that efficiently traverse all open access microbial genomes and assemble non-redundant genomic information. The pipelines result in two species-resolution microbial reference databases of relatively small sizes: reprDB, which assembles microbial representative or reference genomes, and panDB, for which we developed a novel iterative alignment algorithm to identify and assemble non-redundant genomic regions in multiple sequenced strains. With the databases, we managed to assign taxonomic labels and genome positions to the majority of metagenomic reads from human skin and gut microbiomes, demonstrating a significant improvement over a previous database-guided analysis on the same datasets.

Conclusions

reprDB and panDB leverage the rapid increases in the number of open access microbial genomes to more fully profile metagenomic samples. Additionally, the databases exclude redundant sequence information to avoid inflated storage or memory space and indexing or analyses time. Finally, the novel iterative alignment algorithm significantly increases efficiency in pan-genome identification and can be useful in comparative genomic analyses.
Urbanization-driven changes in web-building are decoupled from body size in an orb-web spider
Authors: Dahirel Maxime , De Cock Maarten , Vantieghem Pieter , Bonte Dries
Published: November 2017

In animals, behavioural responses may play an important role in determining population persistence in the face of environmental changes. Body size is a key trait central to many life history traits and behaviours. While behaviours are typically assumed to be highly plastic, size correlations may impose constraints on their adaptive value when size itself is subject to environmental changes.

Urbanization is an important human-induced rapid environmental change that imposes multiple selection pressures on both body size and (size-constrained) behaviour. How these combine to shape behavioural responses of urban-dwelling species is unclear.

Using web-building, an easily quantifiable behaviour linked to body size, and the garden spider Araneus diadematus as a model, we disentangle direct behavioural responses to urbanization and body size constraints across a network of 63 selected populations differing in urbanization intensity at two spatial scales.

Spiders were smaller in highly urbanized sites (local scale only), in line with expectations based on reduced prey biomass availability and the Urban Heat Island effect. The use of multivariate mixed modelling reveals that although web traits and body size are correlated within populations, behavioural responses to urbanization do not appear to be constrained by size: there is no evidence of size-web correlations among populations or among landscapes. Spiders thus altered different components of their web-building behaviours independently in response to urbanization: mesh width and web surface decreased independently with urbanization at the local scale, while web surface also increased with urbanization at the landscape scale. These responses are expected to compensate, at least in part, for reduced prey biomass availability.

Our results demonstrate that responses in typically size-dependent behaviours may be decoupled from size changes, thereby allowing fitness maximisation in novel environments. The spatial scale of the behavioural responses to urbanization suggest contributions of both genetic adaptation and plasticity. Although fecundity decreased with local-scale urbanization, Araneus diadematus abundances were remarkably similar across urbanization gradients; behavioural responses thus appear overall successful at the population level.