bluuebunny/crossref_metadata_2025 huggingface dataset:
13C‐Labeled‐Starch Breath Test in Congenital Sucrase‐isomaltase Deficiency
Authors: Robayo‐Torres Claudia C. , Diaz‐Sotomayor Marisela , Hamaker Bruce R. , Baker Susan S. , Chumpitazi Bruno P. , Opekun Antone R. , Nichols Buford L.
Published: May 2018

Background and Hypotheses:

Human starch digestion is a multienzyme process involving 6 different enzymes: salivary and pancreatic α‐amylase; sucrase and isomaltase (from sucrose‐isomaltase [SI]), and maltase and glucoamylase (from maltase‐glucoamylase [MGAM]). Together these enzymes cleave starch to smaller molecules ultimately resulting in the absorbable monosaccharide glucose. Approximately 80% of all mucosal maltase activity is accounted for by SI and the reminder by MGAM. Clinical studies suggest that starch may be poorly digested in those with congenital sucrase‐isomaltase deficiency (CSID). Poor starch digestion occurs in individuals with CSID and can be documented using a noninvasive 13C‐breath test (BT).

Methods:

13C‐Labled starch was used as a test BT substrate in children with CSID. Sucrase deficiency was previously documented in study subjects by both duodenal biopsy enzyme assays and 13C‐sucrose BT. Breath 13CO2 was quantitated at intervals before and after serial 13C‐substrate loads (glucose followed 75 minutes later by starch). Variations in metabolism were normalized against 13C‐glucose BT (coefficient of glucose absorption). Control subjects consisted of healthy family members and a group of children with functional abdominal pain with biopsy‐proven sucrase sufficiency.

Results:

Children with CSID had a significant reduction of 13C‐starch digestion mirroring that of their duodenal sucrase and maltase activity and 13C‐sucrase BT.

Conclusions:

In children with CSID, starch digestion may be impaired. In children with CSID, starch digestion correlates well with measures of sucrase activity.
PD-1 Expression in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Large B-cell Richter Transformation (DLBCL-RT)
Authors: He Rong , Ding Wei , Viswanatha David S. , Chen Dong , Shi Min , Van Dyke Daniel , Tian Shulan , Dao Linda N. , Parikh Sameer A. , Shanafelt Tait D. , Call Timothy G. , Ansell Stephen M. , Leis Jose F. , Mai Ming , Hanson Curtis A. , Rech Karen L.
Published: May 2018

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a low-grade B-cell neoplasm and ∼2% to 9% patients develop an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (Richter transformation, DLBCL-RT). Programmed death-1 (PD-1) pathway plays a crucial role in tumor host immunity evasion and its blockade has emerged as an effective anti-cancer immunotherapy. PD-L1 and PD-1 expression has shown predictive value in anti-PD cancer immunotherapy; however, it has not been well documented in CLL/SLL and DLBCL-RT. We evaluated PD-1 and PD-L1 expression by immunohistochemistry in 39 CLL/SLL, 15 DLBCL-RT, and 26 other DLBCL. In CLL/SLL, neoplastic B-cell PD-1 expression was weak and restricted to prolymphocytes/paraimmunoblasts within proliferation centers (PCs) and accentuated PCs of all sizes. Neoplastic B-cell PD-1 expression was highly prevalent and demonstrated increased intensity in DLBCL-RT, but in contrast was only rarely seen in other DLBCL (12/15 vs. 1/26; P<0.0001). An excellent correlation (90% concordance) was observed between neoplastic B-cell PD-1 immunohistochemistry positivity and molecularly defined CLL/SLL clonal relatedness in DLBCL-RT. PD-L1 expression was observed on the neoplastic B cells in rare DLBCL-RT and other DLBCL cases (1/15 vs. 1/26; P>0.05) as well as background histiocytes and dendritic cells. Overall survival of DLBCL-RT was significantly inferior to that of the other DLBCL (median, 16.9 vs. 106.1 mo; P=0.002). Our findings suggest a biological continuum from prolymphocytes/paraimmunoblasts in CLL/SLL PCs to the neoplastic B-cells in DLBCL-RT. The characteristic PD-1 expression in DLBCL-RT makes it a potential surrogate marker for determining clonal relatedness to CLL/SLL, which may have important prognostic and therapeutic implications.
Hemodynamic Shock Caused by Tension Pneumoperitoneum in a 5-Year-Old Girl
Authors: Zentar Marie-Sophie , Berteloot Laureline , Khen Dunlop Naziha , Bustarret Olivier , Pigneur Bénédicte , Cheron Gérard , Angoulvant François
Published: May 2018

Tension pneumoperitoneum is a relatively rare occurrence in the pediatric population. However, tension pneumoperitoneum is associated with significant morbidity and mortality if it is not promptly diagnosed and treated. A 5-year-old girl was admitted to emergency department with abdominal pain. She was in shock, and the radiograph film of the abdomen revealed a voluminous tension pneumoperitoneum. Aggressive fluid challenges were performed in intensive care followed by urgent laparotomy. Primary abdominal compartment due to trapped gas caused a decreased venous return and visceral perfusion. In the absence of hemodynamic improvement after vascular filling, needle decompression was performed before surgery.
Toddler's Paralysis
Authors: Kahne Kimberly Renee , Tay Ee Tein
Published: May 2018

