bluuebunny/crossref_metadata_2025 huggingface dataset:
Two case reports of neonatal autoantibody-associated congenital heart block
Authors: Li Xiaoxia , Huang Xianmei , Lu Hui
Published: November 2018

Rationale:

Neonatal lupus erythematosus (NLE) is an infrequent disease caused by transplacental maternal autoantibodies. The most common effects of NLE include cutaneous involvement and congenital heart block (CHB), although it might involve multiple organs, such as the liver, lungs, blood, and nervous or digestive systems. Izmirly PM1 and Tonello et al recently reported cutaneous manifestations of neonatal lupus and risk of subsequent CHB. The most serious complication of NLE is complete atrioventricular (AV) block.

Patient concerns:

We experienced 2 cases of NLE that were diagnosed in the past year in our Neonatal Intensive Care Unit. These cases showed 2 different clinical spectrums (CHB, multisystemic effects). One case was a 32-week pregnant woman with combined liver damage and fever, and her fetus was premature due to bradycardia and pericardial effusion. The second case was a young pregnant woman who had systemic lupus erythematosus for 2 years and had been taking methylprednisolone and hydroxychloroquine for a long time since her illness. When prenatal testing at 28 weeks of pregnancy showed that the fetus had CHB, the mother began taking dexamethasone.

Diagnosis:

The first case was diagnosed as NLE with CHB after birth, while the second was diagnosed as NLE with CHB, ductus arteriosus, and atrial septal defect when she was born at 34 weeks.

Interventions:

Both of 2 cases were treated with steroids, intravenous immunoglobulin, and a diuretic. But the second case was treated with isoprenaline in addition to the above.

Outcomes:

Both of the infants was followed up and found to be clinically normal. During the clinic follow-up of the first case, the 8-month-old infant was still asymptomatic with normal growth and development. Her heart rate fluctuated from 40 to 90 beats/minute.

Lessons:

Autoimmune CHB is a severe, potentially life-threatening disorder associated with passive transfer of maternal anti-Sjogren's syndrome A/Ro and anti-Sjogren's syndrome B/La autoantibodies. Mothers who are positive for these autoantibodies are recommended to have serial echocardiography and obstetric ultrasonography from the early second trimester. Newborns should be delivered at an early stage of gestation if there is evidence of pericardial effusion, ascites, increasing ventricular ectopy, reduced ventricular shortening fraction, or AV valve regurgitation. Aggressive medical management after birth should be coupled with pacemaker implantation in infants who do not respond to medical therapies alone.
Coronary artery aneurysm formation after drug-coated balloon treatment of de novo lesions
Authors: Zhang Hui-Ping , Yu Xue , Ji Fu-Sui , Sun Fu-Cheng
Published: November 2018

Rationale:

The safety and efficacy of drug-coated balloon (DCB) technology have primarily been proven in the treatment of coronary in-stent restenosis. Whereas increasing evidences show that DCB use was feasible in certain de novo coronary lesions. In 2012, Vassilev reported the 1st case in which a coronary aneurysm formed after a DCB was used to treat drug-eluting stent (DES) restenosis. To date, limited information has been reported on coronary artery aneurysm (CAA) development following DCB treatment of de novo lesions.

Patient concerns:

A 42-year-old male underwent delayed coronary angiography due to extensive anterior wall myocardial infarction. After balloon predilation in the mid-left anterior descending (LAD) artery, the residual 30% stenosis without major dissection was treated with a DCB. Angiographic follow-up at 6 and 12 months revealed an aneurysm in the treated area of the LAD artery, with positive vascular remodeling behind this aneurysm. A 54-year-old male with nonstent thrombosis elevation myocardial infarction underwent elective catheterization. Coronary angiography revealed critical stenosis in the LAD and significant narrowing at the distal segments of both the left circumflex artery (LCX) and the nondominant right coronary artery. After predilation of the lesion in the LCX, the residual 30% stenosis was treated with a DCB. The lesion in the LAD was treated with a DCB either. Angiography follow-up at 6 months revealed good results in the LAD; however, an aneurysm was observed in the DCB-treated area of the LCX.

Diagnosis:

The CAA formation after DCB treatment of de novo lesions.

Interventions and outcomes:

Because the 2 patients were asymptomatic upon diagnosis, the aneurysms were left untreated. Long-term dual antiplatelet therapy and intense follow-up were recommended.

Lessons:

Our cases raise questions regarding the safety of DCB treatment for de novo lesions in real-world contexts. There might be a need to clarify the appropriate doses for drugs coated on DCBs. Although indications for DCB treatment for de novo coronary lesions should not be overly aggressively broadened, the potential role of such treatment in this context merits additional elucidation in future studies.
Viral Respiratory Infections Diagnosed After PICU Admission
Authors: Moynihan Katie M. , Barlow Andrew , Heney Claire , Clark Julia E. , Schlebusch Sanmarié , Schlapbach Luregn J.
Published: November 2018

Objectives:

Reduction of nosocomial infections represents an increasingly recognized aspect of PICU benchmarking. We investigated the prevalence and outcomes of viral respiratory infections acquired during admission to PICU.

Design:

Multicenter, statewide retrospective linkage study.

Setting:

Tertiary PICU.

