bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Flow Oxygen and Other Noninvasive Respiratory Support Therapies in Bronchiolitis: Systematic Review and Network Meta-Analyses
Authors: Gutiérrez Moreno Miriam , del Villar Guerra Pablo , Medina Alberto , Modesto i Alapont Vicent , Castro Bournissen Leandro , Mirás Veiga Alicia , Ochoa-Sangrador Carlos
Published: January 2023

OBJECTIVES:

We present a systematic review on the effectiveness of noninvasive respiratory support techniques in bronchiolitis.

DATA SOURCES:

Systematic review with pairwise meta-analyses of all studies and network meta-analyses of the clinical trials.

STUDY SELECTION:

Patients below 24 months old with bronchiolitis who require noninvasive respiratory support were included in randomized controlled trials (RCTs), non-RCT, and cohort studies in which high-flow nasal cannula (HFNC) was compared with conventional low-flow oxygen therapy (LFOT) and/or noninvasive ventilation (NIV).

DATA EXTRACTION:

Emergency wards and hospitalized patients with bronchiolitis.

DATA SYNTHESIS:

A total of 3,367 patients were analyzed in 14 RCTs and 8,385 patients in 14 non-RCTs studies. Only in nonexperimental studies, HFNC is associated with a lower risk of invasive mechanical ventilation (MV) than NIV (odds ratio, 0.49; 95% CI, 0.42–0.58), with no differences in experimental studies. There were no differences between HFNC and NIV in other outcomes. HFNC is more effective than LFOT in reducing oxygen days and treatment failure. In the network meta-analyses of clinical trials, NIV was the most effective intervention to avoid invasive MV (surface under the cumulative ranking curve [SUCRA], 57.03%) and to reduce days under oxygen therapy (SUCRA, 79.42%), although crossover effect estimates between interventions showed no significant differences. The included studies show methodological heterogeneity, but it is only statistically significant for the reduction of days of oxygen therapy and length of hospital stay.

CONCLUSIONS:

Experimental evidence does not suggest that high-flow oxygen therapy has advantages over LFOT as initial treatment nor over NIV as a rescue treatment.
Pathobiology, Severity, and Risk Stratification of Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference
Authors: Grunwell Jocelyn R. , Dahmer Mary K. , Sapru Anil , Quasney Michael W. , Flori Heidi ,   on behalf of the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) for the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Published: January 2023

OBJECTIVES:

To review the literature for studies published in children on the pathobiology, severity, and risk stratification of pediatric acute respiratory distress syndrome (PARDS) with the intent of guiding current medical practice and identifying important areas for future research related to severity and risk stratification.

DATA SOURCES:

Electronic searches of PubMed and Embase were conducted from 2013 to March 2022 by using a combination of medical subject heading terms and text words to capture the pathobiology, severity, and comorbidities of PARDS.

STUDY SELECTION:

We included studies of critically ill patients with PARDS that related to the severity and risk stratification of PARDS using characteristics other than the oxygenation defect. Studies using animal models, adult only, and studies with 10 or fewer children were excluded from our review.

DATA EXTRACTION:

Title/abstract review, full-text review, and data extraction using a standardized data collection form.

DATA SYNTHESIS:

The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize relevant evidence and develop recommendations for clinical practice. There were 192 studies identified for full-text extraction to address the relevant Patient/Intervention/Comparator/Outcome questions. One clinical recommendation was generated related to the use of dead space fraction for risk stratification. In addition, six research statements were generated about the impact of age on acute respiratory distress syndrome pathobiology and outcomes, addressing PARDS heterogeneity using biomarkers to identify subphenotypes and endotypes, and use of standardized ventilator, physiologic, and nonpulmonary organ failure measurements for future research.

CONCLUSIONS:

Based on an extensive literature review, we propose clinical management and research recommendations related to characterization and risk stratification of PARDS severity.
Outcomes of Children Surviving Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference
Authors: Killien Elizabeth Y. , Maddux Aline B. , Tse Sze Man , Watson R. Scott ,   on behalf of the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Published: January 2023

OBJECTIVES:

To summarize the evidence for the Second Pediatric Acute Lung Injury Consensus Conference-2 (PALICC-2) recommendations for assessment of outcomes among patients surviving pediatric acute respiratory distress syndrome (PARDS).

DATA SOURCES:

MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost).

STUDY SELECTION:

We conducted a scoping review to identify studies evaluating outcomes following PARDS. We included studies of survivors of PARDS, acute respiratory failure with a high proportion of PARDS patients, or other critical illnesses if PARDS-specific outcomes could be extracted.

DATA EXTRACTION:

Title/abstract review, full-text review, and data extraction using a standardized data collection form.

