bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphaturic Mesenchymal Tumor of Soft Tissue of the Foot: Report of a Case With Review of the Literature
Authors: Bisceglia Michele , Galliani Carlos A. , Fraternali Orcioni Giulio , Perrone Elio , Del Giudice Antonio , Scillitani Alfredo
Published: July 2019

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that ectopically secretes fibroblast growth factor 23, a bone cell–derived protein that regulates phosphate homeostasis. The overproduction of fibroblast growth factor 23 causes a paraneoplastic syndrome characterized by hyperphosphaturia, hypophosphatemia, hypovitaminosis D, and vitamin D refractory rickets/osteomalacia, effects that disappear with tumor removal. The PMT may occur in several anatomic regions, mainly in the limbs, usually involving both soft tissue and bone. Acral locations occur in 10% to 15% of the cases, mostly in the feet, with 95 cases reported in this anatomic region to date. We report a case of a PMT in a young adult male who presented in 2007 with the classic constellation of signs and symptoms. A small soft-tissue tumor was detected in his right heel, 3 years after exhaustively seeking for it by various imaging techniques performed at different institutions. Before the tumor was detected, attempts to manage this patient’s osteomalacia with phosphate and vitamin D (both calcitriol and ergocalciferol) supplementation were unsuccessful. Following surgical resection, the patient experienced prompt correction of the phosphaturia and gradual reconstitution of his bone mineralization. The pathologic diagnosis was (benign) PMT, mixed connective tissue type. In 2019, 12 years after resection, the patient is asymptomatic, and his bone mineral homeostasis has been restored.
Utility of Cyclin D1 in the Diagnostic Workup of Hematopoietic Neoplasms: What Can Cyclin D1 Do for Us?
Authors: Wang Wei , Medeiros L. Jeffrey
Published: July 2019

Cyclin D1, encoded by CCND1, promotes cell cycle progression from G1 to S phase. Its expression is induced by MAPK/ERK pathway as well as translocations/rearrangements involving CCND1 gene. The evaluation of cyclin D1 expression by immunohistochemistry plays an important role in the diagnostic workup of various hematopoietic diseases. In this review, we aimed to discuss the value of cyclin D1 immunostain in the diagnosis and different diagnosis of hematopoietic neoplasms.
Dual Expression of TCF4 and CD123 Is Highly Sensitive and Specific For Blastic Plasmacytoid Dendritic Cell Neoplasm
Authors: Sukswai Narittee , Aung Phyu P. , Yin C. Cameron , Li Shaoying , Wang Wei , Wang Sa A. , Ortega Victor , Lyapichev Kirill , Nagarajan Priyadharsini , Alfattal Rasha , Angelova Evgeniya , Tang Zhenya , Loghavi Sanam , Kanagal-Shamanna Rashmi , Miranda Roberto N. , Pemmaraju Naveen , Bhalla Kapil , Konopleva Marina , Medeiros L. Jeffrey , Khoury Joseph D.
Published: July 2019

The diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) has been based on the expression status of multiple markers, including CD123. TCF4 was discovered recently to be an obligatory master regulator of plasmacytoid dendritic cells. We postulated that a tissue-based assay designed to detect dual CD123 and TCF4 expression would provide a highly reliable and practical marker for BPDCN in biopsy material. We designed, optimized, and validated a dual-color TCF4/CD123 immunohistochemistry stain for use in formalin-fixed paraffin-embedded tissue sections. The performance characteristics of the TCF4/CD123 stain were evaluated in 48 confirmed BPDCN cases. TCF4/CD123 coexpression was detected reproducibly in plasmacytoid dendritic cells. In BPDCN, the TCF4/CD123 stain showed coexpression in all (48/48; 100%) cases analyzed. Cases with concurrent samples from different anatomic sites showed comparable staining characteristics. In contrast, of 464 non-BPDCN cases comprising a wide range of hematolymphoid neoplasms and cutaneous lesions that might enter in the differential diagnosis of BPDCN, we identified dual expression of TCF4 and CD123 in only 1 case of B-lymphoblastic leukemia/lymphoma. On the basis of these findings, the TCF4/CD123 dual-color immunohistochemical stain had an analytic sensitivity of 100% and a specificity of 99.8%. Receiver operator characteristic analysis demonstrated an area under the curve of 1.000 (95% confidence interval: 0.999-1.000). In summary, the dual-color TCF4/CD123 immunohistochemistry stain provides a robust standalone and cost-effective assay for the diagnosis of BPDCN.
Functional Status Scale: Cross-Cultural Adaptation and Validation in Brazil
Authors: Pereira Gabriela Alves , Schaan Camila Wohlgemuth , Ferrari Renata Salatti , Normann Tatiana Coser , Rosa Nathalia Vieira , Ricachinevsky Claudia Pires , Reppold Caroline Tozzi , Lukrafka Janice Luisa
Published: July 2019

Objective:

The goal of the present study was to perform a cross-cultural adaptation and clinical validation of the Functional Status Scale for use in the Brazilian population.

Design:

Cross-cultural adaptation study followed by a cross-sectional validation study.

Setting:

Single-center PICU at a hospital in Porto Alegre, Brazil.