Patients:

All children less than 16 years requiring PICU admission for greater than 48 hours from January 1, 2008, until December 31, 2013.

Intervention:

Testing was performed in symptomatic patients using an extended panel polymerase chain reaction capturing nine respiratory viruses. Duration of intubation and total duration of respiratory support were primary outcomes.

Measurements and Main Results:

Of 3,607 patients admitted to PICU for greater than 48 hours, 102 (2.8%) were diagnosed with a PICU-associated viral infection out of 702 patients (19.4%) undergoing viral testing, reflecting a rate of 2.8 PICU-associated viral infections per 1,000 PICU patient days. Compared with negative/untested patients, those with PICU-associated viral infections had greater intubation duration (median 164 vs 67; p< 0.001), longer respiratory support (204 vs 68 hr; p < 0.001), were more likely to require extracorporeal life support (odds ratio, 5.3; 2.7–10.3; p < 0.001), high-frequency oscillatory ventilation (odds ratio, 3.0; 1.7–5.4; p < 0.001), and inhaled nitric oxide (odds ratio, 2.7; 1.5–5.0; p = 0.001). When comparing patients with PICU-associated viral infection with patients who tested negative for respiratory viruses, no substantial difference in these outcomes was found.

Conclusions:

The acquisition of viral infections during PICU admission is less frequent compared with previous reports on bacterial and fungal hospital-acquired infections. We did not observe worse patient-centered outcomes when comparing virus positive versus tested but negative patients. Our findings challenge the clinical value of performing viral respiratory diagnostics in PICU patients evaluated for infection.
Role of Hemodialysis in the Management of Cyanide Intoxication From Apricot Kernels in a 3-Year-Old Child
Authors: Dalkıran Tahir , Kandur Yasar , Ozaslan Mustafa , Acıpayam Can , Olgar Seref
Published: November 2018

Cyanide (CN) is one among the most potent and rapidly acting lethal poisons, and it may cause death unless immediately diagnosed and treated. We report an unusual case of pediatric CN poisoning after ingestion of apricot kernels containing amygdalin, who survived with antidotal therapy and hemodialysis. A 3-year-old girl presented with respiratory distress and coma following tonic-clonic convulsions after ingestion of 3 apricot kernels. She had severe metabolic acidosis (pH 6.91, bicarbonate [HCO3
−] 5.6 mEq/L, base excess −26.0 mEq/L). Her blood CN level was measured 3.15 mg/L, 3 hours after ingestion. Hydroxocobalamin could not be administered immediately because it had to be brought from a medical center 4 hours apart. Therefore, a 3-hour hemodialysis session was carried out, following which she showed some clinical improvement. In addition, when hydroxocobalamin was obtained, it was then administered. During follow-up, she was completely asymptomatic with blood pressure, and other hemodynamic parameters normalized. This case presents hemodialysis as a way to correct metabolic derangements from CN poisoning and suggests that it may have a role in select cases of pediatric CN poisoning, especially when CN-scavenging antidotes may be unavailable.
Paraplegia After Basketball Play
Authors: Vijay Chickajajur S. , Nield Timothy R. , Nield Linda S.
Published: November 2018

Pediatric emergency medicine providers must be astute at generating the differential diagnosis and performing the appropriate evaluation to promptly determine the underlying cause of new onset paraplegia. Spinal cord infarction (SCI) is a potential etiology of paraplegia in children, and fibrocartilaginous embolization is a rare underlying cause of SCI. We present an illustrative case of SCI secondary to fibrocartilaginous embolization in an otherwise healthy adolescent who developed symptoms of spinal cord dysfunction after basketball play.
Impact of contrast extravasation on computed tomography of the psoas major muscle in patients with blunt torso trauma
Authors: Yumoto Tetsuya , Naito Hiromichi , Hiraki Takao , Yamakawa Yasuaki , Yamada Taihei , Nakao Atsunori
Published: November 2018

BACKGROUND

The clinical significance of contrast extravasation (CE) on computed tomography (CT) of the psoas major muscle after blunt torso trauma and the optimal management of patients requiring transcatheter arterial embolization (TAE) of the lumbar artery have not been well elucidated. The aim of this study was to investigate the impact of CE on CT to determine the need for TAE of the lumbar artery.

METHODS

We examined a single-center retrospective cohort of blunt torso trauma patients who underwent contrast-enhanced CT from 2008 to 2017. Basic demographics and clinical data were obtained, including the number of lumbar transverse process fractures (LTPFs) and maximum psoas major muscle hematoma (PMMH) size and ratio. Maximum PMMH size was analyzed by measuring the cross-sectional area of hematoma size at the level of CE. Psoas major muscle hematoma size ratio was obtained by dividing maximum PMMH size by psoas major muscle size of the unaffected side at the same slice level.

RESULTS

A total of 762 patients were included. One hundred seventeen patients had LTPFs and/or PMMH. Of 117 patients, 25 had CE on CT of the psoas major muscle and had significantly higher rates of older age and severe injury compared with those without CE. Of the 25 patients with CE, 13 required TAE of the lumbar artery. Patients who required TAE had a significantly higher number of LTPFs (4 vs. 2, p = 0.011) and higher PMMH size ratio (2.10 vs. 1.32, p = 0.016). Psoas major muscle hematoma size ratio revealed moderate accuracy (area under the receiver operating characteristic curve, 0.782).