DATA SYNTHESIS:

The Grading of Recommendations Assessment, Development and Evaluation approach was used to identify and summarize evidence and develop recommendations. Of 8,037 abstracts screened, we identified 20 articles for inclusion. Morbidity following PARDS was common and affected multiple domains of pulmonary and nonpulmonary function. There was insufficient evidence to generate any evidence-based recommendations. We generated eight good practice statements and five research statements. A panel of 52 experts discussed each proposed good practice statement and research statement, and the agreement rate was measured with an online voting process. Good practice statements describe the approach to clinical outcome assessment, assessment of pulmonary outcomes of children surviving PARDS, and assessment of nonpulmonary outcomes of children surviving PARDS including health-related quality of life and physical, neurocognitive, emotional, family, and social functioning. The five research statements relate to assessment of patient preillness status, use of postdischarge endpoints for clinical trials, the association between short-term and longer term outcomes, the trajectory of recovery following PARDS, and practices to optimize follow-up.

CONCLUSIONS:

There is increasing evidence that children are at risk for impairments across a range of pulmonary and nonpulmonary health domains following hospitalization for PARDS. The results of this extensive scoping review and consensus conference involving experts in PARDS research, clinical care, and outcomes assessment provide guidance to clinicians and researchers on postdischarge follow-up to optimize the long-term health of patients surviving PARDS.
Nonpulmonary Treatments for Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference
Authors: Valentine Stacey L. , Kudchadkar Sapna R. , Ward Shan , Morrow Brenda M. , Nadkarni Vinay M. , Curley Martha A. Q. ,   on behalf of the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Published: January 2023

OBJECTIVES:

To provide an updated review of the literature on nonpulmonary treatments for pediatric acute respiratory distress syndrome (PARDS) from the Second Pediatric Acute Lung Injury Consensus Conference.

DATA SOURCES:

MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost)

STUDY SELECTION:

Searches were limited to children with PARDS or hypoxic respiratory failure focused on nonpulmonary adjunctive therapies (sedation, delirium management, neuromuscular blockade, nutrition, fluid management, transfusion, sleep management, and rehabilitation).

DATA EXTRACTION:

Title/abstract review, full-text review, and data extraction using a standardized data collection form.

DATA SYNTHESIS:

The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize evidence and develop recommendations. Twenty-five studies were identified for full-text extraction. Five clinical practice recommendations were generated, related to neuromuscular blockade, nutrition, fluid management, and transfusion. Thirteen good practice statements were generated on the use of sedation, iatrogenic withdrawal syndrome, delirium, sleep management, rehabilitation, and additional information on neuromuscular blockade and nutrition. Three research statements were generated to promote further investigation in nonpulmonary therapies for PARDS.

CONCLUSIONS:

These recommendations and statements about nonpulmonary treatments in PARDS are intended to promote optimization and consistency of care for patients with PARDS and identify areas of uncertainty requiring further investigation.
Invasive Ventilatory Support in Patients With Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference
Authors: Fernández Analía , Modesto Vicent , Rimensberger Peter C. , Korang Steven K. , Iyer Narayan P. , Cheifetz Ira M. ,   on behalf of the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Published: January 2023

OBJECTIVE:

To provide evidence for the Second Pediatric Acute Lung Injury Consensus Conference updated recommendations and consensus statements for clinical practice and future research on invasive mechanical ventilation support of patients with pediatric acute respiratory distress syndrome (PARDS).

DATA SOURCES:

MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost).

STUDY SELECTION:

We included clinical studies of critically ill patients undergoing invasive mechanical ventilation for PARDS, January 2013 to April 2022. In addition, meta-analyses and systematic reviews focused on the adult acute respiratory distress syndrome population were included to explore new relevant concepts (e.g., mechanical power, driving pressure, etc.) still underrepresented in the contemporary pediatric literature.

DATA EXTRACTION:

Title/abstract review, full text review, and data extraction using a standardized data collection form.

DATA SYNTHESIS:

The Grading of Recommendations Assessment, Development and Evaluation approach was used to identify and summarize relevant evidence and develop recommendations, good practice statements and research statements. We identified 26 pediatric studies for inclusion and 36 meta-analyses or systematic reviews in adults. We generated 12 recommendations, two research statements, and five good practice statements related to modes of ventilation, tidal volume, ventilation pressures, lung-protective ventilation bundles, driving pressure, mechanical power, recruitment maneuvers, prone positioning, and high-frequency ventilation. Only one recommendation, related to use of positive end-expiratory pressure, is classified as strong, with moderate certainty of evidence.

CONCLUSIONS:

Limited pediatric data exist to make definitive recommendations for the management of invasive mechanical ventilation for patients with PARDS. Ongoing research is needed to better understand how to guide best practices and improve outcomes for patients with PARDS requiring invasive mechanical ventilation.
Pulmonary Specific Ancillary Treatment for Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference
Authors: Rowan Courtney M. , Randolph Adrienne G. , Iyer Narayan Prabhu , Korang Steven Kwasi , Kneyber Martin C. J. ,   on behalf of the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Published: January 2023

OBJECTIVES:

We conducted an updated review of the literature on pulmonary-specific ancillary therapies for pediatric acute respiratory distress syndrome (PARDS) to provide an update to the Pediatric Acute Lung Injury Consensus Conference recommendations and statements about clinical practice and research.

DATA SOURCES:

MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost).

STUDY SELECTION:

Searches were limited to children, PARDS or hypoxic respiratory failure and overlap with pulmonary-specific ancillary therapies

DATA EXTRACTION:

Title/abstract review, full-text review, and data extraction using a standardized data collection form.

