bluuebunny/crossref_metadata_2025_split huggingface dataset:
Total Daily Production and Periodicity of Melatonin Metabolite in Critically Ill Children*
Authors: Foster Jennifer R. , Tijssen Janice A. , Miller Michael R. , Seabrook Jamie A. , Fraser Douglas D. 
Published: July 2020

Objectives:
To determine whether total daily 6-sulfatoxymelatonin excretion and diurnal variation of melatonin secretion was maintained during the early phase of PICU admission through examination of the melatonin urinary metabolite, 6-sulfatoxymelatonin.

Design:
Exploratory prospective, observational study.

Setting:
Twelve-bed medical-surgical PICU of a Children’s Hospital.

Patients:
Fifty children 3 months to 18 years old enrolled within 24 hours of PICU admission with access for urinary sampling.

Interventions:
None.

Measurements and Main Results:
Urine samples were collected at 4-hour intervals for 24 hours and stored at –80oC. 6-sulfatoxymelatonin was determined in duplicate by direct enzyme-linked immunosorbent assay. Patients were heterogeneous for diagnosis, had a mean age of 8.1 years (sd = 6.1 yr), and median (interquartile range) Pediatric Risk of Mortality III of 10 (4–13). Mean (sd) total daily 6-sulfatoxymelatonin production was 30.0 µg (25.6 µg) for the first 24 hours, which did not differ significantly from the means on days 2 (p = 0.56) or 3 (p = 0.29), and was similar to literature controls. Mean 6-sulfatoxymelatonin production for the population fit a periodic function well, with a reliable amplitude of 326 ng/hr and peak excretion from 04:00 to 08:00 (F = 4.4, p = 0.01), even when 6-sulfatoxymelatonin was corrected for body weight (F = 3.4, p = 0.03) and when sedation was included in the model (F = 3.95, p = 0.004). There was no significant correlation between lighting and 6-sulfatoxymelatonin excretion at any time period (R
2 values: 0.11–0.25, p = 0.10–0.94). Mean 6-sulfatoxymelatonin excretion did not fit the model for a periodic function well for the subpopulations studied (sepsis [n = 18, F = 1.1, p = 0.32], respiratory failure requiring deep sedation [n = 10, F = 0.4, p = 0.66], and neurologic injury [n = 7, F = 0.6, p = 0.55]).

Conclusions:
Total daily and diurnal variation of 6-sulfatoxymelatonin excretion is heterogeneously maintained early in pediatric critical illness. However, this may not hold true for specific diagnostic categories.
The Role of Therapeutic Plasma Exchange in the Treatment of Childhood Intoxication: A Single-Center Experience*
Authors: Özkale Murat , Özkale Yasemin 
Published: July 2020

Objectives:
Therapeutic plasma exchange is used to treat neurologic, hematological, renal, and autoimmune diseases with a known or suspected etiopathogenesis. However, there is incomplete understanding of the use of therapeutic plasma exchange in pediatric cases of intoxication. This study investigated 5 years of experience with therapeutic plasma exchange to treat intoxication cases.

Design:
A retrospective, case series, single-center study.

Setting:
PICU of Baskent University, Dr. Turgut Noyan Teaching, and Medical Research Center Hospital in Adana, Turkey.

Patients:
Fourteen patients diagnosed with intoxication who underwent therapeutic plasma exchange between January 2013 and January 2018.

Interventions:
None.

Measurements and Main Results:
Data pertaining to 14 patients, including their medical history (exposure to drugs/toxicants), demographics, initial presentation, and severity of clinical symptoms (requirement of mechanical ventilation, Glasgow Coma Scale score, and the pediatric severity of illness score [Pediatric Logistic Organ Dysfunction] were retrospectively reviewed. The most common indication for therapeutic plasma exchange was multiple drug intoxication, followed by amitriptyline, Amanita phalloides mushroom, carbamazepine, mercury, verapamil, and botulism. All patients underwent therapeutic plasma exchange and two patients underwent hemodialysis before therapeutic plasma exchange. There was no mortality or complications related to the therapeutic plasma exchange procedure. Clinical improvement was observed after therapeutic plasma exchange in 13 of the 14 patients; one patient with verapamil intoxication died.

Conclusions:
Therapeutic plasma exchange appears to be safe and effective for treating pediatric cases of intoxication, including multidrug and amitriptyline intoxication, and is associated with significant recovery in the majority of severely affected patients. Treatment of intoxication with therapeutic plasma exchange should be guided primarily by the properties of the causative toxic substances/drugs, and consideration of patient age, the severity of clinical symptoms, Pediatric Logistic Organ Dysfunction score and response to initial supportive and antidotal treatment.
Delirium Detection Based on the Clinical Experience of Pediatric Intensivists
Authors: de Castro Roberta Esteves Vieira , de Magalhães-Barbosa Maria Clara , Cunha Antônio José Ledo Alves da , Cheniaux Elie , Prata-Barbosa Arnaldo 
Published: July 2020

Objectives:
To estimate the frequency of delirium detected by pediatric intensivists, based only on their clinical experience, without a valid and reliable tool.

