bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebrospinal Fluid Leaks From the Lateral Ventricle: A Case Series
Authors: Saltagi Mohamad Z. , Fraser Amy L. , Alwani Mohamedkazim M. , Mosier Kristine M. , Nelson Rick F.
Published: June 2021

Objectives:

Describe the diagnosis and management of lateral skull base (LSB) cerebrospinal fluid (CSF) leaks originating from the lateral ventricle.

Study design:

Retrospective case review.

Setting:

Tertiary referral academic center.

Patients:

Patients with CSF leaks with direct communication to the lateral ventricle on preoperative imaging.

Intervention:

Surgical repair via the middle cranial fossa (MCF) approach.

Main outcome measures:

CSF leak patient characteristics (age, sex, body mass index [BMI]) and postoperative course (complications and CSF leak resolution) were collected.

Results:

Three patients had CSF leaks from the lateral ventricle and all patients demonstrated encephalomalacia of the temporal lobe on preoperative imaging. Encephalomalacia resulted from trauma in one case (age 5) and neurodegeneration in two cases (age 77 and 84). BMI ranged from 16.3 to 26.6 mg/kg2 and follow-up ranged from 4 to 21 months. Two patients presented with preoperative meningitis and all patients had resolution of CSF leaks after MCF repair. With the exception of the higher rate of meningitis, patient presentations did not differ from other spontaneous CSF leaks through middle fossa defects. There were no minor or major postoperative complications.

Conclusions:

CSF leaks from the lateral ventricle represent a rare subset of LSB CSF leaks and can occur in non-obese patients secondary to temporal lobe encephalomalacia. The MCF approach allows for repair of the dura and skull base in this cohort of patients with high-flow CSF leaks and loss of brain parenchyma.
Morphological Effect of Vitamin D Deficiency on Globular Substances in Mice
Authors: Song Penglong , Zhao Xianshu , Xu Yanjun , Zhao Zhigang , Liu Yang , Gao Qian
Published: June 2021

Objective:

Many authors, including us, elucidated that vitamin D deficiency was a risk factor for benign paroxysmal position vertigo. We speculated vitamin D deficiency was likely to intervene otoconia formation by globular substance (GS).

Methods:

Kunming mice were randomly divided into three groups: vitamin D sufficient group (12-wk standard control diet), vitamin D deficiency group (16-wk vitamin D deficiency diet), and vitamin D supplement group (16-wk vitamin D deficiency diet and followed 8-wk standard control diet). At 12, 16, and 24 weeks, blood was collected for measuring vitamin D and macula utriculi were obtained for research under scanning electron microscope (SEM). We randomly selected 10 SEM photographs of macula utriculi in each mouse, counted cilium and GS, and measured diameters of counted GS. The ratio of the number of GS to cilium in each SEM photograph was defined as density of GS.

Results:

The diameter and density of GS were larger and higher in vitamin D deficiency group than sufficient group (p < 0.05; p < 0.05). There was no significant difference in density and diameters of GS between vitamin D deficiency and supplement group. The rough and grainy surface became smoother and smoother along with vitamin D deficiency, and reappeared after vitamin D supplement for 8 weeks.

Conclusion:

GS secreted as a precursor of mature otoconia is affected by vitamin D deficiency and vitamin D supplementation can mitigate the effects in mice. The density of GS, a quantitative method we designed, can quantify GS well.
Endoscopic Management of Early Stage Middle Ear Paragangliomas – An Australian Case Series
Authors: Quick Mark E. , Acharya Aanand , Friedland Peter , Kong Jonathan H. K. , Saxby Alexander J. , Patel Nirmal P. , Kadhim Latif
Published: June 2021

Objective:

To analyze the outcomes of the endoscopic transcanal approach for removal of early stage middle ear paraganglioma tumors (MEPT).

Study design:

Cases series with chart review.

Setting:

Two tertiary Australian Otology centers.

Patients:

Adult patients with middle ear paraganglioma tumors treated with transcanal endoscopic approach from 2/2016 to 12/2019. Tumor staging was described using the Modified Fisch-Mattox (MFM). Inclusion criteria included patients with an MFM Class A or B. Exclusion criteria included higher staged or syndromic disease.

Intervention:

All tumors were managed with transcanal endoscopic approach.

Main outcome measures:

Primary outcome measures included disease clearance and hearing measured according to the AAO-HNS guidelines. Secondary outcomes included complications, duration of surgery, and length of stay.

Results:

Ten patients underwent totally endoscopic transcanal resection of MEPT (9 female, mean age of 45.5 years, 70% were left sided). Mean tumor size was 6.1 mm (SD 3.4 mm). Five cases (50%) were classified using the MFM system as class A1, two cases were class A2, and three cases were class B1. Three cases required canalplasty for access but were completed entirely endoscopically. Nine of the 10 cases had complete audiometric data. Pre- and postoperative mean air conduction remained stable with a decrease in mean air-bone gap of 2.84 dB. Postoperative complications include one pinhole perforation. There were no facial nerve complications. Mean follow-up period was 10 months (range 4–25 mo) with all cases having resolution of pulsatile tinnitus and no tumor recurrence.