DATA SYNTHESIS:

The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize evidence and develop recommendations. Twenty-six studies were identified for full-text extraction. Four clinical recommendations were generated, related to use of inhaled nitric oxide, surfactant, prone positioning, and corticosteroids. Two good practice statements were generated on the use of routine endotracheal suctioning and installation of isotonic saline prior to endotracheal suctioning. Three research statements were generated related to: the use of open versus closed suctioning, specific methods of airway clearance, and various other ancillary therapies.

CONCLUSIONS:

The evidence to support or refute any of the specific ancillary therapies in children with PARDS remains low. Further investigation, including a focus on specific subpopulations, is needed to better understand the role, if any, of these various ancillary therapies in PARDS.
eHealth to Improve Psychological Functioning and Self-Management of People With Chronic Kidney Disease: A Randomized Controlled Trial
Authors: Cardol Cinderella K. , van Middendorp Henriët , Dusseldorp Elise , van der Boog Paul J. M. , Hilbrands Luuk B. , Navis Gerjan , Sijpkens Yvo W. J. , Evers Andrea W. M. , van Dijk Sandra ,   on behalf of the E-GOAL Study Group
Published: January 2023

Objective

Psychological distress is common among patients with chronic kidney disease and can interfere with disease self-management. We assessed the effectiveness of the personalized E-GOAL electronic health care pathway with screening and cognitive-behavioral therapy including self-management support, aimed to treat psychological distress and facilitate self-management among people with chronic kidney disease not on dialysis (N= 121).

Methods

Primary outcome of the open two-arm parallel randomized controlled trial in four Dutch hospitals was psychological distress at posttest directly after the intervention and at 3-month follow-up. Secondary outcomes were physical and mental health-related quality of life, self-efficacy, chronic disease self-management, and personalized outcomes, that is, perceived progress compared with the previous time point on functioning (e.g., mood or social functioning) and self-management (e.g., dietary or medication adherence) outcomes that were prioritized by each individual.

Results

Linear mixed-effects analyses showed no significant time-by-group interaction effects for psychological distress, health-related quality of life, self-efficacy, and chronic condition self-management, whereas analyses of covariance showed significantly more perceived progress in the intervention group at posttest on personally prioritized areas of functioning (b= 0.46, 95% confidence interval = 0.07–0.85) and self-management (b= 0.55, 95% confidence interval = 0.16–0.95), with Cohendvalues of 0.46 and 0.54 (medium effects), respectively. Effects on personalized outcomes were maintained at follow-up.

Conclusions

Compared with regular care only, the electronic health intervention did not reduce psychological distress, whereas personalized outcomes did improve significantly after intervention. Future studies could consider personalized outcomes that reflect individually relevant areas and treatment goals, matching person-tailored treatments.

Trial Registration

Registered at the Netherlands Trial Register with study number NTR7555 (https://trialsearch.who.int/Trial2.aspx?TrialID=NTR7555).
Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery
Authors: Dijkstra Esmée A. , Nilsson Per J. , Hospers Geke A.P. , Bahadoer Renu R. , Meershoek-Klein Kranenbarg Elma , Roodvoets Annet G.H. , Putter Hein , Berglund Åke , Cervantes Andrés , Crolla Rogier M.P.H. , Hendriks Mathijs P. , Capdevila Jaume , Edhemovic Ibrahim , Marijnen Corrie A.M. , van de Velde Cornelis J.H. , Glimelius Bengt , van Etten Boudewijn ,   Collaborative Investigators
Published: January 2023

Objective:

To analyze risk and patterns of locoregional failure (LRF) in patients of the RAPIDO trial at 5 years.

Background:

Multimodality treatment improves local control in rectal cancer. Total neoadjuvant treatment (TNT) aims to improve systemic control while local control is maintained. At 3 years, LRF rate was comparable between TNT and chemoradiotherapy in the RAPIDO trial.

Methods:

A total of 920 patients were randomized between an experimental (EXP, short-course radiotherapy, chemotherapy, and surgery) and a standard-care group (STD, chemoradiotherapy, surgery, and optional postoperative chemotherapy). LRFs, including early LRF (no resection except for organ preservation/R2 resection) and locoregional recurrence (LRR) after an R0/R1 resection, were analyzed.

Results:

Totally, 460 EXP and 446 STD patients were eligible. At 5.6 years (median follow-up), LRF was detected in 54/460 (12%) and 36/446 (8%) patients in the EXP and STD groups, respectively (P=0.07), in which EXP patients were more often treated with 3-dimensional-conformed radiotherapy (P=0.029). In the EXP group, LRR was detected more often [44/431 (10%) vs. 26/428 (6%); P=0.027], with more often a breached mesorectum (9/44 (21%) vs. 1/26 (4); P=0.048). The EXP treatment, enlarged lateral lymph nodes, positive circumferential resection margin, tumor deposits, and node positivity at pathology were the significant predictors for developing LRR. Location of the LRRs was similar between groups. Overall survival after LRF was comparable [hazard ratio: 0.76 (95% CI, 0.46–1.26); P=0.29].

