bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cryo-EM Structure of the Pol Polyprotein Provides Insights into HIV Maturation
Authors: Harrison Jerry Joe E. K. , Passos Dario Oliveira , Bruhn Jessica F. , Bauman Joseph D. , Tuberty Lynda , DeStefano Jeffrey J. , Ruiz Francesc Xavier , Lyumkis Dmitry , Arnold Eddy 
Published: October 2021

AbstractMany retroviral proteins are initially translated from unspliced full-length RNA as polyprotein precursors that are subsequently processed by the viral protease (PR) to yield the mature forms. In HIV-1, the enzymes, PR, reverse transcriptase (RT), and integrase (IN), are produced as part of the Gag-Pol polyprotein. While structures of the mature proteins have aided our understanding of catalytic mechanisms and the design of antiretroviral drugs, knowledge of the architecture and functional implications of the immature forms prior to PR-mediated cleavage is limited. We developed a system to produce and purify the HIV-1 Pol polyprotein intermediate precursor and determined its high-resolution cryo-EM structure. The RT portion of the polyprotein has an architecture similar to the mature RT p66/p51 heterodimer, and dimerization of the RT portion draws together two PR monomers to activate proteolytic processing. HIV-1 thus may leverage the dimerization interfaces in Pol to regulate the assembly and maturation of the polyprotein precursors.
A novel method for producing functionalized vesicles that efficiently deliver oligonucleotidesin vitroin cancer cells andin vivo in mice
Authors: Jain Pragati , Roberts Arthur G. 
Published: October 2021

AbstractNano-based delivery systems have enhanced our ability to administer and target drugs and macromolecules to their targets. Oligonucleotide drugs have great therapeutic potential but often have off-target effects and stability issues. Therefore, they are often encapsulated in vesicles with targeting ligands such as antibodies (Ab) to deliver their cargo. Herein, we describe a novel, scalable and straightforward approach to producing functionalized vesicles called the “Functionalized Lipid Insertion Method,” which differs from the older “Detergent-Dialysis Method.” The latter method required excess detergent and extensive dialysis over many hours to produce the functionalized vesicles. With our method, only the functionalized lipid is detergent-solubilized during the engineering of the vesicle. The approach reduces the dialysis time, keeps the vesicles intact while orienting the targeting moieties of the functionalized lipid toward the outside of the vesicle. Pilotin vitroandin vivoexperiments was performed to show the feasibility of our method. Dynamic light scattering (DLS) experiments suggested that the original vesicular structure was relatively unperturbed, and the functionalized lipid was inserted externally. Our approach efficiently delivered oligonucleotides and affected the function of liver cancer HepG2 cells. Furthermore, functionalized vesicles achieved targeted delivery of oligonucleotides in mice without inducing a significant innate immune response. The industrial and therapeutic significance and implications of functionalized vesicles produced by our method are also discussed. Additional experiments and analyses are recommended to bring out the full potential of this molecular delivery technology.
Slow oscillations provide the spatio-temporal framework for long-range neural communication during sleep
Authors: Niknazar Hamid , Malerba Paola , Mednick Sara C. 
Published: October 2021

AbstractSlow oscillations (SOs, <1Hz) during non-rapid eye movement sleep are thought to reflect sleep homeostasis and support memory consolidation. Yet, the fundamental properties of SOs and their impact on neural network communication are not understood. We used effective connectivity to estimate causal information flow across the electrode manifold during SOs and found two peak of information flow in specific phases of the SO. We show causal communication during non-rapid eye movement sleep peaks during specific phases of the SO, but only across long distances. We confirmed this prediction by cluster analysis demonstrating greater flow in global, compared with local, SOs. Finally, we tested the functional significance of these results by examining which SO properties supported overnight episodic memory improvement, with the underlying assumption that memory consolidation would engage global, long-range communication. Indeed, episodic memory improvement was predicted only by the SO properties with greatest causal information flow, i.e., longest distances between sinks and sources and global, but not local, SOs. These findings explain how NREM sleep (characterized as a state of low brain connectivity) leverages SO-induced selective information flow to coordinate a wide network of brain regions during memory formation.
Development and validation of a length- and habitus-based method of ideal and lean body weight estimation for critically ill adults requiring urgent weight-based medical intervention
Authors: Wells Mike , Goldstein Lara , Cattermole Giles 
Published: October 2021

