bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of Tularemia Among Health Care Providers With Close Contact With Infected Patients—A Case Series
Authors: Nelson Christina A , Brown Jennifer , Riley Linda , Dennis Anne , Oyer Ryan , Brown Catherine
Published: November 2019

Francisella tularensis has a low infectious dose and can infect laboratory staff handling clinical specimens. The risk to health care providers exposed during patient care is poorly defined. We describe 9 examples of health care providers who did not develop tularemia after significant exposures to infected patients.
The Living Spine Model: A Biomimetic Surgical Training and Education Tool
Authors: Bohl Michael A , McBryan Sarah , Pais Danielle , Chang Steve W , Turner Jay D , Nakaji Peter , Kakarla U Kumar
Published: November 2019

BACKGROUND

The Living Spine Model (LSM) is a three-dimensionally printed, surgical training platform developed by neurosurgical residents.

OBJECTIVE

To evaluate the face and content validity of this model as a training tool for open posterior lumbar surgery.

METHODS

Six surgeons with varying experience were asked to complete L3-5 pedicle screw fixation and L3-4 laminectomy on an LSM. Face validity was measured using a questionnaire, and content validity was measured using the National Aeronautics and Space Administration Task Load Index (NASA TLX) tests. Student's t-test was used to compare NASA TLX responses between junior and senior residents and to compare responses for live surgery vs simulated surgery on the LSM.

RESULTS

Junior residents took the longest time to complete the procedure, followed by senior residents and the attending surgeon (136.5, 98.3, and 84 min, respectively). The junior residents placed fewer successful pedicle screws (7/12) than senior residents and attending surgeon (18/18). All tested components of the model had excellent face validity, with scores ranging from 60% to 97%. Content validity testing demonstrated that the LSMs created overall workloads and specific types of work like live operating conditions.

CONCLUSION

The overall validity testing of the LSM demonstrates the high-potential utility of this model as a surgical education and testing platform for open posterior lumbar procedures. The LSM has great potential as an adjunct to surgical education, and it may become an increasingly important component of surgical resident curricula in the future.
Childhood vasculitis
Authors: Ozen Seza , Sag Erdal
Published: November 2019

Vasculitis is a challenging disease for paediatricians. Certain vasculitides are quite common in children whereas others are much rarer compared with adults. The most common vasculitides in childhood are IgA-associated vasculitis (Henoch–Schönlein purpura) and Kawasaki disease, which are usually self-limiting vasculitides although children do develop complications as a result. We now have much better knowledge of how to manage these patients and prevent the deleterious complications. This review provides an up-to-date discussion on childhood vasculitides, including diagnosis, treatment and follow-up strategies, together with a comparison with vasculitides in adults. It also discusses the newly defined monogenic vasculitides that often present during early childhood.
Differences in three-dimensional upper airway anatomy between Asian and European patients with obstructive sleep apnea
Authors: Xu Liyue , Keenan Brendan T , Wiemken Andrew S , Chi Luqi , Staley Bethany , Wang Zhifang , Wang Jianjun , Benedikstdottir Bryndis , Juliusson Sigurdur , Pack Allan I , Gislason Thorarinn , Schwab Richard J
Published: November 2019

Study Objectives

This study evaluated differences in upper airway, soft tissues and craniofacial structures between Asians from China and Europeans from Iceland with OSA using three-dimensional magnetic resonance imaging (MRI).

Methods

Airway sizes, soft tissue volumes, and craniofacial dimensions were compared between Icelandic (N = 108) and Chinese (N = 57) patients with oxygen desaturation index (ODI) ≥ 10 events/h matched for age, gender, and ODI. Mixed effects models adjusting for height or BMI and residual differences in age and ODI were utilized.

Results

In our matched sample, compared to Icelandic OSA patients, Chinese patients had smaller BMI (p < 0.0001) and neck circumference (p = 0.011). In covariate adjusted analyses, Chinese showed smaller retropalatal airway size (p ≤ 0.002), and smaller combined soft tissues, tongue, fat pads, and pterygoid (all p ≤ 0.0001), but male Chinese demonstrated a larger soft palate volume (p ≤ 0.001). For craniofacial dimensions, Chinese demonstrated bigger ANB angle (p ≤ 0.0196), differently shaped mandibles, including shorter corpus length (p < 0.0001) but longer ramus length (p < 0.0001), and a wider (p < 0.0001) and shallower (p ≤ 0.0001) maxilla.

Conclusions

Compared to Icelandic patients of similar age, gender and ODI, Chinese patients had smaller retropalatal airway and combined soft tissue, but bigger soft palate volume (in males), and differently shaped mandible and maxilla with more bony restrictions. Results support an ethnic difference in upper airway anatomy related to OSA, which may inform targeted therapies.
Comparing the institutional constructive trust with the remedial constructive trust
Authors: Raphael David K L
Published: November 2019