Patients:

Children and adolescents of both sexes, 1 month and under 18 years old, who had been treated at the PICU.

Interventions:

The cross-cultural adaptation consisted of the following stages: translation, synthesis of the translated versions, back translations, synthesis of the back translations, committee review, and pretesting. For the clinical validation stage, the Brazilian Functional Status Scale was applied within 48 hours after discharge from the PICU. The Brazilian Functional Status Scale’s reliability and validity properties were tested.

Measurements and Main Results:

A total of 314 patients were evaluated. Median age was 24 months (7.0–105.0 mo), 54.1% were males, and their overall functional score was 9 ± 2.8. The Brazilian Functional Status Scale demonstrated excellent interobserver reliability, with an intraclass correlation coefficient of 0.98, and κ coefficients between 0.716 and 1.000 for the functional domains, which indicated good to excellent agreement. Using the Bland-Altman method, we confirmed low variability among the evaluator’s responses (0.93 to –1.06 points). Regarding the Brazilian Functional Status Scale’s content validity, there was a correlation between length of PICU stay (r = 0.378; p < 0.001) and time on invasive mechanical ventilation (r = 0.261; p < 0.05), and the test could discriminate between groups with different comorbidity levels (p < 0.001).

Conclusions:

The Functional Status Scale has been culturally adapted and validated for use in Brazil and is now available for use in the assessment of functionality in Brazilian children and adolescents.
Barriers to Communication in a PICU: A Qualitative Investigation of Family and Provider Perceptions*
Authors: Greenway Tyler L. , Rosenthal Marjorie S. , Murtha Tanya D. , Kandil Sarah B. , Talento Desmond L. , Couloures Kevin G.
Published: July 2019

Objectives:

Family and medical provider perceptions of communication barriers within the PICU are poorly understood. We designed a qualitative study to characterize the perspective of families and medical providers of critically ill children regarding communication barriers. The identified barriers may be used to direct efforts to improve communication.

Design:

Semi-structured interviews were conducted from August 2017 to January 2018. Interviews were audio recorded and professionally transcribed verbatim.

Setting:

A PICU at a tertiary care academic center.

Patients:

Forty-two families whose children were admitted to the PICU (excluding patients receiving end-of-life care or with protective services involvement) and 12 PICU staff members, including nurses, residents, fellows, and attending’s.

Interventions:

None.

Measurements and Main Results:

An interprofessional team of a physician, nurse manager, and medical student coded the transcripts. Interviewing continued until thematic saturation was reached. Codes were organized into common themes using a modified constant comparative method. The families interviewed represented 16 previously healthy children, and 26 children with a chronic health condition. Staff interviewed included three residents, three fellows, three attending intensivists, and three nurses. Participants’ perceptions and experiences of barriers to communication included the following: 1) Communication breakdowns related to coordination of care among several services, 2) Family-centered rounds are insufficient for effective communication, 3) Undervaluing the knowledge of families of children with chronic health conditions or special needs, and 4) Communication breakdowns occur across provider hand-offs. Theme 3 was identified by families, but not by providers.

Conclusions:

Families and medical providers both identified several barriers to communication. However, only families identified the barrier “Undervaluing the knowledge of families with chronically ill children.” Future work should explore these barriers and the discrepancy in perception between providers and families to determine if there are interventions that improve both family satisfaction and patient care.
Creation and Initial Validation of a Picture-Based Version of the Limitations of Activity Domain of the SF-36
Authors: Stothers Bennett , Macnab Andrew John
Published: July 2019

Those with limited language comprehension or literacy face problems completing written questionnaires evaluating their health or physical status on which treatment plans are based. This brief report describes how a picture-based version of the 10 items in the limitations of activities section of the short form 36 health survey questionnaire (SF-36) was developed iteratively and then piloted. Study participants were 101 community-living volunteers (58 female and 43 male volunteers aged 18–93 yrs) educated to postsecondary level (52), high school grades 10–12 (44), and grade 9 or less (5). They first completed the picture-based SF-36 LoA and described verbally and in writing what they understood each picture to mean and then completed the English text version of the SF-36 limitations of physical activities domain for comparison assessment. Additional feedback suggested where pictures could be altered to increase information capture. Subjects rated their health as 26.7% excellent, 25.7% very good, 29.8% good, 10.9% fair, and 6.9% poor. Analysis showed strong correlation between text-based SF-36 LoA questions and the picture-based visual score—VSF-36 LoA—(intraclass correlation coefficient = 0.98) with question 10 correlating highest (intraclass correlation coefficient = 0.90) and question 2 lowest (intraclass correlation coefficient = 0.82). The VSF-36 LoA is the first picture-based version of the SF-36; good correlation with the text-based version and global need warrants further development to aid those with limited literacy or language comprehension.
Brow Ptosis: Is Transblepharoplasty Internal Browpexy Suitable for Everyone?
Authors: Nemet Arie Y.
Published: July 2019

Purpose:

Transcutaneous internal browpexy can provide patients with mild-to-moderate lateral brow ptosis, stabilization and modest lift of the lateral brow. Questions regarding effectiveness of this procedure and appropriate indications remain.