Vegetarian and vegan diets are gaining popularity in the United States. Although appropriately planned vegetarian diets, including vegan diets, are healthful and nutritionally adequate and may provide health benefits in the prevention and treatment of certain diseases, not all families are aware of the nutritional supplements that may be required for their children. We describe a case of a 2-year-old previously healthy child consuming a vegan diet who presented to the pediatric emergency department with an acute inability to move her legs. Ionized calcium was found to be 0.89 mmol/L, and symptoms completely resolved within 2 hours of calcium gluconate infusion.
Temporal Uptake Patterns of 18F-Fluorocholine Among Hyperfunctioning Parathyroid Glands
Authors: Morland David , Richard Capucine , Godard François , Deguelte Sophie , Delemer Brigitte
Published: May 2018

Optimal scan time of 18F-fluorocholine (FCH) PET/CT for localization of hyperfunctioning parathyroid glands is poorly documented. We report a small series of 9 histologically proven hyperfunctioning parathyroid gland with heterogeneous temporal uptake profile. Thirty-minute dynamic acquisition starting just after 18F-fluorocholine administration and delayed acquisition were recorded. Three different uptake patterns are seen (early washout, stable uptake, late increase) indicating the importance of an early (5–10 minutes) acquisition. A late acquisition (60 minutes) could be useful when the early acquisition is negative. No correlations were noted between uptake profile and histological or genetic results.
Quality and Safety in Health Care, Part XLIV
Authors: Harolds Jay A.
Published: May 2018

This article discusses 2 specialized implantable cardioverter defibrillator (ICD) devices. A special type of implantable device is available for cardiac resynchronization therapy, which can also have a defibrillator, in which case it is called a CRT-D device. In patients who meet guidelines for eligibility, a CRT-D will diminish the number of significant cardiac events including death. A subcutaneous ICD device does not need any leads placed in the vascular system and therefore does not have some of the complications that may be seen with transvenous ICDs. Also, there are patients who are not candidates for a typical ICD implantation. On the other hand, there are important disadvantages to the subcutaneous ICD.
IgG4-Related Disease Simulating Carcinoma Colon With Diffuse Peritoneal Carcinomatosis on 18F-FDG PET/CT
Authors: Vadi Shelvin Kumar , Parihar Ashwin Singh , Kumar Rajender , Singh Harmandeep , Mittal Bhagwant Rai , Bal Amanjit , Sinha Saroj Kumar
Published: May 2018

IgG4-related disease (IgG4-RD) continues to be a diagnostic challenge and a great mimicker of malignancies. We report here a case of young man who presented with subacute intestinal obstruction with initial imaging and clinical features suggestive of carcinoma colon. 18F-FDG PET/CT showed diffuse peritoneal carcinomatosis pattern typically seen with abdominal malignancies. However, the histopathology and the raised IgG4 levels diagnosed it to be IgG4-RD. Although 18F-FDG PET/CT has typical patterns corresponding to the multisystemic involvement of IgG4-RD, the index case did not show any such findings.
A Case of Juvenile Psammomatoid Ossifying Fibroma on Skull Base
Authors: Kim Do-Youn , Lee Oh Hyeong , Choi Gyeong Cheol , Cho Jin Hee
Published: May 2018

Juvenile psammomatoid ossifying fibroma (JPOF) is a rare tumor that occurs in maxillary sinus or orbit. Complete removal is required due to the aggressive and locally destructive nature. It is hard to distinguish from psammomatoid meningioma in cranial lesion and to remove completely. The authors are presenting a case of 26-year-old male with JPOF on skull base and report this case with review of literature.
A Giant Congenital Soft Tissue Sinonasal Fibromyxoma of the Nose in a Newborn Baby
Authors: Yucel Ekici Nur , Yucel Gül , Haytoğlu Suheyl , Küllahci Özgür
Published: May 2018

Myxomas of the nose are very rare benign neoplasms. They grow slowly, infiltrate the surrounding bone cortex, and develop multiple local recurrences with no distant metastasis. Almost, even knowing seen at any age, it is very rare in newborn. The authors present a patient with sinonasal soft tissue fibromyxoma in a newborn baby nose followed by the literature.
Endoscopy-Assisted Frontal Sinus Obliteration
Authors: Jaźwiec Anna Maria , Rechner Benjamin , Komorowska-Timek Ewa
Published: May 2018

Comminuted fractures of the anterior table of the frontal sinus involving frontonasal ducts are traditionally treated with sinus obliteration. This technique entails precise mucosa removal which requires unimpeded visualization of the bony recesses. To achieve adequate access to the mucosa, temporary removal of a large part of the frontal bone may often be necessary. This in turn increases fracture comminution requiring placement of additional hardware associated with the risk for bony malalignment, infection, plate palpability, and visibility, especially in thin-skin individuals. Endoscopy, offering magnified visualization and less invasive access, is reported to be beneficial in sinus injury management. Therefore, it may be also considered an adjunct in open-approach management of severely comminuted fractures.

The authors’ patient suffered from comminuted fractures of the anterior and posterior tables of the frontal sinus and nasal bone fractures with involvement of the frontonasal ducts. Due to the extent of the injury he underwent frontal sinus obliteration procedure using the pericranial flap. To avoid additional osteotomy, endoscopic approach was undertaken to achieve the complete removal of the sinus mucosa. The fracture by itself offered an “access port” for the endoscope and electrical cautery. The patient's recovery was uneventful.