The concept of the Institutional Constructive Trust was first recognised in Australia in 1907 by the most senior court, i.e. the High Court of Australia, in Black v S Friedman & Co. This arose in a decision involving stolen funds. Its importance was addressed in the State of Victoria in Nolan v Nolan where what was in issue involved the Limitations Act of the State of Victoria. It must be appreciated that in the Commonwealth of Australia, State Acts can, and sometimes do, differ. In 1985, in Muschinski v Dodds, Deane J of the Australian High Court placed different emphasis on the court’s ability to recognise and construe such a trust and gave it the imprimatur of “Remedial Constructive Trust”. The latter, whilst adopted in New Zealand and Canada, has had what might fairly be described as its critics in the UK and, indeed the UK Supreme Court in FHR European Venture LLP v Cedar Capital Partners LLC has stated at [47] that the remedial constructive trust is not part of the law of the UK.
Indirect Reduction and Strut Support of Proximal Humerus Fractures Using a Titanium Mesh in Elderly Patients: A Novel Technique
Authors: Chen Hui , Cui Xueliang , Rui Yunfeng , Ma Binbin , Li He
Published: November 2019

Surgical treatment of unstable proximal humeral fractures is challenging in elderly patients. The locking plate technique has been advocated for the management of these fractures in recent years; however, it is still difficult to achieve stable fixation and maintain intra-operative reduction in patients with low bone mineral density. It is generally accepted that a critical step to enhance clinical results and reduce complications is re-creation of the medial column support. Here, we introduce a novel technique using titanium mesh in the treatment of proximal humerus fractures. Although preliminary results have been encouraging, further study with a larger number of patients and longer follow-up is needed to fully validate this technique.
Cesarean delivery may be protective against neoplasms of the uterine cervix in women of childbearing age
Authors: Choi Won-Il , Jeong Jihyeon , Lee Dong Yoon , Shim Hye-Young , Lee Choong Won
Published: November 2019

Parity has been reported as a risk factor for cervical cancer. However, no study has investigated the risk of neoplasms of the uterine cervix according to the delivery type. We carried out a retrospective cohort study using nationwide data from the Korean Health Insurance Review and Assessment Database to investigate whether cesarean delivery might be associated with less development of neoplasms of the uterine cervix than a vaginal delivery in women of childbearing age. Women aged 20–44 years, who had undergone vaginal or cesarean deliveries in 2009 were included as subjects. Two individual datasets for carcinoma in situ (CIS) and cancer of the cervix were followed for 8 years until either disease outcomes or 31 December 2016. In total, 260 438 and 132 232 women had undergone vaginal only and cesarean only deliveries, respectively. There were 1505 and 423 new cases of CIS and cervical cancer, respectively, with median follow-up durations of 89.9 and 90.0 months for vaginal delivery and cesarean delivery, respectively. The unadjusted CIS risk ratio for cesarean delivery compared with vaginal delivery was 0.90 [95% confidence interval, (CI), 0.80–1.00]. After adjusting for categorical age, residential area, facility types, and number of visits to obstetrics and gynecology clinics, it was 0.83 (95% CI, 0.75–0.93). The unadjusted and adjusted risk ratios for cervical cancer for cesarean delivery were 0.98 (95% CI, 0.80–1.20) and 0.87 (95% CI, 0.71–1.08), respectively. Cesarean delivery may be more protective against CIS than vaginal delivery in women of childbearing age.
Clostridium difficile Infection in Children: Epidemiology and Trend in a Swedish Tertiary Care Hospital
Authors: Malmqvist Lovisa , Ullberg Måns , Hed Myrberg Ida , Nilsson Anna
Published: November 2019

Background:

Several studies have shown an increasing trend in pediatric Clostridium difficile infection (CDI). However, the Public Health Agency in Sweden reports a decreasing incidence of CDI in the Swedish population since 2007. The main aim of this study is to analyze the epidemiology of CDI in children.

Methods:

Retrospective chart-review of patients 1 to <19 years old, positive for Clostridium difficile toxin B, tested at Karolinska University Hospital Units, over the time period from July 1, 2010 to June 30, 2018. Episodes were classified as recurrences (≥2 weeks, ≤8 weeks from previous episode) or new episodes (>8 weeks from previous episode). New episodes were classified as hospital- (HA-CDI) or community-associated (CA-CDI). Annual infection rates/100,000 children in the catchment area were calculated.

Results:

Three hundred twenty-eight positive tests in 206 patients were included of which 259 (79.0%) tests were new episodes and 69 (21.0%) recurrences. In 63/206 (30.6%) children, >1 episode of CDI was recorded. The mean infection rate was 8.5/100,000 children. There was an overall increasing trend in CDI-rate July 2010–June 2018, however not statistically significant (P = 0.061) nor for the incidence in HA-CDI (P = 0.720) or CA-CDI (P = 0.179). Underlying medical conditions were present in 226/259 (87.3%) new episodes of which the most common was malignancy. Of the new episodes, 188/259 (72.6%) were HA-CDI and 46/259 (17.8%) were CA-CDI.

Conclusions:

There was an increasing trend in CDI in children in Sweden from 2010 to 2018, although not statistically significant. CDI was associated with comorbid conditions and repeated episodes were common.
Outcomes of Empirical Antimicrobial Therapy for Pediatric Community-onset Febrile Urinary Tract Infection in the Era of Increasing Antimicrobial Resistance
Authors: Kantamalee Worawit , Santanirand Pitak , Saisawat Pawaree , Boonsathorn Sophida , Techasaensiri Chonnamet , Apiwattanakul Nopporn
Published: November 2019

Background:

Urinary tract infection (UTI) is a common cause of fever in children. Despite the increasing numbers of extended-spectrum beta-lactamase-producing organisms in the community, the empirical therapy of choice is still third-generation cephalosporins. This study was performed to investigate whether inappropriate empirical therapy (IAT) of community-onset UTI results in adverse clinical outcomes.