Conclusion:

The transcanal endoscopic approach for early stage MEPT offers excellent visualization and permits safe and effective removal of disease with the advantages of a minimally invasive technique for patient recovery.
Demographics and risk factors for pediatric recurrent acute pancreatitis
Authors: Gariepy Cheryl E. , Ooi Chee Y. , Maqbool Asim , Ellery Kate M.
Published: June 2021

Purpose of review

Approximately 20–30% of children who experience one episode of acute pancreatitis will have at least one additional episode. For some children, pancreatitis recurs multiple times and in a few years is followed by the diagnosis of chronic pancreatitis. Identifying risk factors for recurrent episodes and disease progression is critical to developing therapeutic interventions.

Recent findings

Obesity is driving an increase in biliary stone disease and severe acute pancreatitis. Recurrent acute pancreatitis (RAP) may lead to the development of diabetes through autoimmune mechanisms. Cystic fibrosis or CFTR-related disorders may present as RAP and CFTR modulator therapy can increase or decrease the risk of acute pancreatitis in these populations. Children with Crohn disease have a three-fold risk of acute pancreatitis over the general population while children with ulcerative colitis are at increased risk for pediatric autoimmune pancreatitis, a disorder that may be distinct from autoimmune pancreatitis described in adults. Obstructive jaundice in the absence of identified mechanical factors may be a presenting sign of pediatric autoimmune pancreatitis.

Pediatric RAP is a painful condition that leads to gland destruction and functional insufficiency. Risk factors are being clarified but preventive treatments remain elusive.
Awareness of Physical Medicine and Rehabilitation as a Specialty Among US Medical Students
Authors: Jumreornvong Oranicha , Haque Abid , Tabacof Laura , Bolds Aaron , Sanchez Ashley , Martinez Claudia I. , Verduzco-Gutierrez Monica , Escalon Miguel X.
Published: June 2021

The objectives were to assess US medical students’ awareness about physical medicine and rehabilitation, their career goals that may align with physical medicine and rehabilitation, and their exposure to physical medicine and rehabilitation and to compare the demographics of those applying to, interested, or not interested in physical medicine and rehabilitation residency. This was a descriptive cross-sectional study. An online survey was distributed to 76 medical schools, and 2067 students responded. First-generation and Hispanic/Latino students are less likely to know about physical medicine and rehabilitation. Medical students who heard about physical medicine and rehabilitation before or during college or who are first-generation students to attend medical school are more likely to be interested in physical medicine and rehabilitation. Medical students identified as female, Black or African American, and more advanced in medical training have lesser interest. Rotating in physical medicine and rehabilitation at their home institution and shadowing a physical medicine and rehabilitation physician also increase the likelihood of respondents to apply to physical medicine and rehabilitation residency. This study highlights that female students and underrepresented minorities in medicine are less likely to know about physical medicine and rehabilitation or be interested in physical medicine and rehabilitation. First-generation medical students know less about the field but the ones who do have increased interest in physical medicine and rehabilitation. These findings support the need for pipeline programs to improve exposure, recruitment, development, promotion, and retention of first-generation minorities and women into physical medicine and rehabilitation.
Semiquantitative Chest Computed Tomography Assessment Identifies Expiratory Central Airway Collapse in Symptomatic Military Personnel Deployed to Iraq and Afghanistan
Authors: Krefft Silpa D. , Oh Andrea , Zell-Baran Lauren M. , Wolff Jenna , Moore Camille M. , Macedonia Tony V. , Rose Cecile S.
Published: June 2021

Purpose:

We noted incidental findings on chest computed tomography (CT) imaging of expiratory central airway collapse (ECAC) in dyspneic patients after military deployment to southwest Asia (mainly Iraq and Afghanistan). We developed a standardized chest CT protocol with dynamic expiration to enhance diagnostic reliability and investigated demographic, clinical, and deployment characteristics possibly associated with ECAC.

Materials and Methods:

We calculated ECAC in 62 consecutive post-9/11 deployers with dyspnea who underwent multi-detector chest CT acquisition. ECAC was defined as ≥70% reduction in the cross-sectional tracheal area at dynamic expiration. We compared demographics (age, smoking, body mass index), comorbid conditions (gastroesophageal reflux, obstructive sleep apnea [OSA]), and clinical findings (air trapping, forced expiratory volume in 1 second percent predicted) in deployers with and without ECAC. We examined associations between ECAC and forced expiratory volume in 1 second percent predicted, air trapping, OSA, deployment duration, and blast exposure.