Methods:

The authors measured consecutive patients who underwent upper eyelid blepharoplasty with transblepharoplasty internal browpexy (TIB) September 2014 to December 2017. Pre- and postoperative brow elevation was assessed based on before and after photographs of each patient. Patient photographs were assessed for medial and lateral brow elevation, brow contouring and asymmetry. Optimal lateral brow elevation was classified as bilateral symmetrical and above the supraorbital rim for women, and symmetrical and at the supraorbital rim for men.

Results:

A total of 239 patients underwent bilateral TIB and 39 underwent unilateral TIB (517 eyelids in total). Pre- and post-operative measurements were taken in 98 patients (41%), with an average elevation of the lateral brow position of 2.54 mm.

Six patients had an underlying infection in the first postoperative week that resolved completely. Three patients underwent a second stage direct brow lift repair and 3 needed unrecognized ptosis repair as a second stage.

Conclusions:

Transblepharoplasty internal browpexy is an important tool that can be used in most patients with lateral and central brow ptosis, asymmetric brow ptosis and irregular contour of the brow. Additionally, browpexy adds to the success and longevity of upper blepharoplasty, while preventing early recurrence of lateral upper eyelid hooding. Patients with significant ptosis, heavy brows, medial greater than lateral ptosis, and post-facial palsy may not be good candidates for this procedure.
Defining the Zygomaticosphenoidal Angle as a Guide to Anatomic Zygomaticomaxillary Complex Fracture Reduction
Authors: De Ruiter Brandon J. , Levin Avinoam , Nash David , Kamel George , Mostafa Evan , Baghdasarian Daniel , Davidson Edward H.
Published: July 2019

Background:

Alignment of the zygomaticosphenoid suture is fundamental to reduction of zygomaticomaxillary complex fractures. To prevent a rotational deformity, the correct angle of the zygoma relative to the cranial base must be restored. Clinically, this can be a challenge, especially when there is comminution of the zygomaticosphenoid suture. Defining a zygomaticosphenoidal angle would provide a reference for use with stereotactic navigation to achieve anatomic reduction.

Methods:

A single-center retrospective analysis of 100 patients was designed to determine normative zygomaticosphenoidal angle values. An angle subtended by the midline and a best-fit line through the zygomaticosphenoid suture on axial computed tomography was measured bilaterally in patients with isolated mandibular or nasal fractures. The mean of this measurement for 3 vertically adjacent cuts was calculated with position of central cut determined by the equator of the globe and trigone of the sphenoid. Multivariate regression was completed to identify changes in zygomaticosphenoidal angle with age, sex, and race.

Results:

The mean zygomaticosphenoidal angle was 47° (range 39°–55°). 97% of angles were within 2 standard deviations (8°) of mean. Regression analysis demonstrated no significant change in angle with age (P = 0.74) or sex (P = 0.89). For each angle, the variation across the 3 sample cuts was ≤4.5°. Patients demonstrated high fidelity in zygomaticosphenoidal angle bilaterally with mean difference of 3°.

Conclusion:

The zygomaticosphenoidal angle is a useful reference, in conjunction with stereotactic navigation, for reduction of zygomaticomaxillary complex fractures. Contralaterally obtained patient-specific data may be used to guide unilateral repair. Normative values may serve as reference in bilateral injury.
Evaluation of the Foramen Magnum Area Calculated by Different Methods: A Radioanatomic Study
Authors: Beger Orhan , Erdoğan Osman , Çetin Zeynep , Kara Engin , Vayisoğlu Yusuf , Hamzaoğlu Vural , Özalp Hakan , Dağtekin Ahmet , Bağdatoğlu Celal , Öztürk Ahmet Hakan , Talas Derya Ümit
Published: July 2019

Purpose:

The main objective of the study was to evaluate the probable diversity in the area of the foramen magnum (FM) calculated by different measuring methods.

Methods:

The study was conducted on 24 dry skulls, present in the collection of the Anatomy Department, Faculty of Medicine, Mersin University. The area of FM was calculated by different measurement methods including automatic field setting, Teixeria and Radinsky formulas obtained from anatomic (ASM), photographic (PSM) and radiologic (RSM) skull measurements.

Results:

The areas of FMs calculated by Teixeria formula in RSM, PSM, and ASM were as follows: 857.96 ± 99.97 mm2, 796.68 ± 105.08 mm2, and 820.86 ± 96.40 mm2, respectively. The areas calculated by Radinsky formula in RSM, PSM, and ASM were as follows: 851.37 ± 99.68 mm2, 792.63 ± 104.18 mm2, and 814.85 ± 94.99 mm2, respectively. Lastly, the areas calculated by the automatic field setting of RSM and PSM software were as follows: 799.75 ± 103.38 mm2 and 752.83 ± 105.60 mm2, respectively.