Conclusions:

The EXP treatment was associated with an increased risk of LRR, whereas the reduction in disease-related treatment failure and distant metastases remained after 5 years. Further refinement of the TNT in rectal cancer is mandated.
A workflow for incorporating cross-sectional data into the calibration of dynamic models
Authors: Fischer-Holzhausen Sophie , Röblitz Susanna
Published: January 2023

Abstract

Mathematical modelling and dynamic simulations are commonly used in systems medicine to investigate the interactions between various biological entities in time. The level of model complexity is mainly restricted by the number of model parameters that can be estimated from available experimental data and prior knowledge. The calibration of dynamic models usually requires longitudinal data from multiple individuals, which is challenging to obtain and, consequently, not always available. On the contrary, the collection of cross-sectional data is often more feasible. Here, we demonstrate how the parameters of individual dynamic models can be estimated from such cross-sectional data using a Bayesian updating method. We illustrate this approach on a model for puberty in girls with cross-sectional hormone measurement data.
Species delimitation of eight ascidian (Tunicata) species from the North Eastern Mediterranean
Authors: Karahan Arzu , Temiz Berivan , Öztürk Esra , Douek Jacob , Rinkevich Baruch
Published: January 2023

Members of the tunicates, a subphylum of marine filter-feeder chordates, inhabit all marine and oceanic habitats from the subtidal to the abyssal. Considered as the closest relatives to the vertebrates, the tunicates are widely used as model organisms for evo-devo, allorecognition, senescence, and whole-body regeneration studies. Yet, species boundaries are poorly understood due to high morphological and genetic plasticity that characterize many tunicates taxa. Here we study taxonomy and the distribution of eight tunicate species (Botrylloides niger Herdman, 1886/ aff. leachii, Botrylloides israelienseBrunetti, 2009,Botrylloides sp., Botrylloides anceps(Herdman, 1891),Botryllus schlosseri(Pallas, 1766),Didemnum perlucidumMonniot F., 1983,Symplegma brakenhielmi(Michaelsen, 1904) andPolyclinum constellatumSavigny, 1816) sampled from six Turkish North Eastern Mediterranean Sea sites and employed the mitochondrial barcoding marker (COI) for evaluating the relationships among geographically restricted and widely spread ascidian species. Species delimitation analysis was conducted using NCBI and the present study sequences. Morphological examinations were first done in the field and then, styelide colonies were cultured in the laboratory and studied using stereo and light microscopes. A putative newBotrylloidesspecies (Botrylloides sp.) from the Antalya region was revealed, with 99% matching on the COI gene from Saudi Arabia, further awaiting for detailed traditional taxonomy.
Tipifarnib potentiates the antitumor effects of PI3Kα inhibition inPIK3CA- andHRAS-dysregulated HNSCC via convergent inhibition of mTOR activity
Authors: Smith Alison E. , Chan Stacia , Wang Zhiyong , McCloskey Asako , Reilly Quinn , Wang Jayden Z. , Patel Hetika Vora , Koshizuka Keiichi , Soifer Harris S. , Kessler Linda , Dayoub Ashley , Villaflor Victoria , Adkins Douglas , Bruce Justine , Ho Alan , Batista Cesar Perez , Hanna Glenn , Gascó Hernández Amaya , Saunders Andrew , Dale Stephen , Gutkind J. Silvio , Burrows Francis , Malik Shivani
Published: January 2023

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival ranging from 6 to 18 months. For those who progress on standard of care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. We find that tipifarnib synergizes with alpelisib at the level of mTOR in PI3Kα-or HRAS-dependent HNSCCs, leading to marked cytotoxicityin vitroand tumor regressionin vivo. Based on these findings, we have launched the KURRENT-HN trial to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy.

Significance

Backed by strong mechanistic rationale, the combination of alpelisib and tipifarnib has the potential to benefit >45% of R/M HNSCC patients. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, thereby enhancing their clinical utility.
Genomic screening of 16 UK native bat species through conservationist networks uncovers coronaviruses with zoonotic potential
Authors: Tan Cedric C.S. , Trew Jahcub , Peacock Thomas P. , Mok Kai Yi , Hart Charlie , Lau Kelvin , Ni Dongchun , Orme C. David L. , Ransome Emma , Pearse William D. , Coleman Christopher M. , Bailey Dalan , Thakur Nazia , Quantrill Jessica L. , Sukhova Ksenia , Richard Damien , Kahane Laura , Woodward Guy , Bell Thomas , Worledge Lisa , Nunez-Mino Joe , Barclay Wendy , van Dorp Lucy , Balloux Francois , Savolainen Vincent
Published: January 2023