CONCLUSIONS

Approximately half of the blunt torso trauma patients with CE on CT of the psoas major muscle will require TAE of the lumbar artery. Higher number of LTPFs and larger PMMH size can be a predictor of the need for TAE of the lumbar artery among patients with CE on CT.

LEVEL OF EVIDENCE

Therapeutic/care management, level IV.
A comparison of cholecystitis grading scales
Authors: Madni Tarik D. , Nakonezny Paul A. , Imran Jonathan B. , Taveras Luis , Cunningham Holly B. , Vela Ryan , Clark Audra T. , Minshall Christian T. , Eastman Alexander L. , Luk Stephen , Phelan Herb A. , Cripps Michael W.
Published: November 2018

BACKGROUND

Previously, our group developed the Parkland grading scale for cholecystitis (PGS) to stratify gallbladder (GB) disease severity that can be determined immediately when performing laparoscopic cholecystectomy (LC). In prior studies, PGS demonstrated excellent interrater reliability and was internally validated as an accurate measure of LC outcomes. Here, we compare PGS against a more complex cholecystitis severity score developed by the national trauma society, American Association for the Surgery of Trauma (AAST), which requires clinical, operative, imaging, and pathologic inputs, as a predictor of LC outcomes.

METHODS

Eleven acute care surgeons prospectively graded 179 GBs using PGS and filled out a postoperative questionnaire regarding the difficulty of the surgery. Three independent raters retrospectively graded these GBs using PGS from images stored in the electronic medical record. Three additional surgeons then assigned separate AAST scores to each GB. The intraclass correlation coefficient statistic assessed rater reliability for both PGS and AAST. The PGS score and the median AAST score became predictors in separate linear, logistic, and negative binomial regression models to estimate perioperative outcomes.

RESULTS

The average intraclass correlation coefficient of PGS and AAST was 0.8647 and 0.8341, respectively. Parkland grading scale for cholecystitis was found to be a superior predictor of increasing operative difficulty (R
2, 0.566 vs. 0.202), case length (R
2, 0.217 vs. 0.037), open conversion rates (area under the curve, 0.904 vs. 0.757), and complication rates (area under the curve, 0.7039 vs. 0.6474) defined as retained stone, small-bowel obstruction, wound infection, or postoperative biliary leak. Parkland grading scale for cholecystitis performed similar to AAST in predicting partial cholecystectomy, readmission, bile leak rates, and length of stay.

CONCLUSION

Both PGS and AAST are accurate predictors of LC outcomes. Parkland grading scale for cholecystitis was found to be a superior predictor of subjective operative difficulty, case length, open conversion rates, and complication rates. Parkland grading scale for cholecystitis has the advantage of being a simpler, operative-based scale which can be scored at a single point in time.

LEVEL OF EVIDENCE

Single institution, retrospective review, level IV.
Effect of Case Volume on Mortality After Pediatric Liver Transplantation in Korea
Authors: Lee Hannah , Jang Eun Jin , Kim Ga Hee , Yi Nam Joon , Kim Dal Ho , Yoo Seokha , Row Hyung Sang , Jung Chul-Woo , Oh Seung-Young , Ryu Ho Geol
Published: November 2018

Background.

The purpose of this study was to evaluate whether institutional case-volume affects clinical outcomes after pediatric liver transplantation.

Methods.

We conducted a nationwide retrospective cohort study using the database of Korean National Healthcare Insurance Service. Between January 2007 and December 2016, 521 pediatric liver transplantations were performed at 22 centers in Korea. Centers were categorized according to the average annual number of liver transplantations: >10, 1 to 10, and <1.

Results.

In-hospital mortality rates in the high-, medium-, and low-volume centers were 5.8%, 12.5%, and 32.1%, respectively. After adjustment, in-hospital mortality was significantly higher in low-volume centers (adjusted odds ratio, 9.693; 95% confidence interval, 4.636-20.268; P < 0.001) and medium-volume centers (adjusted odds ratio, 3.393; 95% confidence interval, 1.980-5.813; P < 0.001) compared to high-volume centers. Long-term survival for up to 9 years was better in high-volume centers.

Conclusions.

Centers with higher case volume (>10 pediatric liver transplantations/y) had better outcomes after pediatric liver transplantation, including in-hospital mortality and long-term mortality, compared to centers with lower case volume (≤10 liver transplantations/y).
TH2BS12P histone mark is enriched in the unsynapsed axes of the XY body and predominantly associates with H3K4me3-containing genomic regions in mammalian spermatocytes
Authors: Mahadevan Iyer Aditya , Pentakota Satyakrishna , Roy Raktim , Bhaduri Utsa , Satyanarayana Rao Manchanahalli R.
Published: November 2018