Endoscopy employed in frontal sinus obliteration appears to be instrumental in obtaining meticulous mucosa removal, obviating the need for additional osteotomy of the frontal bone.
Extended Release Liposomal Bupivacaine Injection (Exparel) for Early Postoperative Pain Control Following Palatoplasty
Authors: Day Kristopher M. , Nair Narayanan M. , Sargent Larry A.
Published: May 2018

Introduction:

Liposomal bupivacaine (LB) is a long-acting local anesthetic reported to decrease postoperative pain in adults. The authors demonstrate the safe use of LB in pediatric patients with improved pain control following palatoplasty.

Materials and Methods:

Retrospective patient series of all single-surgeon palatoplasty patients treated at a tertiary craniofacial center from August 2014 to December 2015 were included. All patients received 1.3% LB intraoperatively as greater palatal nerve and surgical field blocks in 2-flap V–Y pushback palatoplasty. Postoperative oral intake, opioids administered, duration of hospitalization, and FLACC (face, legs, activity, cry, consolability) pain scores were measured.

Results:

Twenty-seven patients (16 males and 11 females, average age of 10.8 months, weight 8.8 kg) received 2.9 ± 0.9 mL (2.6 ± 1.9 mg/kg) 1.3% LB. Average FLACC scores were 2.4 ± 2.2/10 in the postanesthesia care unit and 3.8 ± 1.8/10 while inpatients. Oral intake was first tolerated 10.3 ± 11.5 hours postoperatively and tolerated 496.4 ± 354.2 mL orally in the first 24 hours postoperatively. Patients received 8.5 ± 8.4 mg hydrocodone equivalents (0.46 ± 0.45 mg/kg per d hydrocodone equivalents) and were discharged 2.1 ± 1.3 days postoperatively. Opioid-related adverse events included emesis in 7.4% and pruritis in 3.7% of patients.

Conclusions:

The LB may be used safely in pediatric patients. Intraoperative injection of LB during palatoplasty can yield low postoperative opioid use and an early and adequate volume of oral intake over an average hospital stay. Further cost-efficacy studies of LB are needed to assess its value in pediatric plastic surgery.
Sensitive detection of pre-integration intermediates of LTR retrotransposons in crop plants
Authors: Cho Jungnam , Benoit Matthias , Catoni Marco , Drost Hajk-Georg , Brestovitsky Anna , Oosterbeek Matthijs , Paszkowski Jerzy
Published: May 2018

Retrotransposons have played an important role in the evolution of host genomes1,2. Their impact on host chromosomes is mainly deduced from the composition of DNA sequences, which have been fixed over evolutionary time. These studies provide important “snapshots” reflecting historical activities of transposons but do not predict current transposition potential. We previously reported Sequence-Independent Retrotransposon Trapping (SIRT) as a methodology that, by identification of extrachromosomal linear DNA (eclDNA), revealed the presence of active LTR retrotransposons inArabidopsis9. Unfortunately, SIRT cannot be applied to large and transposon-rich genomes of crop plants. We have since developed an alternative approach named ALE-seq (amplification ofLTR ofeclDNAs followed bysequencing). ALE-seq reveals sequences of 5’ LTRs of eclDNAs after two-step amplification:in vitrotranscription and subsequent reverse transcription. Using ALE-seq in rice, we detected eclDNAs for a novelCopiafamily LTR retrotransposon,Go-on, which is activated by heat stress. Sequencing of rice accessions revealed thatGo-onhas preferentially accumulated inindicarice grown at higher temperatures. Furthermore, ALE-seq applied to tomato fruits identified a developmentally regulatedGypsyfamily of retrotransposons. Importantly, a bioinformatic pipeline adapted for ALE-seq data analyses allows the direct and reference-free annotation of new active retroelements. This pipeline allows assessment of LTR retrotransposon activities in organisms for which genomic sequences and/or reference genomes are unavailable or are of low quality.
The workings and failings of clustering T-cell receptor beta-chain sequences without a known epitope preference
Authors: Meysman Pieter , De Neuter Nicolas , Gielis Sofie , Bui Thi Danh , Ogunjimi Benson , Laukens Kris
Published: May 2018

The T-cell receptor is responsible for recognizing potentially harmful epitopes presented on cell surfaces. The binding rules that govern this recognition between receptor and epitope is currently an unsolved problem, yet one of great interest. Several methods have been proposed recently to perform supervised classification of T-cell receptor sequences, but this requires known examples of T-cell sequences for a given epitope. Here we study the viability of various methods to perform unsupervised clustering of distinct T-cell receptor sequences and how these clusters relate to their target epitope. The goal is to provide an overview of the performance of various distance metrics on two large independent T-cell receptor sequence data sets. Our results confirm the presence of structural distinct T-cell groups that target identical epitopes. In addition, we put forward several recommendations to perform T-cell receptor sequence clustering.
Ularcirc: Visualisation and enhanced analysis of circular RNAs via back and canonical forward splicing
Authors: Humphreys David T , Fossat Nicolas , Tam Patrick P L , Ho Joshua W K
Published: May 2018