Results:

Among 62 consecutive deployers with persistent dyspnea, 37% had ECAC. Three had severe (>85%) collapse. Those with ECAC were older (mean age 46 vs. 40 y, P=0.02), but no other demographic or clinical characteristics were statistically different among the groups. Although not statistically significant, ECAC odds were 1.5 times higher (95% confidence interval: 0.9, 2.5) for each additional year of southwest Asia deployment. Deployers with ECAC had 1.6 times greater odds (95% confidence interval: 0.5, 4.8) of OSA.

Conclusions:

Findings suggest that ECAC is common in symptomatic southwest Asia deployers. Chest high-resolution CT with dynamic expiration may provide an insight into the causes of dyspnea in this population, although risk factors for ECAC remain to be determined. A standardized semiquantitative approach to CT-based assessment of ECAC should improve reliable diagnosis in dyspneic patients.
Introduction to the theme issue: Measuring physiology in free-living animals
Authors: Hawkes L. A. , Fahlman A. , Sato K.
Published: June 2021

By describingwhereanimals go, biologging technologies (i.e. animal attached logging of biological variables with small electronic devices) have been used to document the remarkable athletic feats of wild animals since the 1940s. The rapid development and miniaturization of physiologging (i.e. logging of physiological variables such as heart rate, blood oxygen content, lactate, breathing frequency and tidal volume on devices attached to animals) technologies in recent times (e.g. devices that weigh less than 2 g mass that can measure electrical biopotentials for days to weeks) has provided astonishing insights into the physiology of free-living animals to documenthowandwhywild animals undertake these extreme feats. Now, physiologging, which was traditionally hindered by technological limitations, device size, ethics and logistics, is poised to benefit enormously from the on-going developments in biomedical and sports wearables technologies. Such technologies are already improving animal welfare and yield in agriculture and aquaculture, but may also reveal future pathways for therapeutic interventions in human health by shedding light on the physiological mechanisms with which free-living animals undertake some of the most extreme and impressive performances on earth.

This article is part of the theme issue ‘Measuring physiology in free-living animals (Part I)’.
Diving physiology of marine mammals and birds: the development of biologging techniques
Authors: Williams Cassondra L. , Ponganis Paul J.
Published: June 2021

In the 1940s, Scholander and Irving revealed fundamental physiological responses to forced diving of marine mammals and birds, setting the stage for the study of diving physiology. Since then, diving physiology research has moved from the laboratory to the field. Modern biologging, with the development of microprocessor technology, recorder memory capacity and battery life, has advanced and expanded investigations of the diving physiology of marine mammals and birds. This review describes a brief history of the start of field diving physiology investigations, including the invention of the time depth recorder, and then tracks the use of biologging studies in four key diving physiology topics: heart rate, blood flow, body temperature and oxygen store management. Investigations of diving heart rates in cetaceans and O2store management in diving emperor penguins are highlighted to emphasize the value of diving physiology biologging research. The review concludes with current challenges, remaining diving physiology questions and what technologies are needed to advance the field.

This article is part of the theme issue ‘Measuring physiology in free-living animals (Part I)’.
An engineering perspective on the development and evolution of implantable cardiac monitors in free-living animals
Authors: Laske Timothy G. , Garshelis David L. , Iles Tinen L. , Iaizzo Paul A.
Published: June 2021

The latest technologies associated with implantable physiological monitoring devices can record multiple channels of data (including: heart rates and rhythms, activity, temperature, impedance and posture), and coupled with powerful software applications, have provided novel insights into the physiology of animals in the wild. This perspective details past challenges and lessons learned from the uses and developments of implanted biologgers designed for human clinical application in our research on free-ranging American black bears (
Ursus americanus
). In addition, we reference other research by colleagues and collaborators who have leveraged these devices in their work, including: brown bears (
Ursus arctos
), grey wolves (
Canis lupus
), moose (
Alces alces
), maned wolves (
Chrysocyon brachyurus
) and southern elephant seals (
Mirounga leonina
). We also discuss the potentials for applications of such devices across a range of other species. To date, the devices described have been used in fifteen different wild species, with publications pending in many instances. We have focused our physiological research on the analyses of heart rates and rhythms and thus special attention will be paid to this topic. We then discuss some major expected step changes such as improvements in sensing algorithms, data storage, and the incorporation of next-generation short-range wireless telemetry. The latter provides new avenues for data transfer, and when combined with cloud-based computing, it not only provides means for big data storage but also the ability to readily leverage high-performance computing platforms using artificial intelligence and machine learning algorithms. These advances will dramatically increase both data quantity and quality and will facilitate the development of automated recognition of extreme physiological events or key behaviours of interest in a broad array of environments, thus further aiding wildlife monitoring and management.

This article is part of the theme issue ‘Measuring physiology in free-living animals (Part I)’.
Convalescent Plasma in Critically ill Patients with Covid-19
Authors:   The REMAP-CAP Investigators, Estcourt Lise J.
Published: June 2021

BACKGROUND

The evidence for benefit of convalescent plasma for critically ill patients with Covid-19 is inconsistent. We hypothesized that convalescent plasma would improve outcomes for critically ill adult patients with Covid-19.