Various studies have focussed on understanding the repertoire and biological function of the post-translational modifications that occur on testis-specific histone variants like TH2B, Transition Proteins etc. In our attempt to decipher the unique functions of histone variant TH2B, we discovered a new modification Serine 12 phosphorylation on TH2B (TH2BS12P) in spermatocytes. Our present study is aimed at understanding the function of the TH2BS12P modification in the context of processes that occur during meiotic prophase I. Immunofluorescence studies revealed that TH2BS12P histone mark is enriched in the unsynapsed axes of the sex body and is associated with XY body axes associated proteins like Scp3, γH2AX, pATM, ATR etc. We also observe that TH2BS12P is associated with DSB initiator Spo11 and with several recombination related proteins like pATM, ATR, Rad51, γH2AX etcin vivo. This modification was also found to associate with transcription and recombination related histone marks like H3K4me3 and H3K36me3 in the context of mononucleosomes. Genome-wide occupancy studies as determined by ChIP sequencing experiments revealed that TH2BS12P is localised to subset of recombination hotspots, but majorly associated with H3K4me3 containing genomic regions like gene promoters. Mass spectrometry analysis of proteins that bind to TH2BS12P containing mononucleosomes revealed many proteins linked with the functions of pericentric heterochromatin, transcription and recombination related pathways. We propose that TH2BS12P modification could act alone or in concert with other histone marks for recruitment of appropriate transcription or recombination protein machinery at specific genomic loci. This is the first report documenting the role of a post-translational modification of a germ cell specific histone variant in meiotic prophase I related events.
Predicting response to motor therapy in chronic stroke patients using Machine Learning
Authors: Tozlu Ceren , Edwards Dylan , Boes Aaron , Labar Douglas , Tsagaris K. Zoe , Silverstein Joshua , Lane Heather Pepper , Sabuncu Mert R. , Liu Charles , Kuceyeski Amy
Published: November 2018

Accurate predictions of motor improvement resulting from intensive therapy in chronic stroke patients is a difficult task for clinicians, but is key in prescribing appropriate therapeutic strategies. Statistical methods, including machine learning, are a highly promising avenue with which to improve prediction accuracy in clinical practice. The first main objective of this study was to use machine learning methods to predict a chronic stroke individual’s motor function improvement after 6 weeks of intervention using pre-intervention demographic, clinical, neurophysiological and imaging data. The second main objective was to identify which data elements were most important in predicting chronic stroke patients’ impairment after 6 weeks of intervention. Data from one hundred and two patients (Female: 31%, age 61±11 years) who suffered first ischemic stroke 3-12 months prior were included in this study. After enrollment, patients underwent 6 weeks of intensive motor and transcranial magnetic stimulation therapy. Age, gender, handedness, time since stroke, pre-intervention Fugl-Meyer Assessment, stroke lateralization, the difference in motor threshold between the unaffected and affected hemispheres, absence or presence of motor evoked potential in the affected hemisphere and various imaging metrics were used as predictors of post-intervention Fugl-Meyer Assessment. Five machine learning methods, including Elastic-Net, Support Vector Machines, Artificial Neural Networks, Classification and Regression Trees, and Random Forest, were used to predict post-intervention Fugl-Meyer Assessment based on either demographic, clinical and neurophysiological data alone or in combination with the imaging metrics. Cross-validated R-squared and root of mean squared error were used to assess the prediction accuracy and compare the performance of methods. Elastic-Net performed significantly better than the other methods for the model containing pre-intervention Fugl-Meyer Assessment, demographic, clinical and neurophysiological data as predictors of post-intervention Fugl-Meyer Assessment (). Pre-intervention Fugl-Meyer Assessment and difference in motor threshold between affected and unaffected hemispheres were commonly found as the strongest two predictors in the clinical model. The difference in motor threshold had greater importance than the absence or presence of motor evoked potential in the affected hemisphere. The various imaging metrics, including lesion overlap with the spinal cord, largely did not improve the model performance. The approach implemented here may enable clinicians to more accurately predict a chronic stroke patient’s individual response to intervention. The predictive models used in this study could assist clinicians in making treatment decisions and improve the accuracy of prognosis in chronic stroke patients.
Comparison of three variant callers for human whole genome sequencing
Authors: Supernat Anna , Vidarsson Oskar Valdimar , Steen Vidar M. , Stokowy Tomasz
Published: November 2018

Testing of patients with genetics-related disorders is in progress of shifting from single gene assays to gene panel sequencing, whole-exome sequencing (WES) and whole-genome sequencing (WGS). Since WGS is unquestionably becoming a new foundation for molecular analyses, we decided to compare three currently used tools for variant calling of human whole genome sequencing data. We tested DeepVariant, a new TensorFlow machine learning-based variant caller, and compared this tool to GATK 4.0 and SpeedSeq, using 30×, 15× and 10× WGS data of the well-known NA12878 DNA reference sample.

According to our comparison, the performance on SNV calling was almost similar in 30× data, with all three variant callers reaching F-Scores (i.e. harmonic mean of recall and precision) equal to 0.98. In contrast, DeepVariant was more precise in indel calling than GATK and SpeedSeq, as demonstrated by F-Scores of 0.94, 0.90 and 0.84, respectively.