Conclusion:

Statistical significance was observed between the areas of FM obtained from RSM, ASM, and PSM when calculated by the automatic field setting, Teixeria formula, and Radinsky formula. The authors think that considering the amorphous shape of FM, the automatic field setting of the software should be used to obtain the most accurate numerical data related to the area of FM.
Effects of Posture and Swallow Volume on Esophageal Motility Morphology and Probability of Bolus Clearance
Authors: Pu Liping , Chavalitdhamrong Disaya , Summerlee Robert J. , Zhang Qing
Published: July 2019

The Chicago classification diagnostic criteria of esophageal motility disorders are based on 5-ml water swallows in the supine position and have not been analyzed for the correlation between the morphology and bolus transit in the upright position and larger volume swallow conditions. This study aimed to evaluate the effect of posture and swallow volume on peristaltic morphology and the probability of bolus clearance in patients with nonspecific esophageal disorder. A total of 139 patients (4,214 swallows) were included for high-resolution impedance manometry analysis in the right lateral recumbent and upright positions, as well as 5- and 10-ml liquid swallows. Intact peristalses were more frequent in the right lateral recumbent position than in the upright position. No difference was reported on failed peristalsis between both positions. Breaks were more frequent in the upright position. A 20 mmHg isobaric contour (compared with 30 mmHg) was associated with decreased bolus clearance. Bolus clearance probability with 10-ml swallows is greater than that with 5-ml swallows. There was no significant difference in the total bolus clearance comparing between the right lateral recumbent and upright positions. The right lateral recumbent position was associated with a higher intact peristalsis. The volume of swallow did not affect the integrality of esophageal peristalsis but did improve the bolus clearance.
Lesion-Constrained Electrical Source Imaging: A Novel Approach in Epilepsy Surgery for Tuberous Sclerosis Complex
Authors: Peters Jurriaan M. , Hyde Damon E. , Chu Catherine J. , Boom Merel , Scherrer Benoit , Madsen Joseph R. , Stone Scellig S. , Ouaalam Hakim , Prabhu Sanjay P. , Sahin Mustafa , Warfield Simon K.
Published: July 2019

Purpose:

Electrical source imaging may yield ambiguous results in multilesional epilepsy. The aim of this study was to test the clinical utility of lesion-constrained electrical source imaging in epilepsy surgery in children with tuberous sclerosis complex.

Methods:

Lesion-constrained electrical source imaging is a novel method based on a proposed head model in which the source solution is constrained to lesions. Using a goodness of fit analysis, we rank-ordered individual tubers by their ability to approximate interictal and ictal EEG data. The overlap with the surgical resection cavity was determined qualitatively, and placed findings in the context of epilepsy surgical outcome, and compared with the low-resolution brain electromagnetic tomography solution.

Results:

Low-resolution brain electromagnetic tomography predicted the surgical cavity in only one patient with good outcome (true positive) and localized to outside of the cavity in two patients with a good outcome (false negative). In one patient with a poor outcome, the interictal low-resolution brain electromagnetic tomography solution overlapped with the cavity (false positive). Lesion-constrained electrical source imaging of ictal EEG data identified tubers concordant with the resection zone in three patients with a good surgical outcome (true positive) and appropriately discordant in three other patients with a poor outcome (true negative).

Conclusions:

Lesion-constrained electrical source imaging on low-resolution EEG data provides complementary information in the presurgical workup for patients with tuberous sclerosis complex, although further validation is required. In the appropriate clinical context, the yield of source localization on low-resolution EEG data may be increased by reduction of the solution space.
Local frustration determines loop opening during the catalytic cycle of an oxidoreductase
Authors: Stelzl Lukas L. , Mavridou Despoina A.I. , Saridakis Emmanuel , Gonzalez Diego , Baldwin Andrew J. , Ferguson Stuart J. , Sansom Mark S.P. , Redfield Christina
Published: July 2019

Local structural frustration, the existence of mutually exclusive competing interactions, may explain why some proteins are dynamic while others are rigid. Frustration is thought to underpin biomolecular recognition and the flexibility of protein binding sites. Here we show how a small chemical modification, the oxidation of two cysteine thiols to a disulfide bond, during the catalytic cycle of the N-terminal domain of the key bacterial oxidoreductase DsbD (nDsbD), introduces frustration ultimately influencing protein function. In oxidized nDsbD, local frustration disrupts the packing of the protective cap-loop region against the active site allowing loop opening. By contrast, in reduced nDsbD the cap loop is rigid, always protecting the active-site thiols from the oxidizing environment of the periplasm. Our results point towards an intricate coupling between the dynamics of the active-site cysteines and of the cap loop which modulates the association reactions of nDsbD with its partners resulting in optimized protein function.
Macrobdella decora: Old World Leech Gut Microbial Community Structure Conserved in a New World Leech
Authors: McClure Emily Ann , Nelson Michael C. , Lin Amy , Graf Joerg
Published: July 2019

Leeches are found in terrestrial, aquatic, and marine habitats on all continents. Sanguivorous leeches have been used in medicine for millennia. Modern scientific uses include studies of neurons, anticoagulants, and gut microbial symbioses.Hirudo verbana, the European medicinal leech, maintains a gut community dominated by two bacterial symbionts,Aeromonas veroniiandMucinivorans hirudinis, which sometimes account for as much as 97% of the total crop microbiota. The highly simplified gut anatomy and microbiome ofH. verbanamake it an excellent model organism for studying gut microbial dynamics. The North American medicinal leech,Macrobdella decora,is a hirudinid leech native to Canada and the northern U.S.A. In this study we show thatM. decorasymbiont communities are very similar to those inH. verbana.This similarity allowed for an extensive study in which wild caught animals were sampled to determine effects of geographic separation, time of collection, and feeding on the microbiome. Through 16S V4 rRNA deep sequencing we show that: i) theM. decoragut and bladder microbial communities are distinct, ii) theM. decoragut community is affected by feeding and long periods of starvation, and iii) geographic separation does not appear to affect the overall gut microbial community structure. We propose thatM. decorais a replacement forH. verbanafor studies of wild-caught animals and offer evidence for the conservation of annelid symbionts. Successful culturing and comparison of dominant symbionts fromM. decoraandH. verbenawill provide the ability to assess host-symbiont co-evolution in future work.