Circular RNAs (circRNAs) are a unique class of transcripts that can only be identified from sequence alignments spanning discordant junctions, commonly referred to as backsplice junctions (BSJ). The challenges of detecting a BSJ from short read high throughput sequencing (HTS) data has steered software development to focus primarily on algorithmic methods to accurately capture BSJs. Here we present Ularcirc, the first software tool that provides a complete circRNA workflow from detection, integrated visualization, quality filtering of BSJ and forward splicing junctions (FSJ), through to sequence retrieval and downstream functional analysis. More importantly, Ularcirc uses an innovative method to filter out false positive circRNAs coined read alignment distribution (RAD) score which allows detection of circRNAs independent of gene annotations. We used Ularcirc to characterise circRNAs from public and in-house generated data sets and demonstrate how to discover (i) novel splicing patterns of parental transcripts, (ii) internal splicing patterns of circRNA, and (iii) the complexity of BSJ formation. Furthermore, we identify circRNAs that have potential open reading frames longer than their linear sequence. Finally, we have identified and validated the presence of a novel class of circRNA generated from ApoA4 transcripts whose BSJ derive from multiple sites within coding exons. Ularcirc can be accessed via https://github.com/VCCRI/Ularcirc.
Marine mammals and sea turtles listed under the U.S. Endangered Species Act are recovering
Authors: Valdivia Abel , Wolf Shaye , Suckling Kieran
Published: May 2018

The U.S. Endangered Species Act (ESA) is the world’s strongest environmental law protecting imperiled plants and animals, and a growing number of marine species have been protected under this law as extinction risk in the oceans has increased. Marine mammals and sea turtles comprise 36% of the 161 ESA-listed marine species, yet analyses of recovery trends after listing are lacking. Here we gather the best available annual population estimates for all marine mammals (n=33) and sea turtles (n=29) listed under the ESA as species. Of these, we quantitatively analyze population trends, magnitude of population change, and recovery status for representative populations of 23 marine mammals and 9 sea turtles, which were listed for more than five years, occur in U.S. waters, and have data of sufficient quality and span of time for trend analyses. Using generalized linear and non-linear models, we found that 78% of marine mammals (n=18) and 78% of sea turtles (n=7) significantly increased after listing; 13% of marine mammals (n=3) and 22% of sea turtles (n=2) showed non-significant changes; while 9% of marine mammals (n=2), but no sea turtles declined after ESA protection. Overall, species with populations that increased in abundance were listed for 20 years or more (e.g., large whales, manatees, and sea turtles). Conservation measures triggered by ESA listing such as ending exploitation, tailored species management, and fishery regulations, among others, appear to have been largely successful in promoting species recovery, leading to the delisting of some species and to increases in most. These findings underscore the capacity of marine mammals and sea turtles to recover from substantial population declines when conservation actions under the ESA are implemented in a timely and effective manner.
DynamicME: Dynamic simulation and refinement of integrated models of metabolism and protein expression
Authors: Yang Laurence , Ebrahim Ali , Lloyd Colton J. , Saunders Michael A. , Palsson Bernhard O.
Published: May 2018

Genome-scale models of metabolism and macromolecular expression (ME models) enable systems-level computation of proteome allocation coupled to metabolic phenotype. We develop dynamicME, an algorithm enabling time-course simulation of cell metabolism and protein expression. Our dynamicME correctly predicted the substrate utilization hierarchy on mixed carbon substrate medium. We also found good agreement between predicted and measured time-course expression profiles. ME models involve considerably more parameters than metabolic models (M models). We thus present two methods to calibrate ME models, specifically using time-course measurements such as from a (fed-) batch culture. Overall, dynamicME and the methods presented provide novel methods for understanding proteome allocation and metabolism under complex and transient environments, and to utilize time-course cell culture data for model-based interpretation or model refinement.
11 Million SNP Reference Profiles for Identity Searching Across Ethnicities, Kinship, and Admixture
Authors: Helfer Brian S. , Ricke Darrell O.
Published: May 2018

High throughput sequencing (HTS) of single nucleotide polymorphisms (SNPs) provides additional applications for DNA forensics including identification, mixture analysis, kinship prediction, and biogeographic ancestry prediction. Public repositories of human genetic data are being rapidly generated and released, but the majorities of these samples are de-identified to protect privacy, and have little or no individual metadata such as appearance (photos), ethnicity, relatives, etc. A reference in silico dataset has been generated to enable development and testing of new DNA forensics algorithms. This dataset provides 11 million SNP profiles for individuals with defined ethnicities and family relationships spanning eight generations with admixture for a panel with 39,108 SNPs.
What is Antagonistic Pleiotropy?
Authors: Mitteldorf Josh
Published: May 2018