There has been limited characterisation of bat-borne coronaviruses in Europe. Here, we screened for coronaviruses in 48 faecal samples from 16 of the 17 bat species breeding in the UK, collected through a bat rehabilitation and conservationist network. We recovered nine (two novel) complete genomes across six bat species: four alphacoronaviruses, a MERS-related betacoronavirus, and four closely related sarbecoviruses. We demonstrate that at least one of these sarbecoviruses can bind and use the human ACE2 receptor for infecting human cells, albeit suboptimally. Additionally, the spike proteins of these sarbecoviruses possess an R-A-K-Q motif, which lies only one nucleotide mutation away from a furin cleavage site (FCS) that enhances infectivity in other coronaviruses, including SARS-CoV-2. However, mutating this motif to an FCS does not enable spike cleavage. Overall, while UK sarbecoviruses would require further molecular adaptations to infect humans, their zoonotic risk is unknown and warrants closer surveillance.
Corticostriatal Responses to Social Reward are Linked to Trait Reward Sensitivity and Subclinical Substance Use in Young Adults
Authors: Wyngaarden James B. , Johnston Camille R. , Sazhin Daniel , Dennison Jeff B. , Zaff Ori , Fareri Dominic , McCloskey Michael , Alloy Lauren B. , Smith David V. , Jarcho Johanna M.
Published: January 2023

Aberrant levels of reward sensitivity have been linked to substance use disorder and are characterized by alterations in reward processing in the ventral striatum (VS). Less is known about how reward sensitivity and subclinical substance use relate to striatal function during social rewards (e.g., positive peer feedback). Testing this relation is critical for predicting risk for development of substance use disorder. In this pre-registered study, participants (N=44) underwent fMRI while completing well-matched tasks that assess neural response to reward in social and monetary domains. Contrary to our hypotheses, aberrant reward sensitivity blunted the relationship between substance use and striatal activation during receipt of rewards, regardless of domain. Moreover, exploratory whole-brain analyses showed unique relations between substance use and social rewards in temporoparietal junction. Psychophysiological interactions demonstrated that aberrant reward sensitivity is associated with increased connectivity between the VS and ventromedial prefrontal cortex during social rewards. Finally, we found that substance use was associated with decreased connectivity between the VS and dorsomedial prefrontal cortex for social rewards, independent of reward sensitivity. These findings demonstrate nuanced relations between reward sensitivity and substance use, even among those without substance use disorder, and suggest altered reward-related engagement of cortico-VS responses as potential predictors of developing disordered behavior.
Mzion enables deep and precise identification of peptides in data-dependent acquisition proteomics
Authors: Zhang Qiang
Published: January 2023

Sensitive and reliable identification of proteins and peptides pertains the basis of proteomics. We introduce Mzion, a new database search tool for data-dependent acquisition (DDA) proteomics. Our tool utilizes an intensity tally strategy and achieves generally a higher performance in terms of depth and precision across twenty datasets, ranging from large-scale to single-cell proteomics. Compared to several other search engines, Mzion matches on average 20% more peptide spectra at tryptic enzymatic specificity and 80% more at no enzymatic specificity from six large-scale, global datasets. Mzion also identifies more phosphopeptide spectra that can be explained by fewer proteins, demonstrated by six large-scale, local datasets corresponding to the global data. Our findings highlight the potential of Mzion for improving proteomic analysis and advancing our understanding of protein biology.
curatedPCaData: Integration of clinical, genomic, and signature features in a curated and harmonized prostate cancer data resource
Authors: Laajala Teemu D , Sreekanth Varsha , Soupir Alex , Creed Jordan , Calboli Federico CF , Singaravelu Kalaimathy , Orman Michael , Colin-Leitzinger Christelle , Gerke Travis , Fidley Brooke L. , Tyekucheva Svitlana , Costello James C
Published: January 2023

Genomic and transcriptomic data have been generated across a wide range of prostate cancer (PCa) study cohorts. These data can be used to better characterize the molecular features associated with clinical outcomes and to test hypotheses across multiple, independent patient cohorts. In addition, derived features, such as estimates of cell composition, risk scores, and androgen receptor (AR) scores, can be used to develop novel hypotheses leveraging existing multi-omic datasets. The full potential of such data is yet to be realized as independent datasets exist in different repositories, have been processed using different pipelines, and derived and clinical features are often not provided or unstandardized. Here, we present thecuratedPCaDataR package, a harmonized data resource representing >2900 primary tumor, >200 normal tissue, and >500 metastatic PCa samples across 19 datasets processed using standardized pipelines with updated gene annotations. We show that meta-analysis across harmonized studies has great potential for robust and clinically meaningful insights.curatedPCaDatais an open and accessible community resource with code made available for reproducibility.
Brain Oscillations during Visuomotor Processing in Children with ASD
Authors: Wilson Emily May , An Kyung-min
Published: January 2023

Autism Spectrum disorder (ASD) has been reported to often involve significant motor dysfunction in addition to other core traits. While individual differences in visual processing have also been noted in individuals with ASD. However, the brain oscillations between visual and motor processing in ASD are poorly understood due to a lack of research surrounding the topic. To elucidate this, we focused on the power-power correlation between visual- and motor-related oscillations. We recorded magnetoencephalography in 18 children with ASD and 19 IQ-matched typically developing children aged 4-7 while they pressed a button during a visual-targeted motor task. We estimated visual- and motor-related brain oscillations and focused on the gamma oscillations. We observed gamma oscillatory power changes during the visual-targeted motor task in both groups. We further found statistically significant differences in motor-related gamma power in the right primary motor cortex, but not in the left primary motor cortex between the two groups. We finally found a significant correlation between the left visual gamma power (50-60 Hz, 150-450ms) and the left motor gamma power (70-90 Hz, 0-100 ms) in the TD group. The current findings revealed differences in visuomotor processing in individuals with ASD compared to TD children. These results may be helpful in understanding the neural mechanisms underlying visuomotor processing in ASD, supporting the development of a potential biomarker for ASD.
Optimal Cellular Phenotypic Adaptation in Fluctuating Environments
Authors: George Jason T.
Published: January 2023