ABSTRACTObjectiveAccurate drug dosing in obese patients requires an estimation of ideal body weight (IBW) or lean body weight (LBW) for dosing hydrophilic medications. Erroneous weight estimates during the management of critically ill adults may contribute to poor outcomes. Existing methods of IBW and LBW estimation or measurement are very difficult to use during emergency care. A new point-of-care model is needed to provide rapid estimates of IBW and LBW for this purpose.MethodsA model was derived based on the PAWPER XL-MAC tape, a paediatric weight estimation system, which uses recumbent length and mid-arm circumference to estimate IBW and LBW. The model was used to generate weight estimations in a derivation sample (n=33155) and a validation sample (n=5926) from National Health and Nutrition Examination Survey (NHANES) datasets. The outcome measure was to achieve >95% of IBW and LBW estimations within 20% of recognised reference standards (P20>95%) and >70% of estimations within 10% of these standards (P10>70%).Main ResultsThe new model achieved a P20 of 100% and a P10 of 99.9% for IBW and a P20 of 98.3% and a P10 of 78.3% for LBW. This accuracy was maintained in both sexes, all ages, all ethnic groups, all lengths and in all habitus-types, except for the morbidly obese female subgroup.ConclusionsThe modified PAWPER XL-MAC model proved to be an accurate method of IBW and LBW estimation. It could, therefore, have an important role in facilitating emergency drug dose calculations in acutely or critically ill obese adult patients.Article summary1)Why is this topic important?Errors in weight estimation, or the use of an inappropriate weight scalar, can translate into medication errors and potential patient harm. The ability to easily estimate TBW, IBW and LBW would enhance patient safety and make correct drug dosing more accessible during the provision of emergency and critical care.2)What does this study attempt to show?This study describes the derivation and validation of a point of care model to provide estimates of IBW and LBW for the purposes of weight based dosing. The model is an adult version of a well-studied paediatric weight estimation system.3)What are the key findings?The model was able to provide accurate estimations of IBW and LBW in a wide range of patient-types. It was the first study to have evaluated such a system. It established that this system would be useful to test in clinical trials.4)How is patient care impacted?The PAWPER XL-MAC system could provide quick and easy estimations of IBW and LBW which can be used in obese patients for appropriate drug dose calculations. This would improve the accuracy of dosing with a potential reduction in medication errors and patient harm.
Causal meditation analysis to understand how different components of a complex psychological intervention improved symptoms (or not) of depression in Goa, India
Authors: Seward Nadine , Vansteelandt Stijn , Moreno-Agostino Darío , Patel Vikram , Araya Ricardo 
Published: October 2021

AbstractBackgroundUnderstanding how and under what circumstances a highly effective psychological intervention, improved symptoms of depression is important to bring this evidence-informed intervention to scale, particularly in resource-poor settings. We aim to estimate the indirect effects of potentially important mediators to improve symptoms of depression in the Healthy Activity Program (HAP) trial.MethodsInterventional in(direct) effects were used to simultaneously decompose the total effect of the intervention on depression symptoms measured through the Patient Health Questionnaire (PHQ-9). The following indirect effects were considered: characteristics of sessions including the number of sessions and homework completed; behavioural activation according to an adapted version of the Behavioural Activation for Depression Short Form (BADS-SF), and extra sessions offered to participants who did not respond to the intervention.ResultsOf the total effect of the intervention measured through the difference in PHQ-9 scores between treatment arms (mean difference: -2.2, 95% bias-corrected CI: -3.2, -0.8), 45% was mediated through improved levels of behavioural activation (−1.0, -1.3, -0.6). There was no evidence to support the mediating role of characteristics of the sessions nor the extra sessions offered to participants who did not respond to the treatment.ConclusionsFindings from our robust mediation analyses, confirmed the importance of behavioural activation in improving depression symptoms. Contrary to published literature, our findings suggest that neither the number of sessions nor proportion of homework completed, improved outcomes. Moreover, results indicate that the extra sessions were insufficient to improve symptoms of depression for participants who did not respond to the intervention.
Increase in preterm stillbirths and reduction in iatrogenic preterm births for fetal compromise: a multi-centre cohort study of COVID-19 lockdown effects in Melbourne, Australia
Authors: Hui Lisa , Marzan Melvin Barrientos , Potenza Stephanie , Rolnik Daniel L. , Pritchard Natasha , Said Joanne M. , Palmer Kirsten R , Whitehead Clare L. , Sheehan Penelope M. , Ford Jolyon , Mol Ben W. , Walker Susan P. 
Published: October 2021