We conclude that the DeepVariant tool has great potential and usefulness for analysis of WGS data in medical genetics.
Magnetoelectric materials for miniature, wireless neural stimulation at therapeutic frequencies
Authors: Singer Amanda , Dutta Shayok , Lewis Eric , Chen Ziying , Chen Joshua C. , Verma Nishant , Avants Benjamin , Feldman Ariel K. , O’Malley John , Beierlein Michael , Kemere Caleb , Robinson Jacob T.
Published: November 2018

A fundamental challenge for bioelectronics is to deliver power to miniature devices inside the body. Wires are common failure points and limit device placement. On the other hand, wireless power by electromagnetic or ultrasound waves must overcome absorption by the body and impedance mismatches between air, bone, and tissue. In contrast, magnetic fields suffer little absorption by the body or differences in impedance at interfaces between air, bone, and tissue. These advantages have led to magnetically-powered stimulators based on induction or magnetothermal effects. However, fundamental limitations in these power transfer technologies have prevented miniature magnetically-powered stimulators from applications in many therapies and disease models because they do not operate in clinical “high-frequency” ranges above 50 Hz. Here we show that magnetoelectric materials – applied in bioelectronic devices – enable miniature magnetically-powered neural stimulators that can operate up to clinically-relevant high-frequencies. As an example, we show that ME neural stimulators can effectively treat the symptoms of a hemi-Parkinson’s disease model in freely behaving rodents. We further demonstrate that ME-powered devices can be miniaturized to mm-sized devices, fully implanted, and wirelessly powered in freely behaving rodents. These results suggest that ME materials are an excellent candidate for wireless power delivery that will enable miniature bioelectronics for both clinical and research applications.
Label-Free Density-Based Detection of Adipocytes of Bone Marrow Origin Using Magnetic Levitation
Authors: Sarigil Oyku , Anil-Inevi Muge , Mese Gulistan , Cumhur Tekin H. , Ozcivici Engin
Published: November 2018

Adipocyte hypertrophy and hyperplasia are important parameters in describing abnormalities in adipogenesis that are concomitant to diseases such as obesity, diabetes, anorexia nervosa and osteoporosis. Therefore, technical developments in detection of adipocytes become an important driving factor in adipogenesis research. Current techniques such as optical microscopy and flow cytometry are available in detection and examination of adipocytes, driving cell- and molecular-based research of adipogenesis. Even though microscopy techniques are common and straightforward, they are restricted for manipulation and separation of the cells. Flow cytometry is an alternative, but mature adipocytes are fragile and cannot withstand the flow process. Other separation methods usually require labeling of the cells or usage of microfluidic platforms that utilize fluids with different densities. Magnetic levitation is a novel label-free technology with the principle of movement of cells towards the lower magnetic field in a paramagnetic medium depending on their individual densities. In this study, we used magnetic levitation device for density-based single cell detection of differentiated adipogenic cells in heterogeneous populations. Results showed that magnetic levitation platform was sensitive to changes in lipid content of mesenchymal stem cells committed to adipogenesis and it could be successfully used to detect adipogenic differentiation of cells.
Analysis of cholesterol export from endo-lysosomes by Niemann Pick C2 protein using combined fluorescence and X-ray microscopy
Authors: Dupont Alice , Lund Frederik W. , Jensen Maria Louise V. , Szomek Maria , Nielsen Gitte K. , Heegaard Christian W. , Guttmann Peter , Werner Stephan , McNally James , Schneider Gerd , Kapishnikov Sergey , Wüstner Daniel
Published: November 2018

The Niemann-Pick C2 protein (NPC2) is a sterol transfer protein in late endosomes and lysosomes (LE/LYSs). How its capacity to transport cholesterol between membranes is linked to endo-lysosomal membrane trafficking is not known. Using quantitative fluorescence imaging combined with soft X-ray tomography (SXT); we show that NPC2 mediated sterol efflux is accompanied by large changes in distribution, size and ultrastructure of endocytic organelles. We observed clearance of intra-luminal lipid deposits, a decrease in number of autophagosomes, formation of membrane contact sites (MCSs) to the endoplasmic reticulum and extensive tubulation of LE/LYSs in three-dimensional SXT reconstructions of NPC2 treated human fibroblasts. The cells could recycle the cholesterol analog dehydroergosterol (DHE) from LE/LYSs slowly also in the absence of NPC2 protein but internalized NPC2 synchronized and accelerated this process significantly. Most fluorescent NPC2 was retained in LE/LYSs while DHE was selectively removed from these organelles, at least partially by non-vesicular exchange with other membranes. During sterol efflux LE/LYSs were reallocated to the cell periphery, where they could fuse with newly formed endosomes. Surface shedding of micro-vesicles was found, suggesting a pathway for cellular sterol release. We conclude that NPC2 mediated sterol efflux from LE/LYSs controls membrane traffic through the endo-lysosomal pathway.
Comprehensive profiling of antibodies against multiple infectious diseases in serum and the airway mucosa using synthetic peptide-based linear epitope microarrays
Authors: Sande Charles J , Chege Timothy , Mutunga Martin N , Gicheru Elijah , Nokes D James , Green Christopher A , Tuju James
Published: November 2018

Background

Despite the considerable progress that has been achieved in the development of vaccines, infectious diseases continue to be the major cause of morbidity and mortality in developing countries. The first year of life remains the time of greatest risk with more than half of all deaths caused by infectious diseases in children under the age of five years occurring during this period. For most infections, antibodies are the strongest immune correlate of protective immunity and characterizing the breadth of the antibody repertoire against infectious diseases in early life is key to profiling individual disease risk.