Phenotypic adaptation is a core design feature of bacterial populations and multicellular systems navigating highly variable environments. Recent empirical data implicates the role of memory-driven decision-making in cellular systems navigating uncertain future nutrient environments based on prior experience, wherein a distinct growth phenotype emerges in fluctuating conditions. We develop a simple stochastic mathematical model to describe the cellular decision-making required for systems to optimally navigate such uncertainty. We demonstrate that adaptive populations capable of sensing their environment and estimating the nutrient landscape more efficiently traverse changing environments. We find during environmental transitions that larger memory capacities strike a trade-off between inertia of past environmental memory and higher resolution for estimating the optimal phenotype whenever the underlying landscape is close to a critical break-even point. Moreover, systems that tune their memory capacity avoid growth penalties resulting from maladaptive phenotypes following changes to the metabolic landscape. Our model predicts that the nutrient availability of adaptive cells is universally reduced in fluctuating nutritional environments relative to those in constant ones, which recapitulates empirical observations in bacterial systems. Our findings demonstrate that this deviation is a consequence of environmental mis-estimation together with bet-hedging in uncertain adaptive landscapes, and suggests that this deviation is fully determined by cellular memory capacity and the proximity of the environmental landscape to the system’s critical break-even environment. We anticipate that our mathematical framework will be more broadly useful for studying memory-driven cellular decision-making in biological contexts where there is a trade-off for cells selecting from multiple phenotypic states. Such a tool can be used for predicting the response of complex systems to environmental alterations and for testing therapeutically relevant policies.
Approximations to the Solution of the Kushner-Stratonovich Equation for the Stochastic Chemostat*
Authors: Fontenele Magalhães José Augusto , Emzir Muhammad Fuady , Corona Francesco
Published: January 2023

In order to characterise the dynamics of a biochemical system such as the chemostat, we consider a differential description of the evolution of its state under environmental fluctuations. We present solutions to the filtering problem for a chemostat subjected to geometric Brownian motion. Under this modelling assumption, our best knowledge about the state of the system is given by its distribution in time, given the distribution of the initial state. Such a function solves a deterministic partial differential equation, the Kolmogorov forward equation. In this paper, however, we refine our knowledge about the state of the chemostat when additional information about the system is available in the form of measurements. More formally, we are interested in obtaining the distribution of the state conditional on measurements as the solution to a non-linear stochastic partial integral differential equation, the Kushner-Stratonovich equation. For the chemostat, this solution is not available in closed form, and it must be approximated. We present approximations to the solution to the Kushner-Stratonovich equation based on methods for partial differential equations. We compare the solution with a linearisation method and with a classical sequential Monte Carlo method known as the bootstrap particle filter.
Classification of Primary Angle Closure Disease by Hierarchical Cluster Analysis of Ocular Biometrics in the Dark and Light
Authors: Cho Austin , Lewinger Juan Pablo , Pardeshi Anmol A. , Aroca Galo Apolo , Torres Mina , Nongpiur Monisha , Jiang Xuejuan , McKean-Cowdin Roberta , Varma Rohit , Xu Benjamin Y.
Published: January 2023

Purpose

To investigate the classification of eyes with primary angle closure disease (PACD) based on hierarchical cluster analysis of ocular biometrics measured in the dark and light using anterior segment OCT (AS-OCT).

Methods

Participants of the Chinese American Study received complete eye exams, including gonioscopy and AS-OCT imaging, to identify primary angle closure suspects (PACS) and primary angle closure without/with glaucoma (PAC/G). Biometric parameters analyzed included angle opening distance (AOD750) and trabecular iris space area (TISA750), iris area (IA), iris thickness (IT750), iris curvature (IC), lens vault (LV), anterior chamber width (ACW) and anterior chamber depth (ACD). Hierarchical cluster analysis was performed using Ward’s method and Euclidean distance.

Results

Analysis of 159 eyes with PACS or PAC/G produced 2 clusters in both dark and light. In both analyses, the primary cluster (N=132 in the dark, N=126 in the light) was characterized by smaller AOD750 and TISA750, greater IC, and greater LV (p<0.001). The proportion of PACS to PAC/PACG eyes was significantly different between clusters in the light (p=0.02) but not the dark cluster analysis (p=0.08). On multivariable logistic regression analysis, smaller TISA750 (OR=0.84 per 0.01μm2) and AOD750 (OR=0.93 per 0.01mm) in the light and smaller TISA750 (OR=0.86 per 0.01μm2) in the dark were significantly associated (p≤ 0.02) with higher odds of PAC/G.