IMPORTANCE

Building evidence implicates the gut microbiome in regulating animal digestion, nutritional acquisition, immune regulation, development, and even mood regulation. Because of the difficulty of assigning causative relationships in complex gut microbiomes a simplified model for testing hypotheses is necessary. Previous research inHirudo verbanahas suggested this animal as a highly simplified and tractable animal model of gut symbioses. Our data show thatMacrobdella decoramay work just as well asH. verbanawithout the drawback of being an endangered organism and with the added convenience of easy access to field-caught specimens. The similarity of the microbial community structure of species from two different continents reveals the highly-conserved nature of the microbial symbionts in sanguivorous leeches and confirms the medicinal leech as a highly simplified, natural animal model in which to study gut symbioses.
Epigenetic dysregulation underpins tumorigenesis in a cutaneous tumor syndrome
Authors: Davies Helen R. , Hodgson Kirsty , Schwalbe Edward , Coxhead Jonathan , Sinclair Naomi , Zou Xueqing , Cockell Simon , Husain Akhtar , Nik-Zainal Serena , Rajan Neil
Published: July 2019

Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes 1,2. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel driver mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic and methylation profiling suggest that mutated DNMT3A drives tumorigenesis mechanistically through Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm the phenomenon of benign pulmonary metastases from primary skin lesions. In malignant tumors, additional epigenetic modifiers MBD4, CREBBP, KDM6A and EP300 were mutated. We thus present epigenetic dysregulation as a driver in CCS tumorigenesis and propose this may account for the diverse histophenotypic patterns despite the paucity of mutations seen. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.
A pipeline for multidimensional confocal analysis of mitochondrial morphology, function and dynamics in pancreatic β-cells
Authors: Chaudhry Ahsen , Shi Rocky , Luciani Dan S.
Published: July 2019

Live-cell imaging of mitochondrial function and dynamics can provide vital insights into both physiology and pathophysiology, including of metabolic diseases like type 2 diabetes. However, without super-resolution microscopy and commercial analysis software it is challenging to accurately extract features from dense multi-layered mitochondrial networks, such as those in insulin-secreting pancreatic β-cells. Motivated by this, we developed a comprehensive pipeline, and associated ImageJ plugin, that enables 2D/3D quantification of mitochondrial network morphology and dynamics in mouse β-cells, and by extension other similarly challenging cell-types. The approach is based on standard confocal microscopy and shareware, making it widely accessible. The pipeline was validated using mitochondrial photo-labelling and unsupervised cluster analysis, and is capable of morphological and functional analyses on a per-organelle basis, including in 4D (xyzt). Overall, this tool offers a powerful framework for multiplexed analysis of mitochondrial state/function, and provides a valuable resource to accelerate mitochondrial research in health and disease.
A role of cellular translation regulation associated with toxic Huntingtin protein
Authors: Joag Hiranmay , Ghatpande Vighnesh , Sarkar Maitheli , Raina Anshu , Desai Meghal , Shinde Mrunalini , Bose Tania , Majumdar Amitabha
Published: July 2019

Huntington’s disease (HD) is a severe neurodegenerative disorder caused by poly Q repeat expansion in the Huntingtin (Htt) gene. While the Htt amyloid aggregates are known to affect many cellular processes, its role in translation is not addressed. Here we report pathogenic Htt expression causes protein synthesis deficit in cells. We find a functional prion-like protein, the translation regulator Orb2 to be sequestered by Htt aggregates. Coexpression of Orb2 can partially rescue the lethality associated with poly Q expanded Htt. These findings can be relevant for HD as human homologs of Orb2 also can be sequestered by pathogenic Htt aggregates. Our work suggests that translation dysfunction could be one of the contributors in the pathogenesis of HD and new therapies targeting protein synthesis pathways might help alleviate disease symptoms.
A near-full-length HIV-1 genome from 1966 recovered from formalin-fixed paraffin-embedded tissue
Authors: Gryseels Sophie , Watts Thomas D. , Kabongo Jean-Marie M. , Larsen Brendan B. , Lemey Philippe , Muyembe-Tamfum Jean-Jacques , Teuwen Dirk E. , Worobey Michael
Published: July 2019