Methods:

We retrospectively studied a cohort of pediatric patients with first-episode community-onset UTI caused by Escherichia coli, Klebsiella pneumoniae and Proteus spp. at Ramathibodi Hospital from 2011 to 2017. The patients were classified into IAT and appropriate empirical therapy (AT) groups. Medical records were reviewed to assess clinical outcomes.

Results:

One hundred fifty-one eligible patients were enrolled in this study. The most common causative organism was E. coli (88.8% and 96.2% in the AT and IAT groups, respectively). Among the causative organisms, 19.8% were extended-spectrum beta-lactamase-producing organisms. There was no significant difference in clinical failure, microbiologic failure, relapse or time to defervescence between the 2 groups. No patients in either group developed sepsis after receiving empirical therapy. However, the length of hospital stay was significantly longer in the IAT than AT group [4.00 (4.50–6.00) vs. 7.00 (5.00–11.25) days, respectively; P = 0.000].

Conclusions:

No significant difference in treatment outcomes was found between pediatric patients receiving AT and IAT for the treatment of UTI. In the era of increasing antimicrobial resistance, third-generation cephalosporins may still be a good choice as an empirical antimicrobial for children diagnosed with community-onset UTI.
NAVA and PAV+ for lung and diaphragm protection
Authors: Vaporidi Katerina
Published: November 2019

Purpose of review

Complications of mechanical ventilation, such as ventilator-induced lung injury (VILI) and ventilator-induced diaphragmatic dysfunction (VIDD), adversely affect the outcome of critically ill patients. Although mostly studied during control ventilation, it is increasingly appreciated that VILI and VIDD also occur during assisted ventilation. Hence, current research focuses on identifying ways to monitor and deliver protective ventilation in assisted modes. This review describes the operating principles of proportional modes of assist, their implications for lung and diaphragm protective ventilation, and the supporting clinical data.

Recent findings

Proportional modes of assist, proportional assist ventilation, PAV, and neurally adjusted ventilatory assist, NAVA, deliver a pressure assist that is proportional to the patient's effort, enabling ventilation to be better controlled by the patient's brain. This control underlies the potential of proportional modes to avoid over-assist and under-assist, improve patient--ventilator interaction, and provide protective ventilation. Indeed, in clinical studies, proportional modes have been associated with reduced asynchronies, enhanced diaphragmatic recovery, and limitation of excessive tidal volume. Additionally, proportional modes facilitate better monitoring of the delivery of protective assisted ventilation.

Physiological rationale and clinical data suggest a potential role for proportional modes of assist in providing and monitoring lung and diaphragm protective ventilation.
Local Health Jurisdiction Staff Deliver Health Promotion to Small Worksites, Washington
Authors: Harris Jeffrey R. , Hammerback Kristen , Brown Meagan , Ryan Daron E. , Coe Norma B. , Pike K. Joanne , Santiago Patti M. , Hannon Peggy A.
Published: November 2019

Context:

Worksites can serve as community sites for local health jurisdictions (LHJs) to assist with implementation of evidence-based interventions (EBIs) to prevent and control chronic diseases.

Objective:

To assess the feasibility and effectiveness of using LHJ staff to disseminate Connect to Wellness (CtW), an effective dissemination package for increasing implementation of EBIs for chronic disease control by small worksites.

Design:

Single-arm, multisite intervention trial, with measurement at baseline, after 6 months of intervention, and after a maintenance period of 6 months.

Setting:

Six geographically dispersed counties in Washington State. Target worksites had 20 to 250 employees.

Participants:

Nine staff members from 6 LHJs delivered CtW to 35 worksites.

Intervention:

Connect to Wellness seeks to increase worksites' implementation of 14 EBIs classified as communication, policy, or program approaches to increasing 4 behaviors: cancer screening, healthy eating, physical activity, and tobacco cessation.

Main Outcome Measure:

Evidence-based intervention implementation measured on a scale from 0% to 100%.

Results:

Participating worksites showed a significant increase (P < .001, t test) in total mean implementation scores from baseline (33%) to 6-month follow-up (47%). Increases in implementation for communications, policy, healthy eating, and tobacco EBIs were statistically significant at 6 months and maintained at 12 months. Increased implementation at 6 months of a group physical activity program was not sustained after the program became unavailable, and total implementation scores at 12 months (38%) showed little change from baseline.

Conclusions:

Local health jurisdiction–delivered CtW increased worksites' implementation of EBIs at 6 months, and increased implementation in communication, policy, healthy eating, and tobacco was maintained at 12 months. This package, delivered by LHJ staff working part-time on CtW, was nearly as successful as prior delivery by staff working full-time on CtW.
Scratching beneath the surface: intentionality in great ape signal production
Authors: Graham Kirsty E. , Wilke Claudia , Lahiff Nicole J. , Slocombe Katie E.
Published: November 2019

Despite important similarities having been found between human and animal communication systems, surprisingly little research effort has focussed on whether the cognitive mechanisms underpinning these behaviours are also similar. In particular, it is highly debated whether signal production is the result of reflexive processes, or can be characterized as intentional. Here, we critically evaluate the criteria that are used to identify signals produced with different degrees of intentionality, and discuss recent attempts to apply these criteria to the vocal, gestural and multimodal communicative signals of great apes and more distantly related species. Finally, we outline the necessary research tools, such as physiologically validated measures of arousal, and empirical evidence that we believe would propel this debate forward and help unravel the evolutionary origins of human intentional communication.