Conclusion

Cluster analysis of ocular biometrics can classify PACD eyes by disease severity. Ocular biometrics appear equally if not more strongly predictive of disease severity when measured in the light than dark. Clustering of biometric measurements obtained in the light could provide a novel method to risk-stratify patients for more severe PACD.
Depletion of theNbCORE receptor drastically improves agroinfiltration productivity in olderNicotiana benthamianaplants
Authors: Dodds Isobel , Chen Changlong , Buscaill Pierre , van der Hoorn Renier A. L.
Published: January 2023

Nicotiana benthamianais increasingly used for transient gene expression to produce antibodies, vaccines, and other pharmaceutical proteins but transient gene expression is low in fully developed, 6-8wk old plants. This low gene expression is thought to be caused by the perception the cold shock protein (CSP) ofAgrobacterium tumefaciens. The CSP receptor is contested because bothNbCSPR andNbCORE have been claimed to perceive CSP. Here, we demonstrate that CSP perception is abolished in 6wk-old plants silenced forNbCORE but notNbCSPR. Importantly, olderNbCORE-silenced plants support a drastically increased level of GFP fluorescence and protein upon agroinfiltration. The drastic increase in transient protein production inNbCORE depleted plants offers new opportunities for molecular farming, where older plants with larger biomass can now be used for efficient protein expression.
Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma
Authors: Xu Yuewei , Spear Sarah , Ma Yurui , Lorentzen Marc P. , Gruet Michael , McKinney Flora , Xu Yitao , Wickremesinghe Chiharu , Shepherd Madelen R , McNeish Iain , Keun Hector C. , Nijhuis Anke
Published: January 2023

Ovarian high-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer with limited therapeutic options. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Therapies disrupting the spliceosome alter cancer transcriptomes and have shown potential to improve PARP inhibitor response. Indisulam (E7070) has been identified as a molecular glue that brings splicing factor RBM39 and DCAF15 E3 ubiquitin ligase in close proximity. Exposure to indisulam induces RBM39 proteasomal degradation through DCAF15-mediated polyubiquitination and subsequent RNA splicing defects. In this study, we demonstrate that loss of RBM39 induces splicing errors in DNA damage repair genes in ovarian cancer, leading to increased sensitivity to PARP inhibitors such as olaparib. Indisulam synergized with olaparib in multiplein vitromodels of ovarian cancer regardless of PARP inhibitor sensitivity and improved olaparib response in mice bearing PARP inhibitor-resistant tumors. DCAF15 expression, but notBRCA1/2mutational status, was essential for the synergy between indisulam and olaparib, suggesting that the combination therapy may benefit patients irrespective of theirBRCA1/2status. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improving PARP inhibitor response in ovarian HGSC.

Graphical Abstract

One Sentence Summary

We identified a novel drug combination that may improve PARP inhibitor response and benefit a large group of ovarian cancer patients.
Informing generative replay for continual learning with long-term memory formation in the fruit fly
Authors: Robinson Brian S. , Joyce Justin , Norman-Tenazas Raphael , Vallabha Gautam K. , Johnson Erik C.
Published: January 2023

Continual learning without catastrophic forgetting is a challenge for artificial systems but it is done naturally across a range of biological systems, including in insects. A recurrent circuit has been identified in the fruit fly mushroom body to consolidate long term memories (LTM), but there is not currently an algorithmic understanding of this LTM formation. We hypothesize that generative replay is occurring to consolidate memories in this recurrent circuit, and find anatomical evidence in synapse-level connectivity that supports this hypothesis. Next, we introduce a computational model which combines an initial experience phase and LTM phase to perform generative replay based continual learning. When evaluated on a CIFAR-100 class-incremental continual learning task, the modeled LTM phase increases classification performance by 20% and approaches within 2% of the performance for a non-incremental upper bound baseline. Unique elements of the proposed generative replay model include: 1) coupling high dimensional sparse activation patterns with generative replay and 2) sampling and reconstructing higher level representations for training generative replay (as opposed to reconstructing sensory-level or processed sensory-level representations). Additionally, we make the experimentally testable prediction that a specific set of synapses would need to undergo experience-dependent plasticity during LTM formation to support our generative replay based model.
“Tumor Treating Fields” delivered via electromagnetic induction have varied effects across glioma cell lines and electric field amplitudes
Authors: Ravin Rea , Cai Teddy X. , Li Aiguo , Briceno Nicole , Pursley Randall H. , Garmendia-Cedillos Marcial , Pohida Tom , Wang Herui , Zhuang Zhengping , Cui Jing , Morgan Nicole Y. , Williamson Nathan H. , Gilbert Mark R. , Basser Peter J.
Published: January 2023