Although estimated to have emerged in humans in Central Africa in the early 1900s, HIV-1, the main causative agent of AIDS, was only discovered in 1983. With very little direct biological data of HIV-1 from before the 1980s, far-reaching evolutionary and epidemiological inferences regarding the long pre-discovery phase of this pandemic are based on extrapolations by phylodynamic models of HIV-1 genomic sequences gathered mostly over recent decades. Here, using a very sensitive multiplex RT-PCR assay, we screened 1,652 formalin-fixed paraffin-embedded tissue specimens collected for pathology diagnostics in Kinshasa, Democratic Republic of Congo (DRC), between 1959 and 1967. We report the near-complete genome of one positive from 1966 (“DRC66”)—a non-recombinant sister lineage to subtype C that constitutes the oldest HIV-1 near-full-length genome recovered to date. Root-to-tip plots showed the DRC66 sequence is not an outlier as would be expected if dating estimates from more recent genomes were systematically biased; and inclusion of DRC66 sequence in tip-dated BEAST analyses did not significantly alter root and internal node age estimates based on post-1978 HIV-1 sequences. There was larger variation in divergence time estimates among datasets that were subsamples of the available HIV-1 genomes from 1978-2015, showing the inherent phylogenetic stochasticity across subsets of the real HIV-1 diversity. In conclusion, this unique archival HIV-1 sequence provides direct genomic insight into HIV-1 in 1960s DRC, and, as an ancient-DNA calibrator, it validates our understanding of HIV-1 evolutionary history.

Significance

Inferring the precise timing of the origin of the HIV/AIDS pandemic is of great importance because it offers insights into which factors did—or did not—facilitate the emergence of the causal virus. Previous estimates have implicated rapid development during the early 20th century in Central Africa, which wove once-isolated populations into a more continuous fabric. We recovered the first HIV-1 genome from the 1960s, and it provides direct evidence that HIV-1 molecular clock estimates spanning the last half-century are remarkably reliable. And, because this genome itself was sampled only about a half-century after the estimated origin of the pandemic, it empirically anchors this crucial inference with high confidence.
POT-1 telomere binding protein promotes a novel form of Transgenerational Epigenetic Inheritance
Authors: Lister-Shimauchi Evan H. , Dinh Michael , Maddox Paul , Ahmed Shawn
Published: July 2019

Transgenerational Epigenetic Inheritance occurs when gametes transmit forms of information without altering genomic DNA1. Although deficiency for telomerase in human families causes transgenerational shortening of telomeres2, a role for telomeres in Transgenerational Epigenetic Inheritance is unknown. Here we show that Protection Of Telomeres 1 (Pot1) proteins, which interact with single-stranded telomeric DNA3,4, function in gametes to regulate developmental expression of telomeric foci for multiple generations. C. elegans POT-1 and POT-25,6 formed abundant telomeric foci in adult germ cells that vanished in 1-cell embryos and gradually accumulated during development. pot-2 mutants displayed abundant POT-1::mCherry foci throughout development. pot-2 mutant gametes created F1 cross-progeny with constitutively abundant POT-1::mCherry and mNeonGreen::POT-2 foci, which persisted for 6 generations but did not alter telomere length. pot-1 mutant and pot-2; pot-1 double mutant gametes gave rise to progeny with constitutively diminished Pot1 foci. Genomic silencing and small RNAs potentiate many transgenerational effects7 but did not affect Pot1 foci. We conclude that C. elegans POT-1 functions at telomeres of pot-2 mutant gametes to create constitutively high levels of Pot1 foci in future generations. As regulation of telomeres and Pot1 have been tied to cancer8,9, this novel and highly persistent form of Transgenerational Epigenetic Inheritance could be relevant to human health.
First Attempt to Identify and Map QTLs Associated with Promiscuous Nodulation in Soybean
Authors: Agoyi Eric E. , Tumuhairwe John B. , Chigeza Godfree , Tukamuhabwa Phinehas , Diers Brian W.
Published: July 2019

To inform possibility of conducting marker assisted breeding of promiscuous soybean varieties, this study used 92 F2 lines from biparental cross to identify QTLs associated with promiscuous nodulation in soybean. GBS; genotyping by sequencing platform was used to generate SNPs through the pipeline 2 in TASSEL 5.0, Bowtie2 version 2.2.8 for tag alignment, Beagle version 4.1 to impute missing SNPs and R-QTL package in R for QTL identification. Four nodulation traits were assessedviznumber of nodules (NN), percent of effective nodules (NE), fresh weight and dry weight of nodules (NFW and NDW). Two QTLs were identified on chromosomes 10 and 13. Both QTLs were associated with NN, only QTL13 was associated NE and only QTL10 was associated with nodule ‘weights. It was observed that NN, NFW and NDW shared QTL10 and NN and NE share QTL13 allowing hypothetize on the existence of pleiotropic genes in those those two regions. Over dominance effect was observed for QTL10 and non additive effect for QTL13. The paper recommend investigations be pursued to validate those QTLs and set foundation for marker assisted selection of promiscuous soybean varieties. Also these findings could serve as starting point for gene cloning to better understand nodulation trait in soybean.
ALI-1, candidate gene of B1 locus, is associated with awn length and grain weight in common wheat
Authors: Wang Dongzhi , Yu Kang , Jin Di , Sun Linhe , Chu Jinfang , Wu Wenying , Xin Peiyong , Li Xin , Sun Jiazhu , Yang Wenlong , Zhan Kehui , Zhang Aimin , Liu Dongcheng
Published: July 2019