Methods

In order to comprehensively profile the antibody repertoire against infectious diseases in early life, we developed a synthetic peptide-based microarray to simultaneously measure antibodies against forty one common infectious diseases. 82 empirically-validated linear B-cell epitopes were selected from the Immune Epitope Database (IEBD), expressed as synthetic peptides and printed onto microarray glass slides (microarray chip). The chip was used to simultaneously measure antigen-specific IgG and IgA in serum and mucosal samples from thirty eight infants and young children presenting to hospital with different illnesses. We also used the data from the microarray to estimate antibody decay kinetics for the five most frequently detected antigens during the first year of life.

Results

A synthetic peptide microarray to measure antibodies against forty one infectious diseases was successfully developed. Although the combination of antigens that were recognized were different for each child, antigens derived from Epstein-Barr virus, poliovirus,Streptococcus pneumoniae, plasmodium falciparum and varicella zoster were recognized by most study participants. While the combination of antigens recognized in serum was generally similar as those recognized in mucosal samples, antibodies to antigens such as herpesvirus, rubella and echinococcus were more predominant in either serum or mucosal samples. With the exception of the pneumococcus, we observed a progressive decline in serum IgG specific to all the infections above in the first six months of life. Pneumococcal IgG in serum exhibited a continuous rise in the first six months of life.

Conclusions

We successfully developed a synthetic peptide microarray and used it to profile the diversity of systemic and mucosal antibody against multiple infectious diseases in children. The data from the slide provide a snapshot overview of the breadth and kinetics of infectious disease antibodies early in life and opens the opportunity for conducting in-depth multi, multi-target serological studies of infectious diseases in future.
A highly divergent picornavirus infecting the gut epithelia of zebrafish (Danio rerio) in research institutions world-wide
Authors: Altan Eda , Kubiski Steven V. , Boros Ákos , Reuter Gábor , Sadeghi Mohammadreza , Deng Xutao , Creighton Erica K. , Crim Marcus J. , Delwart Eric
Published: November 2018

Zebrafish have been extensively used as a model system for research in vertebrate development and pathogen-host interactions. We describe the complete genome of a novel picornavirus identified during a viral metagenomics analysis of zebrafish gut tissue. The closest relatives of this virus showed identity of ≤19.8% in their P1 capsids and ≤35.4% in their RdRp qualifying zebrafish picornavirus 1 (ZfPV1) as member of a novel genus with a proposed name of Cyprivirus. RT-PCR testing of zebrafish from 41 institutions from North America, Europe, and Asia showed ZfPV1 to be highly prevalent world-wide. In situ hybridization of whole zebrafish showed viral RNA was restricted to a subset of enterocytes and cells in the subjacent lamina propria of the intestine and the intestinal mucosa. This naturally occurring and apparently asymptomatic infection (in wild type zebrafish lineage AB) provides a natural infection system to study picornavirus-host interactions in an advanced vertebrate model organism. Whether ZfPV1 infection affects any immunological, developmental or other biological processes in wild type or mutant zebrafish lineages remains to be determined.
High accuracy protein structures from minimal sparse paramagnetic solid-state NMR restraints
Authors: Perez Alberto , Gaalswyk Kari , Jaroniec Christopher P. , MacCallum Justin L.
Published: November 2018

There is a pressing need for new computational tools to integrate data from diverse experimental approaches in structural biology. We present a strategy that combines sparse paramagnetic solid-state NMR restraints with physics-based atomistic simulations. Our approach explicitly accounts for uncertainty in the interpretation of experimental data through the use of a semi-quantitative mapping between the data and the restraint energy that is calibrated by extensive simulations. We apply our approach to solid-state NMR data for the model protein GB1 labeled with Cu2+-EDTA at six different sites. We are able to determine the structure to ca. 1 Å accuracy within a single day of computation on a modest GPU cluster. We further show that in 4 of 6 cases, the data from only a single paramagnetic tag are sufficient to fold the protein to high accuracy.
Glycan cross-feeding drives mutualism betweenFusobacteriumand the vaginal microbiota
Authors: Agarwal Kavita , Robinson Lloyd , Perry Justin , Foster Lynne , Lin Hueylie , Tortelli Brett , O’Brien Valerie P. , Reno Hilary , Gilbert Nicole , Lewis Warren , Lewis Amanda
Published: November 2018

Dysbiosis of the vaginal microbiome is associated with vaginal colonization by potential pathogens includingFusobacterium nucleatum, a bacterium linked with intrauterine infection and preterm birth. However, mechanisms by which such pathogens gain a foothold in the dysbiotic vagina remain obscure. Here we demonstrate that sialidase activity, a biochemical marker of vaginal dysbiosis, promotedF. nucleatumforaging on mammalian sialoglycans, an otherwise inaccessible resource. In mice with sialidase-positive vaginal microbiomes, mutantF. nucleatumunable to consume sialic acids displayed impaired colonization. Furthermore, community- and co-culture experiments showed thatF. nucleatumdid not simply take advantage of sialidase-positive bacteria, but also “gave back” to the community, supporting robust outgrowth of sialidase-producers, includingGardnerella vaginalis. These results illustrate that mutualistic relationships between vaginal bacteria support pathogen colonization and reinforce dysbiosis, adding complexity to the simplistic dogma that the mere absence of “healthy” lactobacilli is what creates a permissive environment for pathogens during dysbiosis.
A comparison of deep learning and linear-nonlinear cascade approaches to neural encoding
Authors: Moskovitz Theodore H. , Roy Nicholas A. , Pillow Jonathan W.
Published: November 2018