Antagonistic Pleiotropy has been the dominant theory for evolution of aging since it was first proposed 60 years ago. Indeed, examples of pleiotropy have been observed, but there are also many examples of mutations that lead to longer lifespan without apparent cost. This poses a dilemma for the logic of the theory, which depends critically on the assumption that pleiotropy has imposed an inescapable precondition on evolution. Another interpretation is possible for the pleiotropy observed in nature. Natural selection may actually favor pleiotropy as an evolved adaptation. This is because the combination of high fertility and long lifespan is a temptation for individuals, but a danger for the health of populations. Predator populations that grow faster than their prey can recover are at risk of extinction. Once a sustainable mix of fertility and longevity has been established by multilevel natural selection, pleiotropy can help to assure that it is not lost. The population is free to shift from (high fertility/short lifespan) to (lower fertility/longer lifespan) as varying environmental conditions demand, without risking population overshoot and collapse. I describe herein experiments with an individual-based computer simulation in which pleiotropy evolves as a group-selected adaptation under a range of assumptions and in a broad swath of parameter space.
Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive demethylation in mammals
Authors: Mulholland Christopher B. , Nishiyama Atsuya , Ryan Joel , Nakamura Ryohei , Yiğit Merve , Glück Ivo M. , Trummer Carina , Qin Weihua , Bartoschek Michael D. , Traube Franziska R. , Parsa Edris , Ugur Enes , Modic Miha , Acharya Aishwarya , Stolz Paul , Ziegenhain Christoph , Wierer Michael , Enard Wolfgang , Carell Thomas , Lamb Don C. , Takeda Hiroyuki , Nakanashi Makoto , Bultmann Sebastian , Leonhardt Heinrich
Published: May 2018

Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. So far, it was unclear how mammals specifically achieve global DNA hypomethylation, given the high conservation of the DNA (de-)methylation machinery among vertebrates. We found that DNA demethylation requires TET activity but mostly occurs at sites where TET proteins are not bound suggesting a rather indirect mechanism. Among the few specific genes bound and activated by TET proteins was the naïve pluripotency and germline markerDppa3(Pgc7, Stella), which undergoes TDG dependent demethylation. The requirement of TET proteins for genome-wide DNA demethylation could be bypassed by ectopic expression ofDppa3. We show that DPPA3 binds and displaces UHRF1 from chromatin and thereby prevents the recruitment and activation of the maintenance DNA methyltransferase DNMT1. We demonstrate that DPPA3 alone can drive global DNA demethylation when transferred to amphibians (Xenopus) and fish (medaka), both species that naturally do not have aDppa3gene and exhibit no post-fertilization DNA demethylation. Our results show that TET proteins are responsible for active and - indirectly also for - passive DNA demethylation; while TET proteins initiate local and gene-specific demethylation in vertebrates, the recent emergence of DPPA3 introduced a unique means of genome-wide passive demethylation in mammals and contributed to the evolution of epigenetic regulation during early mammalian development.
Lead-DBS v2: Towards a comprehensive pipeline for deep brain stimulation imaging
Authors: Horn Andreas , Li Ningfei , Dembek Till A , Kappel Ari , Boulay Chadwick , Ewert Siobhan , Tietze Anna , Husch Andreas , Perera Thushara , Neumann Wolf-Julian , Reisert Marco , Si Hang , Oostenveld Robert , Rorden Christopher , Yeh Fang-Cheng , Fang Qianqian , Herrington Todd M , Vorwerk Johannes , Kühn Andrea A.
Published: May 2018

Deep brain stimulation (DBS) is a highly efficacious treatment option for movement disorders and a growing number of other indications are investigated in clinical trials. To ensure optimal treatment outcome, exact electrode placement is required. Moreover, to analyze the relationship between electrode location and clinical results, a precise reconstruction of electrode placement is required, posing specific challenges to the field of neuroimaging. Since 2014 the open source toolbox Lead-DBS is available, which aims at facilitating this process. The tool has since become a popular platform for DBS imaging. With support of a broad community of researchers worldwide, methods have been continuously updated and complemented by new tools for tasks such as multispectral nonlinear registration, structural / functional connectivity analyses, brain shift correction, reconstruction of microelectrode recordings and orientation detection of segmented DBS leads. The rapid development and emergence of these methods in DBS data analysis require us to revisit and revise the pipelines introduced in the original methods publication. Here we demonstrate the updated DBS and connectome pipelines of Lead-DBS using a single patient example with state-of-the-art high-field imaging as well as a retrospective cohort of patients scanned in a typical clinical setting at 1.5T. Imaging data of the 3T example patient is co-registered using five algorithms and nonlinearly warped into template space using ten approaches for comparative purposes. After reconstruction of DBS electrodes (which is possible using three methods and a specific refinement tool), the volume of tissue activated is calculated for two DBS settings using four distinct models and various parameters. Finally, four whole-brain tractography algorithms are applied to the patient’s preoperative diffusion MRI data and structural as well as functional connectivity between the stimulation volume and other brain areas are estimated using a total of eight approaches and datasets. In addition, we demonstrate impact of selected preprocessing strategies on the retrospective sample of 51 PD patients. We compare the amount of variance in clinical improvement that can be explained by the computer model depending on the method of choice.