METHODS

In an ongoing adaptive platform trial, critically ill patients with confirmed Covid-19, defined as receiving intensive care-level organ support, were randomized to open-label convalescent plasma or not (i.e., control group). The primary end point was organ support-free days (i.e., days alive and free of ICU-based organ support) up to day 21. The primary analysis was a Bayesian cumulative logistic model with predefined criteria for superiority or futility. An odds ratio greater than 1 represented improved survival, more organ support–free days, or both.

RESULTS

The convalescent plasma intervention was stopped after pre-specified criteria for futility were met. At that time, 1084 participants had been randomized to convalescent plasma and 916 to no convalescent plasma (control). The median organ support-free days were 0 (interquartile range, -1 to 16) for the convalescent plasma group and 3 (interquartile range, -1 to 16) days for the control group. The median adjusted odds ratio (OR) was 0.97 (95% credible interval 0.83 to 1.15) and posterior probability of futility (OR < 1.2) was 99.4% for convalescent plasma compared to control. In-hospital mortality was 37.3% (401/1075) in convalescent plasma group, and 38.4% (347/904) in controls. The observed treatment effects were consistent across primary and secondary outcomes.

CONCLUSIONS

In critically ill adults with confirmed Covid-19, treatment with convalescent plasma, did not improve clinical outcomes.

Clinicaltrials.gov:NCT02735707
UK B.1.1.7 variant exhibits increased respiratory replication and shedding in nonhuman primates
Authors: Rosenke K. , Feldmann F. , Okumura A. , Hansen F. , Tang-Huau T. , Meade-White K. , Kaza B. , Smith B.J. , Hanley P. W. , Lovaglio J. , Jarvis M. A. , Shaia C. , Feldmann H.
Published: June 2021

The continuing emergence of SARS-CoV-2 variants calls for regular assessment to identify differences in viral replication, shedding and associated disease. In this study, African green monkeys were infected intranasally with either a contemporary D614G or the UK B.1.1.7 variant. Both variants caused mild respiratory disease with no significant differences in clinical presentation. Significantly higher levels of viral RNA and infectious virus were found in upper and lower respiratory tract samples and tissues from B.1.1.7 infected animals. Interestingly, D614G infected animals showed significantly higher levels of viral RNA and infectious virus in rectal swabs and gastrointestinal tract tissues. Our results indicate that B.1.1.7 infection in African green monkeys is associated with increased respiratory replication and shedding but no disease enhancement similar to human B.1.1.7 cases.

One-Sentence Summary

UK B.1.1.7 infection of African green monkeys exhibits increased respiratory replication and shedding but no disease enhancement
Further Theoretical Considerations for Next-Generation Proteomics
Authors: Palmblad Magnus
Published: June 2021

In a recent Journal of Proteome Researchpaper, I described some general properties and constraints of a hypothetical next generation of proteomics technology based on single-molecule peptide sequencing. This work prompted many interesting questions, both from the reviewers of the initial manuscript and later from readers and colleagues. This follow-up paper addresses some of questions by clarifying the original results, considering alternative metrics, and a number of new simulations. Specifically, the discriminative power of individual amino acids is revisited, simulating additional proteolytic agents. These simulations show allowing missed cleavages generally increases the discriminative power of the amino acids in the proteolytic motif. Additional simulations show the effect of non-ideal conditions modelled on the number of proteins lacking proteotypic reads is very small, and that the average number of proteotypic reads per protein follow the same rule on the performance of the optimal choice of labeled amino acids as the number of distinguishable proteins in NeXtProt. The goal of this paper is to expand prior results and continue the scientific discussion on the possibilities of future proteomics technologies.
The underlying mechanisms of alignment in error backpropagation through arbitrary weights
Authors: Rahmansetayesh Alireza , Ghazizadeh Ali , Marvasti Farokh
Published: June 2021

Understanding the mechanisms by which plasticity in millions of synapses in the brain is orchestrated to achieve behavioral and cognitive goals is a fundamental quest in neuroscience. In this regard, insights from learning methods in artificial neural networks (ANNs) and in particular supervised learning using backpropagation (BP) seem inspiring. However, the implementation of BP requires exact matching between forward and backward weights, which is unrealistic given the known connectivity pattern in the brain (known as “weight transport problem”). Notably, it has been shown that under certain conditions, errorBackPropagationThroughArbitraryWeights (BP-TAW) can lead to a partial alignment between forward and backward weights (weight alignment or WA). This learning algorithm, which is also known as feedback alignment (FA), can result in surprisingly good degrees of accuracy in simple classification tasks. However, the underlying mechanisms and mathematical basis of WA are not thoroughly understood. In this work, we show that the occurrence of WA is governed by statistical properties of the output and error signals of neurons, such as autocorrelation and cross-correlation, and can happen even in the absence of learning or reduction of the loss function. Moreover, we show that WA can be improved significantly by limiting the norm of input weights to neurons and that such a weight normalization (WN) method can improve the classification accuracy of BP-TAW. The findings presented can be used to further improve the performance of BP-TAW and open new ways for exploring possible learning mechanisms in biological neural networks without exact matching between forward and backward weights.
The activity and functions of soil microbial communities in the Finnish sub-Arctic vary across vegetation types
Authors: Viitamäki Sirja , Pessi Igor S. , Virkkala Anna-Maria , Niittynen Pekka , Kemppinen Julia , Eronen-Rasimus Eeva , Luoto Miska , Hultman Jenni
Published: June 2021