ABSTRACTObjectivesThe COVID-19 pandemic has been associated with a worsening of perinatal outcomes in many settings due to the combined impacts of maternal COVID-19 disease, disruptions to maternity care, and overloaded health systems. In 2020, Melbourne endured a unique natural experiment where strict lockdown conditions were accompanied by very low COVID-19 case numbers and the maintenance of health service capacity. The aim of this study was to compare stillbirth and preterm birth rates in women who were exposed or unexposed to lockdown restrictions during pregnancy.DesignRetrospective multi-centre cohort study of perinatal outcomes before and during COVID-19 lockdownSettingBirth outcomes from all 12 public maternity hospitals in metropolitan MelbourneInclusion criteriaSingleton births without congenital anomalies from 24 weeks’ gestation. The lockdown-exposed cohort were those women for whom weeks 20- 40 of gestation would have occurred during the lockdown period of 23 March 2020 to 14 March 2021. The control cohort comprised all pregnancies in the corresponding periods one and two years prior to the exposed cohort.Main outcome measuresOdds of stillbirth, preterm birth (PTB), birth weight < 3rd centile, and iatrogenic PTB for fetal compromise, adjusting for multiple covariates.ResultsThere were 24,017 births in the exposed and 50,017 births in the control group. There was a significantly higher risk of preterm, but not term, stillbirth in the exposed group compared with the control group (0.26% vs 0.18%, aOR 1.49, 95%CI 1.08 to 2.05, P = 0.015). There was also a significant reduction in preterm birth < 37 weeks (5.93% vs 6.23%, aOR 0.93, 95%CI 0.87 to 0.99, P=0.03), largely mediated by a reduction in iatrogenic PTB for live births (3.01% vs 3.27%, aOR 0.89, 95%CI 0.81 to 0.98, P = 0.015), including iatrogenic PTB for suspected fetal compromise (1.25% vs 1.51%, aOR 0.79, 95%CI 0.69 to 0.91, P= 0.001). There was no significant difference in the spontaneous PTB rate between the exposed and control groups (2.69% vs 2.82%, aOR 0.94, 95%CI 0.86 to 0.1.03, P=0.25).ConclusionsLockdown restrictions in a high-income setting, in the absence of high rates of COVID-19 disease, were associated with a significant increase in preterm stillbirths, and a significant reduction in iatrogenic PTB for suspected fetal compromise.Trial registrationThis study was registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976).
Coordination between metabolic transitions and gene expression by NAD+ availability during adipogenic differentiation in human cells
Authors: Sanchez-Ramírez Edgar , Lien Ung Thi Phuong , del Toro-Rios Ximena , Fajardo-Orduña Guadalupe R. , Noriega Lilia G. , Tovar Armando R. , Montesinos Juan José , Orozco-Solís Ricardo , Stringari Chiara , Aguilar-Arnal Lorena 
Published: October 2021