Previous studies reported that alternating electric fields (EFs) in the intermediate frequency (100 – 300 kHz) and low intensity (1 – 3 V/cm) regime — termed “Tumor Treating Fields” (TTFields) — have a specific, anti-proliferative effect on glioblastoma multiforme (GBM) cells. However, the mechanism(s) of action remain(s) incompletely understood, hindering the clinical adoption of treatments based on TTFields. To advance the study of such treatmentin vitro, we developed an inductive device to deliver EFs to cell cultures which improves thermal and osmolar regulation compared to prior devices. Using this inductive device, we applied continuous, 200 kHz electromagnetic fields (EMFs) with a radial EF amplitude profile spanning 0 – 6.5 V/cm to cultures of primary rat astrocytes and several human GBM cell lines — U87, U118, GSC827, and GSC923 — for a duration of 72 hours. Cell density was assessed via segmented pixel densities from GFP expression (U87, U118) or from staining (astrocytes, GSC827, GSC923). Further RNA-Seq analyses were performed on GSC827 and GSC923 cells. Treated cultures of all cell lines exhibited little to no change in proliferation at lower EF amplitudes (0 – 3 V/cm). At higher amplitudes (> 4 V/cm), different effects were observed. Apparent cell densities increased (U87), decreased (GSC827, GSC923), or showed little change (U118, astrocytes). RNA-Seq analyses on treated and untreated GSC827 and GSC923 cells revealed differentially expressed gene sets of interest, such as those related to cell cycle control. Up- and down-regulation, however, was not consistent across cell lines nor EF amplitudes. Our results indicate no consistent, anti-proliferative effect of 200 kHz EMFs across GBM cell lines and thus contradict previousin vitrofindings. Rather, effects varied across different cell lines and EF amplitude regimes, highlighting the need to assess the effect(s) of TTFields and similar treatments on a per cell line basis.
Decoding single-cell multiomics: scMaui - A deep learning framework for uncovering cellular heterogeneity in presence of batch Effects and missing data
Authors: Jeong Yunhee , Ronen Jonathan , Kopp Wolfgang , Lutsik Pavlo , Akalin Altuna
Published: January 2023

The recent advances in high-throughput single-cell sequencing has significantly required computational models which can address the high complexity of single-cell multiomics data. Meticulous single-cell multiomics integration models are required to avoid biases towards a specific modality and overcome the sparsity. Batch effects obfuscating biological signals must also be taken into account. Here, we introduce a new single-cell multiomics integration model, Single-cell Multiomics Autoencoder Integration (scMaui) based on stacked variational encoders and adversarial learning. scMaui reduces the dimensionality of integrated data modalities to a latent space which outlines cellular heterogeneity. It can handle multiple batch effects independently accepting both discrete and continuous values, as well as provides varied reconstruction loss functions to cover various assays and preprocessing pipelines. We show that scMaui accomplishes superior performance in many tasks compared to other methods. Further downstream analyses also demonstrate its potential in identifying relations between assays and discovering hidden subpopulations.
A Clock and Wavefront Self-Organizing Model Recreates the Dynamics of Mouse Somitogenesis in-vivo and in-vitro
Authors: Klepstad Julie , Marcon Luciano
Published: January 2023

During mouse development, presomitic mesoderm cells synchronize Wnt and Notch oscillations, creating sequential phase waves that pattern somites. Traditional somitogenesis models attribute phase waves to global signals that control the frequency of oscillations. However, increasing evidence suggests that they could arise in a self-organizing manner. Here, we introduce the Sevilletor, a novel reaction-diffusion system that serves as a framework to compare different somitogenesis patterning hypotheses. Using this framework, we propose the Clock and Wavefront Self-Organizing model, the first somitogenesis model that generates phase waves via local cell to cell communication independent of global frequency gradients. The model recapitulates the change in relative phase of Wnt and Notch observed during mouse somitogenesis and the formation of multiple phase waves observed upon ectopic expansion of posterior signals. Moreover, it provides a theoretical basis for understanding the excitability of mouse presomitic mesoderm cells observed in vitro.
Super-enhancer driven expression of BAHCC1 promotes melanoma cell proliferation and genome stability
Authors: Berico Pietro , Nogaret Maguelone , Gambi Giovanni , Davidson Guillaume , Cigrang Max , Vokshi Bujamin H , Le Gras Stephanie , Mengus Gabrielle , Ye Tao , Dalmasso Mélanie , Compe Emmanuel , Bertolotto Corine , Davidson Irwin , Coin Frédéric
Published: January 2023

Super enhancers (SE) are stretches of active enhancers ensuring high expression levels of key genes associated with cell function and survival. The identification of cancer-specific SE-driven genes and their functional characterization may prove to be a powerful means for the development of innovative therapeutic strategies. By performing epigenomic profiling in patient-derived short-term melanoma cultures, we identify a SE promoting the specific expression of BAHCC1 in a broad panel of cutaneous and uveal melanoma cells. BAHCC1 is highly expressed in metastatic melanoma, correlates with decreased patient survival and is required for tumor growth. Integrative genomics analyses reveal that BAHCC1 is a transcriptional regulator controlling expression of a subset of E2F/KLF-dependent cell cycle and DNA repair genes. BAHCC1 associates with BRG1-containing remodeling complexes at the promoters of these genes. In agreement, BAHCC1 silencing leads to decreased cell proliferation and delay in DNA repair. Consequently, BAHCC1 deficiency cooperates with PARP inhibition to induce melanoma cell death. Our study identifies a novel SE-driven gene expressed in cutaneous and uveal melanoma and demonstrates how its inhibition can be exploited as a therapeutic target, alone or in combination with DNA damage-inducing agents.