This article is part of the theme issue ‘What can animal communication teach us about human language?’
The neurobiology of innate, volitional and learned vocalizations in mammals and birds
Authors: Nieder Andreas , Mooney Richard
Published: November 2019

Vocalization is an ancient vertebrate trait essential to many forms of communication, ranging from courtship calls to free verse. Vocalizations may be entirely innate and evoked by sexual cues or emotional state, as with many types of calls made in primates, rodents and birds; volitional, as with innate calls that, following extensive training, can be evoked by arbitrary sensory cues in non-human primates and corvid songbirds; or learned, acoustically flexible and complex, as with human speech and the courtship songs of oscine songbirds. This review compares and contrasts the neural mechanisms underlying innate, volitional and learned vocalizations, with an emphasis on functional studies in primates, rodents and songbirds. This comparison reveals both highly conserved and convergent mechanisms of vocal production in these different groups, despite their often vast phylogenetic separation. This similarity of central mechanisms for different forms of vocal production presents experimentalists with useful avenues for gaining detailed mechanistic insight into how vocalizations are employed for social and sexual signalling, and how they can be modified through experience to yield new vocal repertoires customized to the individual's social group.

This article is part of the theme issue ‘What can animal communication teach us about human language?’
Naasia lichenicola sp. nov., an actinobacterium isolated from lichen
Authors: Jiang Long-Qian , Zhang Kun , Li Gui-Ding , Wang Xin-Yu , Shi Song-Biao , Li Qin-Yuan , An De-Feng , Lang Lei , Wang Li-Song , Jiang Cheng-Lin , Jiang Yi
Published: November 2019

A Gram-stain-positive, yellow-pigmented, catalase-positive and oxidase-negative, strictly aerobic actinobacterium, designated strain YIM 131853T, was isolated from lichen collected from the South Bank of the Baltic Sea. The novel strain was non-spore-forming, short rod-shaped and motile with a single polar flagellum. The strain could grow at 4–37 °C (optimum, 28 °C), at pH 4.0–12.0 (pH 6.0) and at 0–3 % (w/v) NaCl (1 %). The DNA G+C content of strain YIM 131853T based on the draft genome sequence was 68.3 mol%. Predominant cellular fatty acids (>10 %) were identified as anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The polar lipid profile included diphosphatidylglycerol, dimannosyldiacylglycerol, three unknown glycolipids, two unknown phospholipids and one unknown lipid. Strain YIM 131853T had 2,4-diaminobutyric acid as the diagnostic cell-wall diamino acid, galactose and glucose as whole-cell sugars, and MK-10, MK-14, MK-13 and MK-12 as the major menaquinones. Although strain YIM 131853T exhibited a highest 16S rRNA gene sequence similarity (96.6 %) to

Amnibacterium kyonggiense

NBRC 109360T, phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain formed a tight lineage with

Naasia aerilata

NBRC 108725T (96.5 % 16S rRNA gene sequence similarity), which was the only species of genus

Naasia

. Based on the results of phenotypic, chemotaxonomic and phylogenetic analyses, strain YIM 131853T should belong to the genus

Naasia

and represents a novel species of the genus

Naasia

, for which the name Naasia lichenicola sp. nov. is proposed. The type strain is YIM 131853T (=CGMCC 4.7565T=NBRC 113605T).
The population genomics of structural variation in a songbird genus
Authors: Weissensteiner Matthias H. , Bunikis Ignas , Catalán Ana , Francoijs Kees-Jan , Knief Ulrich , Heim Wieland , Peona Valentina , Pophaly Saurabh D. , Sedlazeck Fritz J. , Suh Alexander , Warmuth Vera M. , Wolf Jochen B.W.
Published: November 2019

Structural variation (SV) accounts for a substantial part of genetic mutations segregating across eukaryotic genomes with important medical and evolutionary implications. Here, we characterized SV across evolutionary time scales in the songbird genus Corvus using de novo assembly and read mapping approaches. Combining information from short-read (N = 127) and long-read re-sequencing data (N = 31) as well as from optical maps (N = 16) revealed a total of 201,738 insertions, deletions and inversions. Population genetic analysis of SV in the Eurasian crow speciation model revealed an evolutionary young (~530,000 years) cis-acting 2.25-kb retrotransposon insertion reducing expression of the NDP gene with consequences for premating isolation. Our results attest to the wealth of SV segregating in natural populations and demonstrate its evolutionary significance.
Proteasome subunitPSMC3variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress
Authors: Kröll-Hermi Ariane , Ebstein Frédéric , Stoetzel Corinne , Geoffroy Véronique , Schaefer Elise , Scheidecker Sophie , Bär Séverine , Takamiya Masanari , Kawakami Koichi , Zieba Barbara A. , Studer Fouzia , Pelletier Valerie , Speeg-Schatz Claude , Laugel Vincent , Lipsker Dan , Sandron Florian , McGinn Steven , Boland Anne , Deleuze Jean-François , Kuhn Lauriane , Chicher Johana , Hammann Philippe , Friant Sylvie , Etard Christelle , Krüger Elke , Muller Jean , Strähle Uwe , Dollfus Hélène
Published: November 2019