Increased microbial activity in high-latitude soils due to climate change might lead to higher greenhouse gas (GHG) emissions. However, mechanisms of microbial GHG production and consumption in tundra soils are not thoroughly understood. We analyzed 116 soil metatranscriptomes from 73 sites in the Finnish sub-Arctic to investigate how the diversity and functional potential of bacterial and archaeal communities vary across vegetation types and soil layers. Soils differed in physicochemical conditions, with meadow soils being characterized by higher pH and low soil organic matter (SOM) and carbon/nitrogen ratio whereas dwarf shrub-dominated ecosystems with high SOM and low pH. Actinobacteria, Acidobacteria, Alphaproteobacteria, and Planctomycetes predominated all communities but there were significant differences on genus level between vegetation types, as plant polymer degrading groups were more active in shrub-dominated soils compared to meadows. Given that climate change scenarios predict expansion in dwarf shrubs at high latitudes, our results indicate that the rate of carbon turnover in tundra soils may increase in the future. Additionally, transcripts of methanotrophs were detected in the mineral layer of all soils, potentially moderating methane fluxes from deeper layers. In all, this study provides new insights into possible shifts in tundra microbial diversity and activity with climate change.
Regulatory dissection of the severe COVID-19 risk locus introgressed by Neanderthals
Authors: Jagoda Evelyn , Marnetto Davide , Montinaro Francesco , Richard Daniel , Pagani Luca , Capellini Terence D.
Published: June 2021

Individuals infected with the SARS-CoV-2 virus present with a wide variety of phenotypes ranging from asymptomatic to severe and even lethal outcomes. Past research has revealed a genetic haplotype on chromosome 3 that entered the human population via introgression from Neanderthals as the strongest genetic risk factor for the severe COVID-19 phenotype. However, the specific variants along this introgressed haplotype that contribute to this risk and the biological mechanisms that are involved remain unclear. Here, we assess the variants present on the risk haplotype for their likelihood of driving the severe COVID-19 phenotype. We do this by first exploring their impact on the regulation of genes involved in COVID-19 infection using a variety of population genetics and functional genomics tools. We then perform an locus-specific massively parallel reporter assay to individually assess the regulatory potential of each allele on the haplotype in a multipotent immune-related cell line. We ultimately reduce the set of over 600 linked genetic variants to identify 4 introgressed alleles that are strong functional candidates for driving the association between this locus and severe COVID-19. These variants likely drive the locus’ impact on severity by putatively modulating the regulation of two critical chemokine receptor genes: CCR1 and CCR5. These alleles are ideal targets for future functional investigations into the interaction between host genomics and COVID-19 outcomes.
Brain network dynamics codify heterogeneity in seizure propagation
Authors: Rungratsameetaweemana Nuttida , Lainscsek Claudia , Cash Sydney S. , Garcia Javier O. , Sejnowski Terrence J. , Bansal Kanika
Published: June 2021

Dynamic functional brain connectivity facilitates adaptive cognition and behavior. Abnormal alterations within such connectivity could result in disrupted functions observed across various neurological conditions. As one of the most common neurological disorders, epilepsy is defined by the seemingly random occurrence of spontaneous seizures. A central but unresolved question concerns the mechanisms by which extraordinarily diverse dynamics of seizures emerge. Here, we apply a graph-theoretical approach to assess dynamic reconfigurations in the functional brain connectivity before, during, and after seizures that display heterogeneous propagation patterns despite sharing similar origins. We demonstrate unique reconfigurations in globally-defined network properties preceding seizure onset that predict propagation patterns of impending seizures, and in locally-defined network properties that differentiate post-onset dynamics. These results characterize quantitative network features underlying the heterogeneity of seizure dynamics and the accompanying clinical manifestations. Decoding these network properties could improve personalized preventative treatment strategies for epilepsy as well as other neurological disorders.
In silico study for decoding the correlated role of MCM7 gene in progression of breast cancer and Alzheimer’s disorder
Authors: Sriram Navneeth , Mukherjee Sunny , Sah Mahesh Kumar
Published: June 2021