Awn plays a vital role in the photosynthesis, grain production and drought tolerance of common wheat; however, works on the systematic identification or cloning of genes controlling wheat awn length (AL) were seldom reported. Here, we conducted the Genome-wide association study (GWAS) in 364 wheat accessions and identified 25 loci involved in the AL, including dominant awn suppressors B1, B2 and four homologs of awn controlling genes in rice and barley. Furthermore, the B1 locus was mapped to a 125-kb physical interval harboring two genes on chromosome 5AL through map-based cloning. As the candidate gene for B1 locus, a C2H2 zinc finger gene Awn Length Inhibitor 1 (ALI-1) expressed predominantly in the developing spike of awnless individuals and suppresses downstream genes transcriptionally. ALI-1 reduces cytokinin content and simultaneously restrains cytokinin signal transduction, which leads to a stagnation of cell proliferation and reduction of cell number in awn. Noteworthily, ali-1 was the first awn controlling locus that observed increasing grain length in wheat, which is a valuable supplemental attribution of awn on grain weight besides photosynthesis. Thus, ALI-1 pleiotropically regulates awn and grain development, and this work provides a strategy to achieve improved grain yield and address future extreme climate.

Highlight

ALI-1, candidate gene of awn suppressing B1 locus, associates with awn length and grain length, providing a reacquaint of the effect of wheat awn on grain production.
Intestinal delta-6-desaturase activity determines host range forToxoplasmasexual reproduction
Authors: Di Genova Bruno Martorelli , Wilson Sarah K. , Dubey J.P. , Knoll Laura J.
Published: July 2019

Many eukaryotic microbes have complex lifecycles that include both sexual and asexual phases with strict species-specificity. While the asexual cycle of the protistan parasiteToxoplasma gondiican occur in any warm-blooded mammal, the sexual cycle is restricted to the feline intestine1. The molecular determinants that identify cats as the definitive host forT. gondiiare unknown. Here, we defined the mechanism of species specificity forT. gondiisexual development and break the species barrier to allow the sexual cycle to occur in mice. We determined thatT. gondiisexual development occurs when cultured feline intestinal epithelial cells are supplemented with linoleic acid. Felines are the only mammals that lack delta-6-desaturase activity in their intestines, which is required for linoleic acid metabolism, resulting in systemic excess of linoleic acid2, 3. We found that inhibition of murine delta-6-desaturase and supplementation of their diet with linoleic acid allowedT. gondiisexual development in mice. This mechanism of species specificity is the first defined for a parasite sexual cycle. This work highlights how host diet and metabolism shape coevolution with microbes. The key to unlocking the species boundaries for other eukaryotic microbes may also rely on the lipid composition of their environments as we see increasing evidence for the importance of host lipid metabolism during parasitic lifecycles4, 5. Pregnant women are advised against handling cat litter as maternal infection withT. gondiican be transmitted to the fetus with potentially lethal outcomes. Knowing the molecular components that create a conducive environment forT. gondiisexual reproduction will allow for development of therapeutics that prevent shedding ofT. gondiiparasites. Finally, given the current reliance on companion animals to studyT. gondiisexual development, this work will allow theT. gondiifield to use of alternative models in future studies.
Sleep prevents catastrophic forgetting in spiking neural networks by forming joint synaptic weight representations
Authors: Golden Ryan , Delanois Jean Erik , Sanda Pavel , Bazhenov Maxim
Published: July 2019

Artificial neural networks overwrite previously learned tasks when trained sequentially, a phenomenon known as catastrophic forgetting. In contrast, the brain learns continuously, and typically learns best when new learning is interleaved with periods of sleep for memory consolidation. In this study, we used spiking network to study mechanisms behind catastrophic forgetting and the role of sleep in preventing it. The network could be trained to learn a complex foraging task but exhibited catastrophic forgetting when trained sequentially on multiple tasks. New task training moved the synaptic weight configuration away from the manifold representing old tasks leading to forgetting. Interleaving new task training with periods of off-line reactivation, mimicking biological sleep, mitigated catastrophic forgetting by pushing the synaptic weight configuration towards the intersection of the solution manifolds representing multiple tasks. The study reveals a possible strategy of synaptic weights dynamics the brain applies during sleep to prevent forgetting and optimize learning.
A 3D brain unit model to further improve prediction of local drug distribution within the brain
Authors: Vendel Esmée , Rottschäfer Vivi , de Lange Elizabeth C. M.
Published: July 2019

The development of drugs targeting the brain still faces a high failure rate. One of the reasons is a lack of quantitative understanding of the complex processes that govern the pharmacokinetics (PK) of a drug within the brain. While a number of models on drug distribution into and within the brain is available, none of these addresses the combination of factors that affect local drug concentrations in brain extracellular fluid (brain ECF).

Here, we develop a 3D brain unit model, which builds on our previous proof-of-concept 2D brain unit model, to understand the factors that govern local unbound and bound drug PK within the brain. The 3D brain unit is a cube, in which the brain capillaries surround the brain ECF. Drug concentration-time profiles are described in both a blood-plasma-domain and a brain-ECF-domain by a set of differential equations. The model includes descriptions of blood plasma PK, transport through the blood-brain barrier (BBB), by passive transport via paracellular and trancellular routes, and by active transport, and drug binding kinetics. The impact of all these factors on ultimate local brain ECF unbound and bound drug concentrations is assessed.