Whole-genome sequencing was performed on patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome. A unique deep intronic homozygous variant in thePSMC3gene (c.1127+337A>G, p.Ser376Argfs15*), encoding the 26S proteasome ATPase ring subunit 5 (Rpt5) was identified leading to the transcription of a cryptic exon. Patient’s fibroblasts exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient’s fibroblasts. Upon chemical proteasome inhibition this pathway is however impaired. These cells were unable to compensate for proteotoxic stress although a higher proteasome content. Two different zebrafish studies led to inner ear development anomalies as well as cataracts. PSMC3 proteasome subunit dysfunction leads to various neurological manifestations, early onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear, lens and central nervous system development.
A comparison of neuronal population dynamics measured with calcium imaging and electrophysiology
Authors: Wei Ziqiang , Lin Bei-Jung , Chen Tsai-Wen , Daie Kayvon , Svoboda Karel , Druckmann Shaul
Published: November 2019

Calcium imaging with fluorescent protein sensors is widely used to record activity in neuronal populations. The transform between neural activity and calcium-related fluorescence involves nonlinearities and a low-pass filter, but the effects of the transformation on analyses of neural populations are not well understood. We compared neuronal spikes and fluorescence in matched neural populations in behaving mice. We report multiple discrepancies between analyses performed on the two types of data, which were only partially resolved by spike inference algorithms applied to fluorescence. To model the relation between spiking and fluorescence we simultaneously recorded spikes and fluorescence from individual neurons. Using these recordings we developed a model transforming spike trains to synthetic-imaging data. The model recapitulated the differences in analyses. Our analysis highlights challenges in relating electrophysiology and imaging data, and suggests forward modeling as an effective way to understand differences between these data.
Enzymatic degradation of RNA causes widespread protein aggregation in cell and tissue lysates
Authors: Aarum Johan , Cabrera Claudia P , Jones Tania A , Rajendran Shiron , Adiutori Rocco , Giovannoni Gavin , Barnes Michael R , Malaspina Andrea , Sheer Denise
Published: November 2019

Most proteins in cell and tissue lysates are soluble. Here, we show that many of these proteins, including several that are implicated in neurodegenerative diseases, are maintained in a soluble and functional state by association with endogenous RNA, as degradation of RNA invariably leads to protein aggregation. We identify the importance of nucleic acid structure, with single-stranded pyrimidine-rich bulges or loops surrounded by double-stranded regions being particularly efficient in this role, revealing an apparent one-to-one protein-nucleic acid stoichiometry. The relationship of these findings to pathological protein aggregation is suggested by our discovery that protein aggregates isolated from brain tissue from Amyotrophic Lateral Sclerosis patients can be rendered soluble after refolding by both RNA and synthetic oligonucleotides. Together, these findings open new avenues for understanding the mechanism behind protein aggregation and shed light on how certain proteins remain soluble.
Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease
Authors: Werneburg Sebastian , Jung Jonathan , Kunjamma Rejani B. , Ha Seung-Kwon , Luciano Nicholas J. , Willis Cory M. , Gao Guangping , Crocker Stephen J. , Popko Brian , Reich Daniel S. , Schafer Dorothy P.
Published: November 2019

Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on axon loss in MS, far less is known about synaptic changes. Here, in striking similarity to other neurodegenerative diseases, we identify in postmortem human MS tissue and in nonhuman primate and mouse MS models profound synapse loss and microglial synaptic engulfment. These events can occur independently of local demyelination, neuronal degeneration, and peripheral immune cell infiltration, but coincide with gliosis and increased localization of complement component C3, but not C1q, at synapses. Finally, we use AAV9 to overexpress the complement inhibitor Crry at activated C3-bound synapses in mice and demonstrate robust protection of synapses and visual function. These results mechanistically dissect synapse loss as an early pathology in MS. We further provide a novel gene therapy approach to prevent synapse loss by microglia, which may be broadly applicable to other neurodegenerative diseases.
Advances in Spiral fMRI: A High-resolution Study with Single-shot Acquisition
Authors: Kasper Lars , Engel Maria , Heinzle Jakob , Mueller-Schrader Matthias , Graedel Nadine N. , Reber Jonas , Schmid Thomas , Barmet Christoph , Wilm Bertram J. , Stephan Klaas Enno , Pruessmann Klaas P.
Published: November 2019

Spiral fMRI has been put forward as a viable alternative to rectilinear echo-planar imaging, in particular due to its enhanced average k-space speed and thus high acquisition efficiency. This renders spirals attractive for contemporary fMRI applications that require high spatiotemporal resolution, such as laminar or columnar fMRI. However, in practice, spiral fMRI is typically hampered by its reduced robustness and ensuing blurring artifacts, which arise from imperfections in both static and dynamic magnetic fields.

Recently, these limitations have been overcome by the concerted application of an expanded signal model that accounts for such field imperfections, and its inversion by iterative image reconstruction. In the challenging ultra-high field environment of 7 Tesla, where field inhomogeneity effects are aggravated, both multi-shot and single-shot 2D spiral imaging at sub-millimeter resolution was demonstrated with high depiction quality and anatomical congruency.