This work represents a multi-institutional collaborative effort to develop a comprehensive, open source pipeline for DBS imaging and connectomics, which has already empowered several studies, and may facilitate a variety of future studies in the field.
Expression of novel fusion antiviral proteins Ricin A Chain-Pokeweed Antiviral Proteins (RTA-PAPs) in Escherichia coli and their inhibition of protein synthesis and of hepatitis B virus in vitro
Authors: Hassan Yasser , Ogg Sherry , Ge Hui
Published: May 2018

Ricin A chain (RTA) and Pokeweed antiviral proteins (PAPs) are plant-derived N-glycosidase ribosomal-inactivating proteins (RIPs) isolated from Ricinus communis and Phytolacca Americana respectively. This study was to investigate the potential antiviral value of novel fusion proteins between RTA and PAPs (RTA-PAPs). In brief, RTA-Pokeweed antiviral protein isoform 1 from seeds (RTA-PAPS1) was produced in E. coli in vivo expression system, purified from inclusion bodies using gel filtration chromatography and protein synthesis inhibitory activity assayed by comparison to the production of a control protein Luciferase. The antiviral activity of the RTA-PAPS1 against Hepatitis B virus (HBV) in HepAD38 cells was then determined using a dose response assay by quantifying supernatant HBV DNA compared to control virus infected HepAD38 cells. The cytotoxicity in HepAD38 cells was determined by measuring cell viability using a tetrazolium dye uptake assay. Results showed that RTA-PAPS1 could effectively be recovered and purified from inclusion bodies. The refolded protein was bioactive with 50% protein synthesis inhibitory concentration (IC50) of 0.06nM (3.63ng/ml). The results also showed that RTA-PAPS1 had a synergetic activity against HBV with a half-maximal response concentration value (EC50) of 0.03nM (1.82ng/ml) and a therapeutic index of >21818. The fusion protein was further optimized using in silico tools, produced in E. coli in vivo expression system, purified by three-step process from soluble lysate and protein synthesis inhibition activity assayed. Results showed that the optimized protein RTA mutant-Pokeweed antiviral protein isoform 1 from leaves (RTAM-PAP1) could be recovered and purified from soluble lysates with gain of function activity on protein synthesis inhibition with an IC50 of 0.03nM (1.82ng/ml). Collectively, our results demonstrate that RTA-PAPs are amenable to effective production and purification in native form, possess significant antiviral activity against HBV in vitro with a high therapeutic index and, thus, meriting further development as potential antiviral agents against chronic HBV infection.
Functional connectivity alterations of the temporal lobe and hippocampus in semantic dementia and Alzheimer’s disease
Authors: Schwab Simon , Afyouni Soroosh , Chen Yan , Han Zaizhu , Guo Qihao , Dierks Thomas , Wahlund Lars-Olof , Grieder Matthias
Published: May 2018

The severe semantic memory impairments in semantic dementia have been attributed to a pronounced atrophy and functional disruption of the anterior temporal lobes. In contrast, the medial and posterior temporal lobe damage predominantly found in patients with Alzheimer’s disease has been associated with episodic memory disturbance. However, the two dementia subtypes share hippocampal deterioration, despite a relatively spared episodic memory in semantic dementia. To gain more insight into the mutual and divergent functional alterations seen in Alzheimer’s disease and semantic dementia, we assessed the differences in intrinsic functional connectivity between temporal lobe regions in patients with Alzheimer’s disease (n = 16), semantic dementia patients from two international sites (n = 23), and healthy controls (n = 17). In an exploratory study, we used a functional parcellation of the temporal cortex to extract time series. The Alzheimer’s disease group showed a single connection with reduced functional connectivity as compared to the controls. This connection was located between the right orbitofrontal cortex and the right anterior temporal lobe. In contrast, functional connectivity was decreased in the semantic dementia group in six connections, mainly involving the hippocampus, lingual gyrus, temporal pole, and orbitofrontal cortex. We identified a common pathway with semantic dementia, since the functional connectivity between the right anterior temporal lobe and the right orbitofrontal cortex was reduced in both types of dementia. This might be related to social knowledge deficits as part of semantic memory decline. However, such interpretations are preferably made in the context of all disease-specific semantic impairments and functional connectivity changes. Despite some limitations owed to the two database sites, this study provides a first preliminary picture of the brain’s functional dysconnectivity in Alzheimer’s disease and semantic dementia. Future studies are needed to replicate findings of such a common pathway with matched diagnosis, neuropsychological, and data MRI acquisition procedures.
Modelling palaeoecological time series using generalized additive models
Authors: Simpson Gavin L.
Published: May 2018

In the absence of annual laminations, time series generated from lake sediments or other similar stratigraphic sequences are irregularly spaced in time, which complicates formal analysis using classical statistical time series models. In lieu, statistical analyses of trends in palaeoen-vironmental time series, if done at all, have typically used simpler linear regressions or (non-) parametric correlations with little regard for the violation of assumptions that almost surely occurs due to temporal dependencies in the data or that correlations do not provide estimates of the magnitude of change, just whether or not there is a linear or monotonic trend. Alternative approaches have used Loess-estimated trends to justify data interpretations or test hypotheses as to the causal factors without considering the inherent subjectivity of the choice of parameters used to achieve the Loessfit (e.g. span width, degree of polynomial). Generalized additive models (GAMs) are statistical models that can be used to estimate trends as smooth functions of time. Unlike Loess, GAMs use automatic smoothness selection methods to objectively determine the complexity of the fitted trend, and as formal statistical models, GAMs, allow for potentially complex, non-linear trends, a proper accounting of model uncertainty, and the identification of periods of significant temporal change. Here, I present a consistent and modern approach to the estimation of trends in palaeoenvironmental time series using GAMs, illustrating features of the methodology with two example time series of contrasting complexity; a 150-year bulk organic matterδ15N time series from Small Water, UK, and a 3000-year alkenone record from Braya-Sϕ, Greenland. I discuss the underlying mechanics of GAMs that allow them to learn the shape of the trend from the data themselves and how simultaneous confidence intervals and the first derivatives of the trend are used to properly account for model uncertainty and identify periods of change. It is hoped that by using GAMs greater attention is paid to the statistical estimation of trends in palaeoenvironmental time series leading to more a robust and reproducible palaeoscience.
An average-case sublinear exact Li and Stephens forward algorithm
Authors: Rosen Yohei M. , Paten Benedict J.
Published: May 2018