Breast cancer and Alzheimer’s disease (AD) are two of the progressive and detrimental disorders affecting large population around the globe. While the chemotherapy of breast cancer is well established and enriched, the AD still lacks it due to unrecognized peripheral biomarkers for detection and targeted therapy. This study aimed to identify common molecular signature markers in breast cancer (grade 1, 2, and 3) and AD for the diagnosis and prognosis. We used two microarray datasets (GSE42568, GSE33000) respectively for both disorders that led to identification of two common differentially expressed genes (DEGs), namely MCM7 and CD209, as common players in both these two conditions. While the pattern of expression of CD209 gene running upregulated in both disorders, the MCM7 showed unusual contrary in its pattern of expression. The expression of MCM7 is downregulated in breast cancer but upregulated in AD. Gene set and protein overrepresentation analysis, protein-protein interaction (PPI), and protein subcellular localizations analyses of this underrated MCM7 gene was performed with further prediction and validation of its structure. The findings may pave the way in designing therapeutic approaches to ameliorate AD.
Increased apoptotic priming of glioblastoma enables therapeutic targeting by BH3-mimetics
Authors: Koessinger Anna L , Koessinger Dominik , Kinch Kevin , Martínez-Escardó Laura , Paul Nikki R , Elmasry Yassmin , Malviya Gaurav , Cloix Catherine , Campbell Kirsteen J , Bock Florian J , O’Prey Jim , Stevenson Katrina , Nixon Colin , Jackson Mark R , Ichim Gabriel , Stewart William , Blyth Karen , Ryan Kevin M , Chalmers Anthony J , Norman Jim C , Tait Stephen WG
Published: June 2021

IDH wild-type glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. Tackling this, we investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti- apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non- malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti- apoptotic BCL-2 family members. Surprisingly, high anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein- targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3- mimetics.
Reservoir water in Singapore contains ESBL-producing and carbapenem-resistant bacteria with conjugatable conserved gene cluster transfer between different species
Authors: Zhong Yang , Guo Siyao , Schlundt Joergen
Published: June 2021

As the role of the aquatic environment in the “One Health” approach has called increasing attention, the studies of Antimicrobial resistance (AMR) spreading in the water bodies have been reported worldwide. However, there are still limited studies on the AMR carrier in the reservoir water in Singapore. Since 2018, our group has collect water samples from six reservoirs in Singapore and isolated the beta-lactam resistant bacteria from them. We then characterized the isolates with Whole-genome sequencing (WGS) and successfully identified ESBL-producing bacteria from three sampling reservoirs, and confirmed their resistance with both phenotypic and sequencing methods. To better understand the AMR spreading locally, we compared our isolates with isolates from other WGS studies in Singapore covered humans, food, and the enviroment. From there, we noticed the same sequence type (ST) as ST10, ST23, and ST38 has been shared among the environment, food, and humans, as well as the same beta-lactamase genes, are widely distributed among multiple sources. Further genetic environment comparison of beta-lactamase has suggested their spreading as conserved gene clusters among different species and sources. And this hypothesis has been supported by the successful conjugation of blaCTX-M-15 from Klebsiella pneumonia to Escherichia coli (E .coli). We also applied the shotgun metagenomic sequencing to understand the community of bacteria in reservoir water and detect the AMR genes. The composition of bacteria has shown different diversity among different samples. Besides, different beta-lactamase genes have been identified compared to culture depended methods. Here, we suggest that sequencing analysis has great potential in understanding AMR spreading in the “One-Health” approach. A genetic-based AMR risk assessment is in urgent need in Singapore.
Early functional connectivity in the developing sensorimotor network that is independent of sensory experience
Authors: Cross Christine M. , Santos Laura Mediavilla , Whiteley Nick , Luyt Karen , Ashby Michael C.
Published: June 2021

Neonatal sensory experience shapes development of neural pathways carrying sensory information to the cortex. These pathways link to wider functional networks that coordinate activity of separate cortical regions, but it remains unknown when these broader networks emerge or how their maturation is influenced by sensory experience. By imaging activity across the cortex in neonatal mice, we have found unexpectedly early emergence of coordinated activity within a sensorimotor network that includes whisker-related somatosensory cortex and motor cortex. This network is spontaneously active but is not engaged by sensory stimulation, even though whisker deflection reliably drives cortical activity within barrel cortex. Acute silencing of the sensory periphery ablated spontaneous activity that was restricted to barrel cortex but spared this early sensorimotor network coactivity, suggesting that it is driven from elsewhere. Furthermore, perturbing sensory experience by whisker trimming did not impact emergence or early maturation of spontaneous activity in the sensorimotor network. As such, functional sensorimotor cortical networks develop early, in parallel with development of ascending sensory pathways, and their initial maturation is independent of sensory experience.
Altered DNA methylation in ion transport and immune signalling genes is associated with severity in Pancreatic Ductal Adenocarcinoma
Authors: Chatterjee Ankita , Bararia Akash , Ganguly Debopriyo , Roy Paromita , Banerjee Sudeep , Ghosh Shibajyoti , Gulati Sumit , Ghatak Supriyo , Chattopadhay Bitan Kumar , Maitra Arindam , Basu Priyadarshi , Chatterjee Aniruddha , Sikdar Nilabja
Published: June 2021

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading cancers worldwide and has a poor survival, with a relative five-year survival rate of only 8.5%. In this study we investigated epigenetic marksassociated with PDAC severity and prognosis, through studying alterations in DNA methylation patterns.