In this work, we further these advances towards a time series application of spiral readouts, namely, single-shot spiral BOLD fMRI at 0.8 mm in-plane resolution. We demonstrate that high-resolution spiral fMRI at 7 T is not only feasible, but delivers both excellent image quality, BOLD sensitivity, and spatial specificity of the activation maps, with little artifactual blurring. Furthermore, we show the versatility of the approach with a combined in/out spiral readout at a more typical resolution (1.5 mm), where the high acquisition efficiency allows to acquire two images per shot for improved sensitivity by echo combination.

Highlights

This work reports the first fMRI study at 7T with high-resolution spiral readout gradient waveforms.

We achieve spiral fMRI with sub-millimeter resolution (0.8 mm, FOV 230 mm), acquired in a single shot (36 slices in 3.3 s).

Spiral images exhibit intrinsic geometric congruency to anatomical scans, and spatially specific activation patterns.

Image reconstruction rests on a signal model expanded by measured trajectories and static field maps, inverted by cg-SENSE.

We assess generalizability of the approach for spiral in/out readouts, providing two images per shot (1.5 mm resolution).
Nonthermal plasma treatment of polymers modulates biological fouling but can cause material embrittlement
Authors: Learn Greg D. , Lai Emerson J. , Wilson Emily J. , von Recum Horst A.
Published: November 2019

Plasma-based treatment is a prevalent strategy to alter biological response and enhance biomaterial coating quality at the surfaces of biomedical devices and implants, especially polymeric materials. Plasma, an ionized gas, is often thought to have negligible effects on the bulk properties of prosthetic substrates given that it alters the surface chemistry on only the outermost few nanometers of material. However, no studies to date have systematically explored the effects of plasma exposure on both the surface and bulk properties of a biomaterial. This work examines the time-dependent effects of a nonthermal plasma on the surface and bulk properties of polymeric implants, specifically polypropylene surgical meshes and sutures. Findings suggest that plasma exposure improved resistance to fibrinogen adsorption and Escherichia coli attachment, and promoted mammalian fibroblast attachment, although increased duration of exposure resulted in a state of diminishing returns. At the same time, it was observed that plasma exposure can be detrimental to the material properties of individual filaments (i.e. sutures), as well as the structural characteristics of knitted meshes, with longer exposures resulting in further embrittlement and larger changes in anisotropic qualities. Though there are few guidelines regarding appropriate mechanical properties of surgical textiles, the results from this investigation imply that there are ultimate exposure limits for plasma-based treatments of polymeric implant materials when structural properties must be preserved, and that the effects of a plasma on a given biomaterial should be examined carefully before translation to a clinical scenario.
Prediction of liquid-liquid phase separation proteins using machine learning
Authors: Sun Tanlin , Li Qian , Xu Youjun , Zhang Zhuqing , Lai Luhua , Pei Jianfeng
Published: November 2019

The liquid-liquid phase separation (LLPS) of bio-molecules in cell underpins the formation of membraneless organelles, which are the condensates of protein, nucleic acid, or both, and play critical roles in cellular functions. The dysregulation of LLPS might be implicated in a number of diseases. Although the LLPS of biomolecules has been investigated intensively in recent years, the knowledge of the prevalence and distribution of phase separation proteins (PSPs) is still lag behind. Development of computational methods to predict PSPs is therefore of great importance for comprehensive understanding of the biological function of LLPS. Here, a sequence-based prediction tool using machine learning for LLPS proteins (PSPredictor) was developed. Our model can achieve a maximum 10-CV accuracy of 96.03%, and performs much better in identifying new PSPs than reported PSP prediction tools. As far as we know, this is the first attempt to make a direct and more general prediction on LLPS proteins only based on sequence information.
An allosteric hot spot in the tandem-SH2 domain of ZAP-70 regulates T-cell signaling
Authors: Gangopadhyay Kaustav , Manna Bharat , Roy Swarnendu , Kumari Sunitha , Debnath Olivia , Chowdhury Subhankar , Ghosh Amit , Das Rahul
Published: November 2019

T-cell receptor (TCR) signaling is initiated by recruiting ZAP-70 to the cytosolic part of TCR. ZAP-70, a non-receptor tyrosine kinase, is composed of an N-terminal tandem SH2 (tSH2) domain connected to the C-terminal kinase domain. The ZAP-70 is recruited to the membrane through binding of tSH2 domain and the doubly-phosphorylated ITAM motifs of CD3 chains in the TCR complex. Our results show that the tSH2 domain undergoes a biphasic structural transition while binding to the doubly-phosphorylated ITAM-ζ1 peptide. The C-terminal SH2 domain binds first to the phosphotyrosine residue of ITAM peptide to form an encounter complex leading to subsequent binding of second phosphotyrosine residue to the N-SH2 domain. We decipher a network of non-covalent interactions that allosterically couple the two SH2 domains during binding to doubly-phosphorylated ITAMs. Mutation in the allosteric network residues, for example, W165C, uncouples the formation of encounter complex to the subsequent ITAM binding thus explaining the altered recruitment of ZAP-70 to the plasma membrane causing autoimmune arthritis in mice. The proposed mechanism of allosteric coupling is unique to ZAP-70, which is fundamentally different from Syk, a close homolog of ZAP-70 expressed in B-cells.