Hidden Markov models of haplotype inheritance such as the Li and Stephens model allow for computationally tractable probability calculations using the forward algorithms as long as the representative reference panel used in the model is sufficiently small. Specifically, the monoploid Li and Stephens model and its variants are linear in reference panel size unless heuristic approximations are used. However, sequencing projects numbering in the thousands to hundreds of thousands of individuals are underway, and others numbering in the millions are anticipated.

To make the Li and Stephens forward algorithm for these datasets computationally tractable, we have created a numerically exact version of the algorithm with observed average case 𝒪(nk0.35) runtime, avoiding any tradeoff between runtime and model complexity. We demonstrate that our approach also provides a succinct data structure for general purpose haplotype data storage. We discuss generalizations of our algorithmic techniques to other hidden Markov models.

2012 ACM Subject Classification

Theory of computation ⟶ Streaming, sublinear and near linear time algorithms; Applied computing ⟶ Bioinformatics

Supplement Material

https://github.com/yoheirosen/sublinear-Li-Stephens.

Funding

This work was supported by the National Human Genome Research Institute of the National Institutes of Health under Award Number 5U54HG007990, the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number 1U01HL137183-01, and grants from the W.M. Keck foundation and the Simons Foundation.

Acknowledgements

We would like to thank Jordan Eizenga for his helpful discussions throughout the development of this work.
Discovery of a novel stereospecific β-hydroxyacyl-CoA lyase/thioesterase shared by three metabolic pathways inMycobacterium tuberculosis
Authors: Wang Hua , Fedorov Alexander A. , Fedorov Elena V. , Hunt Deborah M. , Rodgers Angela , Garza-Garcia Acely , Bonanno Jeffrey B. , Almo Steven C. , de Carvalho Luiz Pedro S.
Published: May 2018

The vast number of poorly characterised enzymes inMycobacterium tuberculosis(Mtb) is one of the key barriers precluding a better understanding of the biology that underpins pathogenesis. Here, we investigated the Mtb orphan enzyme Rv2498c to delineate its physiological role. Our results fromin vitroenzymatic assays, phylogenetic analysis, X-ray crystallography andin vivoMtb experiments, de-orphan Rv2498c as a multi-functional β-hydroxyacyl-CoA lyase/thioesterase (β-HAClyase/thioesterase) that participates in three different metabolic pathways: L-leucine catabolism, itaconate dissimilation, and glyoxylate shunt. Moreover, the deletion of therv2498cgene from the Mtb genome resulted in attenuation in the mouse model compared to infection with the parent strain. To the best of our knowledge, this is the first report of an (R)-3-hydroxyl-3-methylglutaryl-CoA for leucine catabolism and an itaconate-specific resistance mechanism in Mtb.
Microtubule dynamics is required for rapid coiling of haptonemata in haptophyte algae
Authors: Nomura Mami , Atsuji Kohei , Hirose Keiko , Shiba Kogiku , Nakayama Takeshi , Ishida Ken-ichiro , Inaba Kazuo
Published: May 2018

A haptonema is an elongated microtubule-based motile organelle uniquely present in haptophytes. The most notable and rapid movement of a haptonema is “coiling”, which occurs within a few milliseconds following mechanical stimulation in an unknown motor-independent mechanism. Here, we analyzed the coiling process in detail by high-speed filming and showed that haptonema coiling was initiated by left-handed twisting of the haptonema, followed by writhing to form a helix from the distal tip. On recovery from a mechanical stimulus, the helix slowly uncoiled from the proximal region. Electron microscopy showed that the seven microtubules in a haptonema were arranged mostly in parallel but that one of the microtubules often wound around the others in the extended state. The persistence lengths calculated from the curvature of the haptonematal microtubules indicated their unusual flexibility. A microtubule stabilizer, paclitaxel, inhibited coiling and induced right-handed twisting of the haptonema in the absence of Ca2+, suggesting changes in the microtubule surface lattice. Addition of Ca2+caused bend propagation toward the proximal region. These results indicate that switching microtubule conformation with the aid of Ca2+-binding microtubule-associated proteins is responsible for rapid haptonematal coiling.