Design:
Multicenter, prospective, descriptive, observational study.

Settings:
Three PICUs in Rio de Janeiro, Brazil.

Patients:
Twenty-nine days to 18 years old.

Interventions:
Electronic forms were sent weekly to the pediatric intensivists responsible for the daily care of patients from March to September 2015, to fill in information about the presence of risk factors and diagnosis of delirium in all patients who remained in the PICU in the last week. Demographics and other clinical data were extracted from an electronic system.

Measurements and Main Results:
A total of 504 admissions in the three PICUs (477 patients) were included. The pediatric intensivists reported only two episodes of delirium in two different patients, based on insufficient criteria. Considering all PICUs admissions, the reported frequency of delirium was only 0.4% (2/504).

Conclusions:
The low frequency of delirium detection and the insufficient criteria used for the diagnosis in these units suggest flaws in the recognition of delirium and probably the occurrence of underdiagnosis/misdiagnosis when it is based only on clinical experience, without the use of a valid and reliable tool.
Impact of lock down relaxation on the COVID-19 epidemic trajectory in Bangladesh
Authors: Shimul Shafiun Nahin , Hussain Mofakhar , Faisel Abu Jamil , Hamid Syed Abdul 
Published: July 2020

AbstractIn this projection exercise, we analyzed the circumstances of the COVID-19 pandemic in Bangladesh and used multiple methods to characterize the epidemic curve. We merged several publicly available data sets for the purpose. Projections using actual Government data as of June 16, 2020 reveals that the epidemic curve for Bangladesh may be different from that of developed countries and quite similar to such curves in countries in the region. This is true, both in terms of incidence of cases (total number of cases per million population) and length of the epidemic (months to peak or flatten the epidemic curve). We find that while Bangladesh went into lockdown early, efforts to maintain lockdown at a national level was relaxed and new cases accelerated; with significant growth happening since lifting of lockdown on May 31. Our estimates indicate prevalence of COVID-19 may be between 200,000 and 600,000 towards end of the year, may take 9 months (270 days) to flatten the epidemic curve, lifting of the lockdown may have increased total cases by 60 to 100% and may have prolonged the epidemic by additional 2-3 months.
Discovery of A New Class of Integrin Antibodies for Fibrosis
Authors: Zhang Ji , Wang Tao , Saigal Ashmita , Johnson Josephine , Morrisson Jennifer , Tabrizifard Sahba , Hollingsworth Scott A. , Eddins Michael J. , Mao Wenxian , O’Neill Kim , Garcia-Calvo Margarita , Carballo-Jane Ester , Liu DingGang , Ham Taewon , Zhou Qiong , Dong Weifeng , Meng Hsien-Wei Yvonne , Hicks Jacqueline , Cai Tian-Quan , Akiyama Taro , Pinto Shirly , Cheng Alan C. , Greshock Thomas , Marquis John C. , Ren Zhao , Talukdar Saswata , Shaheen Hussam Hisham , Handa Masahisa 
Published: July 2020

AbstractLung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of all αv integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimab’s yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple αv integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFβ activation. In IPF patient lung fibroblasts, TGFβ treatment induced profound αSMA expression in phenotypic imaging assays and Ab-31 demonstrated superior in vitro activity at inhibiting αSMA expression, suggesting that the integrin antibody is able to modulate TGFβ action though mechanisms beyond the inhibition of latent TGFβ activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases.One Sentence Summarytargeting integrin in lung fibrosis
Supervised and Unsupervised Classification of lncRNA Subtypes
Authors: Sen Rituparno , Fallmann Jörg , Walter Maria Emília M. T. , Stadler Peter F. 
Published: July 2020

AbstractMany small nucleolar RNAs and many of the hairpin precursors of miRNAs are processed from long non-protein-coding (lncRNA) host genes. In contrast to their highly conserved and heavily structured payload, the host genes feature poorly conserved sequences. Nevertheless there is mounting evidence that the host genes have biological functions. No obvious connections between the function of the host genes and the function of their payloads have been reported. Here we inverstigate whether there is an association of host gene function or mechanisms with the type of payload. To assess this hypothesis we test whether the miRNA host genes (MIRHGs), snoRNA host genes (SNHGs), and other lncRNAs host genes can be distinguished based on sequence and structure features. A positive answer would imply a correlation between host genes and their payload. While the three classes can be distinguished reliably when the classifier is allowed to extract features from the payloads, this is no longer the case when only sequence and structure of parts of the host gene distal from the snoRNAs or miRNA payload is used for classification. Our data indicate that the functions of MIRHGs and SNHGs are largely independent of the functions of their payloads. Furthermore, there is no evidence that the MIRHGs and SNHGs form coherent classes of long non-coding RNAs distinguished by features other than their payloads.
Warming indirectly increases invasion success in food webs
Authors: Sentis Arnaud , Montoya Jose M. , Lurgi Miguel 
Published: July 2020