In this article we show that all the above mentioned factors affect brain ECF PK in an interdependent manner. This indicates that for a quantitative understanding of local drug concentrations within the brain ECF, interdependencies of all transport and binding processes should be understood. To that end, the 3D brain unit model is an excellent tool, and can be used to build a larger network of 3D brain units, in which the properties for each unit can be defined independently to reflect local differences in characteristics of the brain.

Author summary

Insights on how a drug distributes within the brain over both time and space are still limited. Here, we develop a ‘3D brain unit model’ in order to understand the factors that control drug concentrations within a small piece of brain tissue, the 3D brain unit. In one 3D brain unit, the brain capillaries, which are the smallest blood vessels of the brain, surround the brain extracellular fluid (ECF). The blood-brain barrier (BBB) is located between the brain capillaries and the brain ECF. The model describes the impact of brain capillary blood flow, transport across the BBB, diffusion, flow and drug binding on the distribution of a drug within the brain ECF. We distinguish between free (unbound) drug and drug that is bound to binding sites within the brain. We show that all of the above mentioned factors affect drug concentrations within brain ECF in an interdependent manner. The 3D brain unit model that we have developed is an excellent tool to increase our understanding of how local drug concentrations within the brain ECF are affected by brain transport and binding processes.
Closer to critical resting-state neural dynamics in individuals with higher fluid intelligence
Authors: Ezaki Takahiro , Reis Elohim Fonseca dos , Watanabe Takamitsu , Sakaki Michiko , Masuda Naoki
Published: July 2019

According to the critical brain hypothesis, the brain is considered to operate near criticality and realize efficient neural computations. Despite the prior theoretical and empirical evidence in favor of the hypothesis, no direct link has been provided between human cognitive performance and the neural criticality. Here we provide such a key link by analyzing resting-state dynamics of functional magnetic resonance imaging (fMRI) networks at a whole-brain level. We develop a data-driven analysis method, inspired from statistical physics theory of spin systems, to map out the whole-brain neural dynamics onto a phase diagram. Using this tool, we show evidence that neural dynamics of human participants with higher fluid intelligence quotient scores are closer to a critical state, i.e., the boundary between the paramagnetic phase and the spin-glass (SG) phase. The present results are consistent with the notion of “edge-of-chaos” neural computation.
A copy number variant is associated with a spectrum of pigmentation patterns in the rock pigeon (Columba livia)
Authors: Bruders Rebecca , Hollebeke Hannah Van , Osborne E.J. , Kronenberg Zev , Yandell Mark , Shapiro Michael D.
Published: July 2019

Rock pigeons (Columba livia) display an extraordinary array of pigment pattern variation. One such pattern, Almond, is characterized by a variegated patchwork of plumage colors that are distributed in an apparently random manner. Almond is a sex-linked, semi-dominant trait controlled by the classicalStipper(St) locus. Heterozygous males (ZStZ+sex chromosomes) and hemizygous Almond females (ZStW) are favored by breeders for their attractive plumage. In contrast, homozygous Almond males (ZStZSt) develop severe eye defects and lack all plumage pigmentation, suggesting that higher dosage of the mutant allele is deleterious. To determine the molecular basis of Almond, we compared the genomes of Almond pigeons to non-Almond pigeons and identified a candidateStlocus on the Z chromosome. We found a copy number variant (CNV) within the differentiated region that captures complete or partial coding sequences of four genes, including the melanosome maturation geneMlana. We did not find fixed coding changes in genes within the CNV, but all genes are misexpressed in regenerating feather bud collar cells of Almond birds. Notably, six other alleles at theStlocus are associated with depigmentation phenotypes, and all exhibit expansion of the same CNV. Structural variation atStis linked to diversity in plumage pigmentation and gene expression, and thus provides a potential mode of rapid phenotypic evolution in pigeons.

AUTHOR SUMMARY

The genetic changes responsible for different animal color patterns are poorly understood, due in part to a paucity of research organisms that are both genetically tractable and phenotypically diverse. Domestic pigeons (Columba livia) have been artificially selected for many traits, including an enormous variety of color patterns that are variable both within and among different breeds of this single species. We investigated the genetic basis of a sex-linked color pattern in pigeons called Almond that is characterized by a sprinkled pattern of plumage pigmentation. Pigeons with one copy of the Almond allele have desirable color pattern; however, male pigeons with two copies of the Almond mutation have severely depleted pigmentation and congenital eye defects. By comparing the genomes of Almond and non-Almond pigeons, we discovered that Almond pigeons have extra copies of a chromosome region that contains a gene that is critical for the formation of pigment granules. We also found that different numbers of copies of this region are associated with varying degrees of pigment reduction. The Almond phenotype in pigeons bears a remarkable resemblance to Merle coat color mutants in dogs, and our new results from pigeons suggest that similar genetic mechanisms underlie these traits in both species. Our work highlights the role of gene copy number variation as a potential driver of rapid phenotypic evolution.