Summary Statement

Microscopy observations and pharmacological experiments revealed that the rapid coiling of a non-motor microtubule-based motile organelle, the haptonema, is explained by conformational changes of microtubules, including twisting and writhing.
Bacterial Glycosyltransferase-mediated Cell-surface Chemoenzymatic Glycan Editing: Methods and Applications
Authors: Hong Senlian , Shi Yujie , Wu Nicholas C. , Grande Geramie , Douthit Lacey , Wilson Ian A. , Xie Jia , Wu Peng
Published: May 2018

Chemoenzymatic glycan editing that modifies glycan structures directly on the cell surface has emerged as a complementary tool to metabolic oligosaccharide engineering. In this article, we report the discovery that three bacterial enzymes—Pasteurella multocidaα2-3-sialyltransferase M144D mutant (Pm2,3ST-M144D),Photobacterium damselα2-6-sialyltransferase (Pd2,6ST) andHelicobacter mustelaeα1-2-fucosyltransferase (Hm1,2FT)—can serve as highly efficient tools for cell-surface glycan editing. Among these three enzymes, the two sialyltransferases were also found to be tolerant to large substituents introduced to the C-5 position of the cytidine monophosphateN-acetylneuraminic acid donor, including biotin and fluorescent dyes. Combining these enzymes with our previously discoveredHelicobacter pyloriα1-3-FT, we developed a live cell-based assay to probe host-cell glycan-mediated influenza A virus (IAV) infection including both wild-type and mutant strains of human H1N1 and H3N2 influenza subtypes. At high SiaNAcα2-6-Gal levels, the ability of a viral strain to induce the host cell death is positively correlated with the SiaNAcα2-6-Gal binding affinity of its haemagglutinin. Surprisingly, the creation of sLeXon the host cell surfacevia in situα1-3-Fuc editing also exacerbated the killing induced by several wild-type IAV strains as well as a mutant known as HK68-MTA. Structural alignment of HAs from the wild-type HK68 and HK68-MTA revealed the formation of a putative hydrogen bond between Trp222 of HA-HK68-MTA and the C-4 hydroxyl group of the α1-3-linked fucose of sLeX. This interaction is likely to be responsible for the better binding affinity of HA-HK68-MTA to sLeXand accordingly the enhanced host-cell killing compared with the wild-type HK68.
Loss-of-function in IRF2BPL is associated with neurological phenotypes
Authors: Marcogliese Paul C. , Shashi Vandana , Spillmann Rebecca C. , Stong Nicholas , Rosenfeld Jill A. , Koenig Mary Kay , Martínez-Agosto Julián A. , Herzog Matthew , Chen Agnes H. , Dickson Patricia I. , Lin Henry J. , Vera Moin U. , Salamon Noriko , Ortiz Damara , Infante Elena , Steyaert Wouter , Dermaut Bart , Poppe Bruce , Chung Hyung-Lok , Zuo Zhongyuan , Lee Pei-Tseng , Kanca Oguz , Xia Fan , Yang Yaping , Smith Edward C. , Jasien Joan , Kansagra Sujay , Spiridigliozzi Gail , El-Dairi Mays , Lark Robert , Riley Kacie , Koeberl Dwight D. , Golden-Grant Katie ,   Program for Undiagnosed Diseases (UD-PrOZA) Undiagnosed Diseases Network, Yamamoto Shinya , Wangler Michael F. , Mirzaa Ghayda , Hemelsoet Dimitri , Lee Brendan , Nelson Stanley F. , Goldstein David B. , Bellen Hugo J. , Pena Loren D.M.
Published: May 2018

The Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.
Genomic analysis of the mesophilic Thermotogae genusMesotogareveals phylogeographic structure and genomic determinants of its distinct metabolism
Authors: Nesbø Camilla L. , Charchuk Rhianna , Pollo Stephen M. J. , Budwill Karen , Kublanov Ilya V. , Haverkamp Thomas H.A. , Foght Julia
Published: May 2018

The genusMesotoga, the only described mesophilicThermotogaelineage, is common in mesothermic anaerobic hydrocarbon-rich environments. Besides mesophily,Mesotogadisplays lineage-specific phenotypes, such as no or little H2production and dependence on sulfur-compound reduction, which may influence its ecological role. We used comparative genomics of 18Mesotogastrains (pairwise 16S rRNA identity > 99%) and a transcriptome ofM. primato investigate how life at moderate temperatures affects phylogeography and to interrogate the genomic features of its lineage-specific metabolism. We propose thatMesotogaaccomplish H2oxidation and thiosulfate reduction using a sulfide dehydrogenase and a hydrogenase-complex and that a pyruvate:ferredoxin oxidoreductase acquired fromClostridiais responsible for oxidizing acetate. Phylogenetic analysis revealed three distinctMesotogalineages (89.6-99.9% average nucleotide identity [ANI] within lineages, 79.3-87.6% ANI between lineages) having different geographic distribution patterns and high levels of intra-lineage recombination but little geneflow between lineages. Including data from metagenomes, phylogeographic patterns suggest that geographical separation historically has been more important forMesotogathan hyperthermophilicThermotogaand we hypothesize that distribution ofMesotogais constrained by their anaerobic lifestyle. Our data also suggest that recent anthropogenic activities and environments (e.g., wastewater treatment, oil exploration) have expandedMesotogahabitats and dispersal capabilities.

Originality-Significance Statement

This study comprises one of the first whole-genome-based phylogeographic analyses of anaerobic mesophiles, and our data suggest that such microbes are more restricted by geography than are thermophiles (and mesophilic aerobes). This is likely to be a general trait for similar anaerobic organisms – and therefore broadly relevant to and testable in other environments. Moreover,Mesotogabacteria are part of the largely understudied subsurface ecosystem that has relatively recently been recognized as a new and important biosphere. Understanding the forces responsible for the distribution of organisms in the subsurface, as well as the identification of genes responsible forMesotoga’s distinct metabolism, will contribute to the understanding of these communities.