ABSTRACTClimate warming and biological invasions are key drivers of biodiversity change. Their combined effects on ecological communities remain largely unexplored. We investigated the direct and indirect influences of warming on invasion success, and their synergistic effects on community structure and dynamics. Using size-structured food web models, we found that warming increased invasion success. The direct physiological effects of warming on invasions were minimal in comparison to indirect effects mediated by changes on food web structure and stability. Warmed communities with less connectivity, shortened food chains and reduced temporal variability were more susceptible to invasions. The directionality and magnitude of invasions effects on food webs varied across warming regimes. Warmer communities became smaller, more connected, and with more predator species when invaded than their colder counterparts. They were also less stable and their species more abundant. Considering food web structure is crucial to predict invasion success and its impacts under warming.
Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution
Authors: Pacini Guido , Dunkel Ilona , Mages Norbert , Mutzel Verena , Timmermann Bernd , Marsico Annalisa , Schulz Edda G 
Published: July 2020

AbstractTo ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist upregulation and silencing are thought to be coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cell RNA-sequencing. Specifically, we assess the onset of random XCI with high temporal resolution in differentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploiting the inter-cellular heterogeneity of XCI onset, we identify Nanog downregulation as its main trigger and discover additional putative Xist regulators. Moreover, we confirm several predictions of the stochastic model of XCI where monoallelic silencing is thought to be ensured through negative feedback regulation. Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known Xce effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo.
Automated phenotyping of mosquito larvae enables high-throughput screening for novel larvicides and offers potential for smartphone-based detection of larval insecticide resistance
Authors: Buckingham Steven D. , Partridge Frederick A. , Poulton Beth C. , Miller Ben , McKendry Rachel A. , Lycett Gareth J , Sattelle David B. 
Published: July 2020

AbstractPyrethroid-impregnated nets have contributed significantly to halving the burden of malaria but resistance threatens their future efficacy and the pipeline of new insecticides is short. Here we report that an invertebrate automated phenotyping platform (INVAPP), combined with the algorithm Paragon, provides a robust system for measuring larval motility inAnopheles gambiae (and An. coluzzi)as well asAedes aegyptiwith the capacity for high-throughput screening for new larvicides. By this means, we reliably quantified both time- and concentration-dependent actions of chemical insecticides faster than using the WHO standard larval assay. We illustrate the effectiveness of the system using an established larvicide (temephos) and demonstrate its capacity for library-scale chemical screening using the Medicines for Malaria Venture (MMV) Pathogen Box library. As a proof-of-principle, this library screen identified a compound, subsequently confirmed to be tolfenpyrad, as an effective larvicide. We have also used the INVAPP / Paragon system to compare responses in larvae derived from WHO classified deltamethrin resistant and sensitive mosquitoes. We show how this approach to monitoring larval response to insecticides can be adapted for use with a smartphone camera application and therefore has potential for further development as a simple portable field-assay with associated real-time, geo-located information to identify hotspots.Author summaryWe have developed an automated platform for recording the motility of mosquito larvae and applied it to larvae of a mosquito vector of malaria and a mosquito vector of dengue, Zika, yellow fever and other human diseases. The platform facilitates high-throughput, chemical screening for new compounds to control mosquito larvae and also detects differences in response in larval progeny from pryethroid resistant adult mosquitoes. Pyrethroid-impregnated bednets have helped to halve the deaths from malaria in recent years but pyrethroid resistance is an important threat to this progress. Our approach assays insecticide actions faster than the current WHO standard test and we show that it can be adapted for use with a smartphone, which offers the prospect of a future field assay to monitor developing resistance associated with behavioural response with the added benefit of precise satellite-based location.
MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells
Authors: Murayama Takahiko , Takeuchi Yasuto , Yamawaki Kaoru , Natsume Toyoaki , Marcela Rojas-Chaverra N. , Nishimura Tatsunori , Kogure Yuta , Nakata Asuka , Tominaga Kana , Sasahara Asako , Yano Masao , Ishikawa Satoko , Ohta Tetsuo , Ikeda Kazuhiro , Horie-Inoue Kuniko , Inoue Satoshi , Seki Masahide , Suzuki Yutaka , Sugano Sumio , Enomoto Takayuki , Tanabe Masahiko , Tada Kei-ichiro , Kanemaki Masato T. , Okamoto Koji , Tojo Arinobu , Gotoh Noriko 
Published: July 2020