A large body of work on neural encoding has focused on “cascade” type models such as the linear-nonlinear-Poisson (LNP) model. This approach seeks to describe the encoding process in terms of a series of stages: (1) projection of the stimulus onto a bank of linear filters; (2) a nonlinear function combining these filter outputs; and (3) a noisy spike generation process. Here we explore the relationship of the LNP modeling framework to more recent approaches arising from the deep learning literature. Specifically, we show that deep neural network (DNN) and convolutional neural network (CNN) models of neural activity sit firmly within the LNP framework, and correspond to particular parametrizations of the nonlinear stage of the LNP model. Using data from primate retina and primary visual cortex, we compare the performance of LNP models fit with deep learning methods to LNP models fit with traditional estimators, including spike-triggered covariance (STC), information-theoretic spike-triggered averaging and covariance (iSTAC), and maximum likelihood estimators also known as “maximally informative dimensions” (MID). We show that models with nonlinearities parametrized by deep networks achieve higher accuracy for a fixed number of filters, and can extract a larger number of informative filters than traditional models. Finally, we perform a dimensionality analysis of LNP models trained with deep learning methods, revealing that a large number of filters are needed to accurately describe the neural responses of many cells even early in the visual pathway. This result overturns one of the central tenets of the LNP modeling framework: that neural computations are low-dimensional, or depend on the stimulus only via its projection onto a small number of linear filters. We discuss the implications of these findings for both the fitting and interpretation of LNP encoding models.
Nanoscale fracture of defective popgraphene monolayer
Authors: Meng Fanchao , Ni Ming , Chen Feng , Song Jun , Wei Dong
Published: November 2018

A new carbon allotrope, namely popgraphene, has been recently demonstrated to possess high potentials for nanodevice applications. Here, the fracture of defective popgraphene was studied using molecular dynamics simulations and continuum modeling. Three scenarios of defects were considered, including an individual point defect, distributed point defects, and nanocracks. It was found that the fracture stress of popgraphene with an individual point defect was governed by both the geometry of the defect and the critical bond where fracture initiates. Moreover, the fracture stress of popgraphene with distributed point defects was discovered to be inversely proportional to the defect density, showing a nice linear trend. Furthermore, for popgraphene with a nanocrack, it failed in a brittle fashion and exhibited a negligible lattice trapping effect. Griffith criterion was subsequently employed with the consideration of crack deflection to accurately predict the dependence of fracture stress on crack size. The present study lays a mechanistic foundation for nanoscale applications of popgraphene and offers a better understanding of the roles of defects in fracture of low-dimensional materials.
Cell rounding causes genomic instability by dissociation of single-stranded DNA-binding proteins
Authors: Guo Qian , Liao Xianglu , Wang Xingwu , Liu Ling , Song Bao
Published: November 2018

Genomic instability can cause a wide range of diseases, including cancer and cellular senescence, which is also a major challenge in stem cell therapy. However, how a single event can cause extremely high levels of genomic instability remains unclear. Using our developed method, cell in situ electrophoresis (CISE), and models of normal, cancer, and embryonic stem cells, we found that cell rounding as a catastrophic source event ubiquitously observed in vivo and in vitro might lead to large-scale DNA deprotection, genomic instability, chromosomal shattering, cell heterogeneity, and senescent crisis by dissociation of single-stranded DNA-binding proteins (SSBs). Understanding the mechanism may facilitate the development of clinical strategies for cancer therapy, improve the safety of stem cell therapy, and prevent pathological aging.
Unraveling the implications of environmental, host and pathogen-specific determinants on clinical presentations and disease progression among Indian melioidosis patients
Authors: Shaw Tushar , Tellapragada Chaitanya , Kamath Asha , Eshwara Vandana Kalwaje , Mukhopadhyay Chiranjay
Published: November 2018

Background

Melioidosis is gaining recognition as an emerging infectious disease with diverse clinical manifestations and high-case fatality rates,worldwide. However, the molecular epidemiology of the disease outside the endemic regions such as,Thailand and Northern Australia remains unclear.

Methods

Clinical data and B. pseudomallei (Bps) isolates obtained from 199 culture-confirmed cases of melioidosis, diagnosed during 2006-2016 inSouth India were used to elucidate the host and pathogen-specific variable virulence determinants associated with clinical presentations and disease progression. Further, we determined the temporal variations and the influence of ecological factors on Bps Lipopolysaccharide (LPS) genotypes causing infections.

Result

Severe forms of the disease were observed amongst 169 (85%) patients. Renal dysfunction and infection due to Bps harboring Bim-ABm variant had significant associations with severe forms of the disease. Diabetes mellitus, septicemic melioidosis and infection due to LPS-B genotype were independent risk factors for mortality. LPS-B (74%) and LPS-A (20.6%) were the prevalent genotypes causing infections. Both genotypes demonstrated temporal variations and had significant correlations with rainfall and humidity.