Significance

T-cell and B-cell signaling is initiated by the same family of non-receptor tyrosine kinases, ZAP-70 and Syk, respectively. ZAP-70 and Syk share homologous sequence and similar structural architecture, yet the two kinases differ in their mode of ligand recognition. ZAP-70 binds cooperatively to its ligand, whereas Syk binds uncooperatively. Spontaneous mutation (W165C) in the regulatory module of ZAP-70 impairs T-cell signaling causes autoimmune arthritis in SKG mice, the mechanism of which is unknown. We showed that ZAP-70 regulatory module undergoes a biphasic structural transition while binding to its ligand, which is fundamentally different from Syk. We presented a molecular mechanism of cooperativity in ZAP-70 regulatory module that explains altered ligand binding by ZAP-70 mutant found in SKG mice.
Metagenomics of the modern and historical human oral microbiome with phylogenetic studies onStreptococcus mutansandStreptococcus sobrinus
Authors: Achtman Mark , Zhou Zhemin
Published: November 2019

We have recently developed bioinformatic tools to accurately assign metagenomic sequence reads to microbial taxa: SPARSE [1] for probabilistic, taxonomic classification of sequence reads, EToKi [2] for assembling and polishing genomes from short read sequences, and GrapeTree [3], a graphic visualizer of genetic distances between large numbers of genomes. Together, these methods support comparative analyses of genomes from ancient skeletons and modern humans [2,4]. Here we illustrate these capabilities with 784 samples from historical dental calculus, modern saliva and modern dental plaque. The analyses revealed 1591 microbial species within the oral microbiome. We anticipated that the oral complexes of Socranskyet al.[5] would predominate among taxa whose frequencies differed by source. However, although some species discriminated between sources, we could not confirm the existence of the complexes. The results also illustrate further functionality of our pipelines with two species that are associated with dental caries,Streptococcus mutansandStreptococcus sobrinus.They were rare in historical dental calculus but common in modern plaque, and even more common in saliva. Reconstructed draft genomes of these two species from metagenomic samples in which they were abundant were combined with modern public genomes to provide a detailed overview of their core genomic diversity.
Evidence for shared ancestry between Actinobacteria and Firmicutes bacteriophages
Authors: Koert Matthew , López-Pérez Júlia , Mattson Courtney , Caruso Steven , Erill Ivan
Published: November 2019

Bacteriophages typically infect a small set of related bacterial strains. The transfer of bacteriophages between more distant clades of bacteria has often been postulated, but remains mostly unaddressed. In this work we leverage the sequencing of a novel cluster of phages infecting Streptomyces bacteria and the availability of large numbers of complete phage genomes in public repositories to address this question. Using phylogenetic and comparative genomics methods, we show that several clusters of Actinobacteria-infecting phages are more closely related between them, and with a small group of Firmicutes phages, than with any other actinobacteriophage lineage. These data indicate that this heterogeneous group of phages shares a common ancestor with well-defined genome structure. Analysis of genomic %GC content and codon usage bias shows that these actinobacteriophages are poorly adapted to their Actinobacteria hosts, suggesting that this phage lineage could have originated in an ancestor of the Firmicutes, adapted to the low %GC content members of this phylum, and later migrated to the Actinobacteria, or that selective pressure for enhanced translational throughput is significantly lower for phages infecting Actinobacteria hosts.
DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance
Authors: Matkarimov Bakhyt , Saparbaev Murat K.
Published: November 2019

A variety of endogenous and exogenous factors induce chemical and structural alterations to cellular DNA, as well as errors occurring throughout DNA synthesis. These DNA damages are cytotoxic, miscoding, or both, and are believed to be at the origin of cancer and other age related diseases. A human cell, in addition to nuclear DNA, contains thousands copies of mitochondrial DNA (mtDNA), a double-stranded, circular molecule of 16,569 bp. It was proposed that mtDNA is a critical target for reactive oxygen species (ROS), by-products of the oxidative phosphorylation (OXPHOS), generated in the organelle during aerobic respiration. Indeed, oxidative damage to mtDNA are more extensive and persistent as compared to that of nuclear DNA. Although, transversions are the hallmarks of mutations induced by ROS, paradoxically, the majority of mtDNA mutations that occurred during ageing and cancer are transitions. Furthermore, these mutations exhibit a striking strand orientation bias: T→C/G→A transitions preferentially occur on the Light strand, whereas C→T/A→G on the Heavy strand of mtDNA. Here, we propose that the majority of mtDNA progenies, created after multiple rounds of DNA replication, are derived from the Heavy strand only, due to asymmetric replication of the DNA strand anchored to inner membraneviaD-loop structure.
MXD/MIZ1 complexes activate transcription of MYC-repressed genes
Authors: Shostak Anton , Schermann Géza , Diernfellner Axel , Brunner Michael
Published: November 2019

MXD proteins are transcription repressors that antagonize the E-box dependent activation of genes by MYC. MYC together with MIZ1 acts also as a repressor of a subset of genes, including cell cycle inhibitor genes such as p15 and p21. A role of MXDs in regulation of MYC-repressed genes is not known. Here we report that MXDs are functionally expressed in U2OS cells and activate transcription of p15 and p21, and other MYC-repressed genes. Activation of transcription was dependent on the interaction of MXDs with MIZ1, and on an intact DNA binding domain. MIZ1-binding deficient MXD mutants interacted with MAX and were active as repressors of MYC-activated genes but failed to activate MYC-repressed genes. Mutant MXDs with reduced DNA binding affinity interacted with MAX and MIZ1 but neither repressed nor activated transcription. Overexpression of MXDs attenuated proliferation of U2OS cells predominantly via MIZ1-dependent induction of p21. Our data show that MXDs and MYC have a reciprocally antagonistic potential to regulate transcription of mutual target genes.
Three-dimensional traction microscopy accounting for cell-induced matrix degradation
Authors: Song Dawei , Seidl D. Thomas , Oberai Assad A
Published: November 2019