Methods

DNA methylome for tumor and adjacent normal tissue samples from PDAC patients (n=7) were generated using Illumina 450K bead chips. Differentially methylated positions (DMPs) were identified with |delta beta| > 0.2 and p-value<0.01 by comparing tumors with the adjacent normal tissues. Validation of differential methylation and associated gene expression at selected genes was carried out in an independent cohort PDAC patient.

Results

We identified 76 DMPs in PDAC patients that mapped to 43 genes. Among them, 44.7% (n=34) were hypo-methylated and 55.3% (n=42) were hyper-methylated DMPs in cancer samples. The trends of change in methylation at these 76 DMPs from well to moderate were like that from moderate to poorly differentiated cancer samples. The gradual trend in differential methylation was observed both in our cohort and the TCGA-PAAD cohort, suggesting methylation marks can serve as early indicators of disease pathology. Altered promoter methylation, which may affect gene expression, was observed for transcription regulators (BHLHE23, GSC2, FOXE1 and TWIST1), gated ion channels (KCNA6, and CACNB2), tumor suppressors (RASSF1, SPRED2, and NPY) and genes functioning in interferon signalling (SIGIRR, MX2, and OAS2). We also have compared the TCGA-PAAD dataset with normal pancreatic tissue data from GTEx V8 dataset leading to a confluent observation.

Conclusions

We reported the first study on methylome in PDAC tumors from patients in India. We identified altered DNA methylation associated with increasing severity in PDAC among some genes like SIGIRR, MX2 along with other previously reported loci. We also concluded a confluence in our observation when comparing the TCGA-PAAD dataset with GTEx V8 dataset.
A high-throughput multiplexing and selection strategy to complete bacterial genomes
Authors: Arredondo-Alonso Sergio , Pöntinen Anna K. , Cléon François , Gladstone Rebecca A. , Schürch Anita C. , Johnsen Pål J , Samuelsen Ørjan , Corander Jukka
Published: June 2021

Background

Bacterial whole-genome sequencing based on short-read sequencing data often results in a draft assembly formed by contiguous sequences. The introduction of long-read sequencing technologies permits to unambiguously bridge those contiguous sequences into complete genomes. However, the elevated costs associated with long-read sequencing frequently limit the number of bacterial isolates that can be long-read sequenced.

Here we evaluated the recently released 96 barcoding kit from Oxford Nanopore Technologies (ONT) to generate complete genomes on a high-throughput basis. In addition, we propose a long-read isolate selection strategy that optimizes a representative selection of isolates from large-scale bacterial collections.

Results

Despite an uneven distribution of long-reads per barcode, near-complete chromosomal sequences (assembly contiguity = 0.89) were generated for 96 Escherichia coli isolates with associated short-read sequencing data. The assembly contiguity of the plasmid replicons was even higher (0.98) which indicated the suitability of the multiplexing strategy for studies focused on resolving plasmid sequences. We benchmarked hybrid and ONT-only assemblies and showed that the combination of ONT sequencing data with short-read sequencing data is still highly desirable: (i) to perform an unbiased selection of isolates for long-read sequencing, (ii) to achieve an optimal genome accuracy and completeness, and (iii) to include small plasmids underrepresented in the ONT library.

Conclusions

The proposed long-read isolate selection ensures completing bacterial genomes of isolates that span the genome diversity inherent in large collections of bacterial isolates. We show the potential of using this multiplexing approach to close bacterial genomes on a high-throughput basis.
Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance
Authors: Dorel Mathurin , Klinger Bertram , Mari Tommaso , Toedling Joern , Blanc Eric , Messerschmidt Clemens , Nadler-Holly Michal , Ziehm Matthias , Sieber Anja , Hertwig Falk , Beule Dieter , Eggert Angelika , Schulte Johannes H. , Selbach Matthias , Blüthgen Nils
Published: June 2021

Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms. We found that negative feedbacks within MAPK signalling and to the IGF receptor mediate re-activation of MAPK signalling upon treatment in resistant cell lines. By using cell-line specific models, we predict that combinations of MEK inhibitors with RAF or IGFR inhibitors can overcome resistance, and tested these predictions experimentally. In addition, phospo-proteomics profiles confirm the cell-specific feedback effects and synergy of MEK and IGFR targeted treatements. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies, and our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma.
Unexpected gene activation following CRISPR-Cas9-mediated genome editing
Authors: Manjón Anna G , Teunissen Hans , de Wit Elzo , Medema René H
Published: June 2021