Conclusion

Our study findings suggest that the pathogen-specific virulence traits, under the influence of ecological factors are the key drivers for geographical variations in the molecular epidemiology of melioidosis.
Phylogenomics of the adaptive radiation ofTriturusnewts supports gradual ecological niche expansion towards an incrementally aquatic lifestyle
Authors: Wielstra B. , McCartney-Melstad E. , Arntzen J.W. , Butlin R.K. , Shaffer H.B.
Published: November 2018

Newts of the genusTriturus(marbled and crested newts) exhibit substantial variation in the number of trunk vertebrae (NTV) and a higher NTV corresponds to a longer annual aquatic period. Because theTriturusphylogeny has thwarted resolution to date, the evolutionary history of NTV, annual aquatic period, and their potential coevolution has remained unclear. To resolve the phylogeny ofTriturus, we generated a c. 6,000 transcriptome-derived marker data set using a custom target enrichment probe set, and conducted phylogenetic analyses using: 1) data concatenation with RAxML, 2) gene-tree summary with ASTRAL, and 3) species-tree estimation with SNAPP. All analyses produce the same, highly supported topology, despite cladogenesis having occurred over a short timeframe, resulting in short internal branch lengths. Our new phylogenetic hypothesis is consistent with the minimal number of inferred changes in NTV count necessary to explain the diversity in NTV observed today. Although a causal relationship between NTV, body form, and aquatic ecology has yet to be experimentally established, our phylogeny indicates that these features have evolved together, and suggest that they may underlie the adaptive radiation that characterizesTriturus.
Divergent effects of acute and prolonged interleukin 33 exposure on mast cell IgE-mediated functions
Authors: Rönnberg Elin , Ghaib Avan , Ceriol Carlos , Enoksson Mattias , Arock Michel , Säfholm Jesper , Ekoff Maria , Nilsson Gunnar
Published: November 2018

Background

Epithelial cytokines, including IL-33 and TSLP, have attracted interest because of their roles in chronic allergic inflammation-related conditions such as asthma. Mast cells are one of the major targets of IL-33, to which they respond by secreting cytokines. Most studies performed thus far have investigated the acute effects of IL-33 on mast cells.

Objective

The objective of this study is to investigate how acute versus prolonged exposure of human mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation.

Methods

Human lung mast cells (HLMCs), cord blood-derived mast cells (CBMCs), and the ROSA mast cell line were used for this study. Surface receptor expression and the levels of mediators were measured after treatment with IL-33 and/or TSLP.

Results

IL-33 induced the acute release of cytokines. Prolonged exposure to IL-33 increased while TSLP reduced intracellular levels of tryptase. Acute IL-33 treatment strongly potentiated IgE-mediated activation. In contrast, four days of exposure to IL-33 decreased IgE-mediated activation, an effect that was accompanied by a reduction in FcεRI expression.

Conclusion & Clinical Relevance

We show that IL-33 plays dual roles for mast cell functions. The acute effect includes cytokine release and the potentiation of IgE-mediated degranulation, whereas prolonged exposure to IL-33 reduces IgE-mediated activation. We conclude that mast cells act quickly in response to the alarmin IL-33 to initiate an acute inflammatory response, whereas extended exposure to IL-33 during prolonged inflammation reduces IgE-mediated responses. This negative feedback effect suggests the presence of a novel IL-33 mediated regulatory pathway that modulates IgE-induced human mast cell responses.
Schistosoma mansonidoes not and cannot oxidize fatty acids, but these are used for biosynthetic purposes instead
Authors: Bexkens Michiel L. , Mebius Mirjam M. , Houweling Martin , Brouwers Jos F. , Tielens Aloysius G.M. , van Hellemond Jaap J.
Published: November 2018

Adult schistosomes, parasitic flatworms that cause the tropical disease schistosomiasis, have always been considered to be homolactic fermenters and in their energy metabolism strictly dependent on carbohydrates. However, more recent studies suggested that fatty acid β-oxidation is essential for egg production by adult femaleSchistosoma mansoni. To address this conundrum, we performed a comprehensive study on the lipid metabolism ofS. mansoni. Incubations with [14C]-labelled fatty acids demonstrated that adults, eggs and miracidia ofS. mansonidid not oxidize fatty acids, as no14CO2production could be detected. We then re-examined theS. mansonigenome using the genes known to be involved in fatty acid oxidation in six eukaryotic model reference species. This showed that the earlier automatically annotated genes for fatty acid oxidation were in fact incorrectly annotated. In a further analysis we could not detect any genes encoding β-oxidation enzymes, which demonstrates thatS. mansonicannot use this pathway in any of its lifecycle stages. The same was true forS. japonicum.Absence of β-oxidation, however, does not imply that fatty acids from the host are not metabolized by schistosomes. Adult schistosomes can use and modify fatty acids from their host for biosynthetic purposes and incorporate them in phospholipids and neutral lipids. Female worms deposit large amounts of these lipids in the eggs they produce, which explains why interference with the lipid metabolism in females will disturb egg formation, even though fatty acid β-oxidation does not occur in schistosomes. Our analyses ofS. mansonifurther revealed that during the development and maturation of the miracidium inside the egg, changes in lipid composition occur which indicates that fatty acids deposited in the egg by the female worm are used for phospholipid biosynthesis required for membrane formation in the developing miracidium.