Tractions exerted by cells on the extracellular matrix (ECM) are critical in many important physiological and pathological processes such as embryonic morpho-genesis, wound healing, and cancer metastasis. Three-dimensional Traction Microscopy (3DTM) is a tool to quantify cellular tractions by first measuring the displacement field in the ECM in response to these tractions, and then using this measurement to infer tractions. Most applications of 3DTM have assumed that the ECM has spatially-uniform mechanical properties, but cells secrete enzymes that can locally degrade the ECM. In this work, a novel computational method is developed to quantify both cellular tractions and ECM degradation. In particular, the ECM is modeled as a hyperelastic, Neo-Hookean solid, whose material parameters are corrupted by a single degradation parameter. The feasibility of determining both the traction and the degradation parameter is first demonstrated by showing the existence and uniqueness of the solution. An inverse problem is then formulated to determine the nodal values of the traction vector and the degradation parameter, with the objective of minimizing the difference between a predicted and measured displacement field, under the constraint that the predicted displacement field satisfies the equation of equilibrium. The inverse problem is solved by means of a gradient-based optimization approach, and the gradient is computed efficiently using appropriately derived adjoint fields. The computational method is validated in-silico using a geometrically accurate neuronal cell model and synthetic traction and degradation fields. It is found that the method accurately recovers both the traction and degradation fields. Moreover, it is found that neglecting ECM degradation can yield significant errors in traction measurements. Our method can extend the range of applicability of 3DTM.
Multi-omics Visualization Platform: An extensible Galaxy plug-in for multi-omics data visualization and exploration
Authors: McGowan Thomas , Johnson James E. , Kumar Praveen , Sajulga Ray , Mehta Subina , Jagtap Pratik D. , Griffin Timothy J.
Published: November 2019

Background

Proteogenomics integrates genomics, transcriptomics and mass spectrometry (MS)-based proteomics data to identify novel protein sequences arising from gene and transcript sequence variants. Proteogenomic data analysis requires integration of disparate ‘omic software tools, as well as customized tools to view and interpret results. The flexible Galaxy platform has proven valuable for proteogenomic data analysis. Here, we describe a novel Multi-omics Visualization Platform (MVP) for organizing, visualizing and exploring proteogenomic results, adding a critically needed tool for data exploration and interpretation.

Findings

MVP is built as an HTML Galaxy plugin, primarily based on JavaScript. Via the Galaxy API, MVP uses SQLite databases as input -- a custom datatype (mzSQLite) containing MS-based peptide identification information, a variant annotation table, and a coding sequence table. Users can interactively filter identified peptides based on sequence and data quality metrics, view annotated peptide MS data, and visualize protein-level information, along with genomic coordinates. Peptides that pass the user-defined thresholds can be sent back to Galaxy via the API for further analysis; processed data and visualizations can also be saved and shared. MVP leverages the Integrated Genomics Viewer JavaScript (IGVjs) framework, enabling interactive visualization of peptides and corresponding transcript and genomic coding information within the MVP interface.

Conclusions

MVP provides a powerful, extensible platform for automated, interactive visualization of proteogenomic results within the Galaxy environment, adding a unique and critically needed tool for empowering exploration and interpretation of results. The platform is extensible, providing a basis for further development of new functionalities for proteogenomic data visualization.
A highly multiplexed melt-curve assay for detecting the most prevalent carbapenemase, ESBL and AmpC genes
Authors: Edwards T. , Williams C. , Teethaisong Y. , Sealey J. , Sasaki S. , Hobbs G. , Cuevas L.E. , Evans K. , Adams E.R.
Published: November 2019

Resistance to third generation cephalosporins and carbapenems in Gram-negative bacteria is chiefly mediated by beta-lactamases including ESBL, AmpC and carbapenemase enzymes. Routine phenotypic detection methods do not provide timely results, and there is a lack of comprehensive molecular panels covering all important markers.

An ESBL/carbapenemase HRM assay (SHV, TEM, CTX-M ESBLs, and NDM, IMP, KPC, VIM and OXA-48-like carbapenemases) and an AmpC HRM assay (16S rDNA control, FOX, MOX, ACC, EBC, CIT and DHA) were designed, and evaluated on 111 Gram-negative isolates with mixed resistance patterns.

The sensitivity for carbapenemase, ESBL and AmpC genes was 96.7% (95%CI:82.8-99.9%), 93.6% (95%CI:85.7-97.9%) and 93.8% (95%CI:82.8-98.7%), respectively with a specificity of 100% (95%CI:95.6-100%), 93.9% (95%CI:79.8-99.3%) and 93.7% (95%CI:84.5-98.2%).

The HRM assays enable the simultaneous detection of the fourteen most important ESBL, carbapenemase and AmpC genes and could be used as a molecular surveillance tool or to hasten detection of AMR for treatment management.