AbstractCancer stem-like cells (CSCs) are responsible for the drug resistance of tumors and recurrence while they experience DNA replication stress. However, the underlying mechanisms that cause DNA replication stress in CSCs and how they compensate for this stress remain unclear. Here we provide evidence that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), which is a firing (activating) factor of the DNA replication origins, to compensate for the DNA replication stress. Expression levels of MCM10 are upregulated in CSCs and maintained by c-Myc. c-Myc-dependent collisions may take place between RNA transcription and DNA replication machinery in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to the collisions to ensure replication progression. Moreover, patient-derived breast CSCs were dependent on MCM10 for their maintenance even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. In addition, MCM10 depletion decreased the growth of cancer cells but not normal cells. Therefore, MCM10 is likely to robustly compensate for DNA replication stress and facilitate genome duplication in the S-phase in cancer cells, which is more pronounced in CSCs. We provide a preclinical rationale to target the c-Myc-MCM10 axis to prevent drug resistance and recurrence.
Sleep loss drives brain region- and cell type-specific alterations in ribosome-associated transcripts involved in synaptic plasticity and cellular timekeeping
Authors: Puentes-Mestril Carlos , Delorme James , Donnelly Marcus , Popke Donald , Jiang Sha , Aton Sara J. 
Published: July 2020

AbstractSleep and sleep loss are thought to impact synaptic plasticity, and recent studies have shown that sleep and sleep deprivation (SD) differentially affect gene transcription and protein translation in the mammalian forebrain. However, much less is known regarding how sleep and SD affect these processes in different microcircuit elements within the hippocampus and neocortex - for example, in inhibitory vs. excitatory neurons. Here we use translating ribosome affinity purification (TRAP) andin situhybridization to characterize the effects of sleep vs. SD on abundance of ribosome-associated transcripts in Camk2a-expressing (Camk2a+) pyramidal neurons and parvalbumin-expressing (PV+) interneurons in mouse hippocampus and neocortex. We find that while both Camk2a+ neurons and PV+ interneurons in neocortex show concurrent SD-driven increases in ribosome-associated transcripts for activity-regulated effectors of plasticity and transcriptional regulation, these transcripts are minimally affected by SD in hippocampus. Similarly we find that while SD alters several ribosome-associated transcripts involved in cellular timekeeping in neocortical Camk2a+ and PV+ neurons, effects on circadian clock transcripts in hippocampus are minimal, and restricted to Camk2a+ neurons. Taken together, our results indicate that SD effects on transcripts destined for translation are both cell type- and brain region-specific, and that these effects are substantially more pronounced in the neocortex than the hippocampus. We conclude that SD-driven alterations in the strength of synapses, excitatory-inhibitory balance, and cellular timekeeping are likely more heterogeneous than previously appreciated.Significance StatementSleep loss-driven changes in transcript and protein abundance have been used as a means to better understand the function of sleep for the brain. Here we use translating ribosome affinity purification (TRAP) to characterize changes in abundance of ribosome-associated transcripts in excitatory and inhibitory neurons in mouse hippocampus and neocortex after a brief period of sleep or sleep loss. We show that these changes are not uniform, but are generally more pronounced in excitatory neurons than inhibitory neurons, and more pronounced in neocortex than in hippocampus.
Distributed Sampling-based Bayesian Inference in Coupled Neural Circuits
Authors: Zhang Wen-Hao , Lee Tai Sing , Doiron Brent , Wu Si 
Published: July 2020

AbstractThe brain performs probabilistic inference to interpret the external world, but the underlying neuronal mechanisms remain not well understood. The stimulus structure of natural scenes exists in a high-dimensional feature space, and how the brain represents and infers the joint posterior distribution in this rich, combinatorial space is a challenging problem. There is added difficulty when considering the neuronal mechanics of this representation, since many of these features are computed in parallel by distributed neural circuits. Here, we present a novel solution to this problem. We study continuous attractor neural networks (CANNs), each representing and inferring a stimulus attribute, where attractor coupling supports sampling-based inference on the multivariate posterior of the high-dimensional stimulus features. Using perturbative analysis, we show that the dynamics of coupled CANNs realizes Langevin sampling on the stimulus feature manifold embedded in neural population responses. In our framework, feedforward inputs convey the likelihood, reciprocal connections encode the stimulus correlational priors, and the internal Poisson variability of the neurons generate the correct random walks for sampling. Our model achieves high-dimensional joint probability representation and Bayesian inference in a distributed manner, where each attractor network infers the marginal posterior of the corresponding stimulus feature. The stimulus feature can be read out simply with a linear decoder based only on local activities of each network. Simulation experiments confirm our theoretical analysis. The study provides insight into the fundamental neural mechanisms for realizing efficient high-dimensional probabilistic inference.