The discovery of the Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR) and its development as a genome editing tool has revolutionized the field of molecular biology. In the DNA damage field, CRISPR has brought an alternative to induce endogenous double-strand breaks (DSB) at desired genomic locations and study the DNA damage response and its consequences. Many systems for sgRNA delivery have been reported in order to efficiency generate this DSB, including lentiviral vectors. However, some of the consequences of these systems are yet not well understood. Here we report that lentiviral-based sgRNA vectors can integrate into the endogenous genomic target location, leading to undesired activation of the target gene. By generating a DSB in the regulatory region of the ABCB1 gene using a lentiviral sgRNA vector, we can induce the formation of taxol-resistant colonies. We show that these colonies upregulated ABCB1 via integration of the EEF1A1 and the U6 promoters from the sgRNA vector. We believe that this is an unreported CRISPR/Cas9 artefact that researchers need to be aware of when using lentiviral vectors for genome editing.
Bacteriophage T4 Vaccine Platform for Next-generation Influenza Vaccine Development
Authors: Li Mengling , Guo Pengju , Chen Cen , Feng Helong , Zhang Wanpo , Gu Changqin , Wen Guoyuan , Rao Venigalla B. , Tao Pan
Published: June 2021

Developing influenza vaccines that protect against a broad range of viruses is a public health priority, and several conserved viral proteins or domains have been identified as promising targets for such vaccine development. However, none of the targets is immunogenic, and vaccine platforms that can incorporate multiple antigens with enhanced immunogenicity are desperately needed. In this study, we provided proof-of-concept for the development of next-generation influenza vaccine using T4 phage virus-like particle (VLP) platform. With extracellular domain of influenza matrix protein 2 (M2e) as a readout, we showed that more than 1,280 M2e molecules can be assembled on a 120×90 nanometer phage capsid to form T4-M2e VLPs, which are highly immunogenic and induced complete protection against influenza virus challenge without any addition adjuvant. Potentially, additional conserved antigens or molecular adjuvants could be incorporated into the T4-M2e VLPs to customize influenza vaccines to address different issues. All the components of T4 VLP vaccines can be mass-produced in E. coli in a short time, therefore, providing a rapid approach to deal with the potential influenza pandemic.
Optimal resource management and allocation for autonomous-vehicle-infrastructure cooperation under mobile edge computing
Authors: Zhou Shengpei , Chang Zhenting , Song Haina , Su Yuejiang , Liu Xiaosong , Yang Jingfeng
Published: June 2021

Purpose

With the continuous technological development of automated driving and expansion of its application scope, the types of on-board equipment continue to be enriched and the computing capabilities of on-board equipment continue to increase and corresponding applications become more diverse. As the applications need to run on on-board equipment, the requirements for the computing capabilities of on-board equipment become higher. Mobile edge computing is one of the effective methods to solve practical application problems in automated driving.

Design/methodology/approach

In this study, in accordance with practical requirements, this paper proposed an optimal resource management allocation method of autonomous-vehicle-infrastructure cooperation in a mobile edge computing environment and conducted an experiment in practical application.

Findings

The design of the road-side unit module and its corresponding real-time operating system task coordination in edge computing are proposed in the study, as well as the method for edge computing load integration and heterogeneous computing. Then, the real-time scheduling of highly concurrent computation tasks, adaptive computation task migration method and edge server collaborative resource allocation method is proposed. Test results indicate that the method proposed in this study can greatly reduce the task computing delay, and the power consumption generally increases with the increase of task size and task complexity.

Originality/value

The results showed that the proposed method can achieve lower power consumption and lower computational overhead while ensuring the quality of service for users, indicating a great application prospect of the method.
Online monitoring experiments of turbo-shaft engine based on electrostatic sensor
Authors: Guo Jiachen , Jiang Heng , Zhong Zhirong , Zuo Hongfu , Zhang Huan
Published: June 2021

Purpose

Electrostatic monitoring technology is a useful tool for monitoring and detecting component faults and degradation, which is necessary for engine health management. This paper aims to carry out online monitoring experiments of turbo-shaft engine to contribute to the practical application of electrostatic sensor in aero-engine.

Design/methodology/approach

Combined with the time and frequency domain methods of signal processing, the authors analyze the electrostatic signal from the short timescale and the long timescale.

Findings

The short timescale analysis verifies that electrostatic sensor is sensitive to the additional increased charged particles caused by abnormal conditions, which makes this technology to monitor typical failures in aero-engine gas path. The long scale analysis verifies the electrostatic sensor has the ability to monitor the degradation of the engine gas path performance, and water washing has a great impact on the electrostatic signal. The spectrum of the electrostatic signal contains not only the motion information of the charged particles but also the rotating speed information of the free turbine.

Practical implications

The findings in this article prove the effectiveness of electrostatic monitoring and contribute to the application of this technology to aero-engine.

Originality/value

The research in this paper would be the foundation to achieve the application of the technology in aero-engine.