ABSTRACTAdipocytes are the main cell type in adipose tissue, a critical regulator of metabolism, highly specialized in storing energy as fat. Adipocytes differentiate from multipotent mesenchymal stromal cells through adipogenesis, a tightly controlled differentiation process involving closely interplay between metabolic transitions and sequential programs of gene expression. However, the specific gears driving this interplay remain largely obscure. Additionally, the metabolite nicotinamide adenine dinucleotide (NAD+) is becoming increasingly recognized as a regulator of lipid metabolism, being postulated as promising therapeutic target for dyslipidemia and obesity. Here, we explored the effect of manipulating NAD+ bioavailability during adipogenic differentiation from human mesenchymal stem cells. We found a previously unappreciated strong repressive role for NAD+ on adipocyte commitment, while a functional NAD+-dependent deacetylase SIRT1 appeared crucial for terminal differentiation of pre-adipocytes. Remarkably, repressing the NAD+ biosynthetic salvage pathway during adipogenesis promoted the adipogenic transcriptional program, suggesting that SIRT1 activity during adipogenesis is independent from the NAD+ salvage pathway, while two photon microscopy and extracellular flux analyses suggest that its activation relies on the metabolic switch. Interestingly, SIRT1-directed control of subcellular compartmentalization of redox metabolism during adipogenesis was evidenced by two-photon fluorescence lifetime microscopy.Significance StatementAdipocyte differentiation occurs from mesenchymal stem cells through the adipogenic process, involving sequential activation of both transcriptional and metabolic programs in a tightly coordinated manner. However, how transcriptional and metabolic transitions reciprocally interact during adipogenic differentiation remains largely obscure. Here we describe that the metabolite NAD+ is suppresses adipogenesis trough rewiring transcription, while a functional NAD+-dependent deacetylase SIRT1 is essential for terminal differentiation of pre-adipocytes. Using two-photon fluorescence lifetime microscopy, we created a metabolic map of NADH and lipid content simultaneously in live cells and described a new role for SIRT1 in the control of compartmentalization of redox metabolism during adipogenesis. These findings advance our understanding to improve therapeutical approaches targeting the NAD+-SIRT1 axis as treatment for obesity and dyslipemia.
Direct carbon capture for production of high-performance biodegradable plastic by cyanobacterial cell factory
Authors: Tan Chunlin , Tao Fei , Xu Ping 
Published: October 2021

AbstractPlastic pollution has become one of the most pressing environmental issues today, leading to an urgent need to develop biodegradable plastics1-3. Polylactic acid (PLA) is one of the most promising biodegradable materials because of its potential applications in disposable packaging, agriculture, medicine, and printing filaments for 3D printers4-6. However, current biosynthesis of PLA entirely uses edible biomass as feedstock, which leads to competition for resources between material production and food supply7,8. Meanwhile, excessive emission of CO2 that is the most abundant carbon source aggravates global warming, and climate instability. Herein, we first developed a cyanobacterial cell factory for the de novo biosynthesis of PLA directly from CO2, using a combinational strategy of metabolic engineering and high-density cultivation (HDC). Firstly, the heterologous pathway for PLA production, which involves engineered D-lactic dehydrogenase (LDH), propionate CoA-transferase (PCT), and polyhydroxyalkanoate (PHA) synthase, was introduced into Synechococcus elongatus PCC7942. Subsequently, different metabolic engineering strategies, including pathway debottlenecking, acetyl-CoA self-circulation, and carbon-flux redirection, were systematically applied, resulting in approximately 19-fold increase to 15 mg/g dry cell weight (DCW) PLA compared to the control. In addition, HDC increased cell density by 10-fold. Finally, the PLA titer of 108 mg/L (corresponding to 23 mg/g DCW) was obtained, approximately 270 times higher than that obtained from the initially constructed strain. Moreover, molecular weight (Mw, 62.5 kDa; Mn, 32.8 kDa) of PLA produced by this strategy was among the highest reported levels. This study sheds a bright light on the prospects of plastic production from CO2 using cyanobacterial cell factories.
Pantothenate biosynthesis is critical for chronic infection by the neurotropic parasite Toxoplasma gondii
Authors: Lunghi Matteo , Kloehn Joachim , Krishnan Aarti , Varesio Emmanuel , Vadas Oscar , Soldati-Favre Dominique 
Published: October 2021

AbstractCoenzyme A (CoA) is an essential molecule acting in metabolism, post-translational modification, and regulation of gene expression. While all organisms synthesize CoA, many, including humans, are unable to produce its precursor, pantothenate. Intriguingly, like most plants, fungi and bacteria, parasites of the coccidian subgroup of Apicomplexa, including the human and animal pathogen Toxoplasma gondii, possess all the enzymes required for de novo synthesis of pantothenate. Here, the importance of CoA and pantothenate biosynthesis for the acute and chronic stages of T. gondii infection was dissected through genetic, biochemical and metabolomic approaches, revealing that CoA synthesis is essential for T. gondii tachyzoites, due to the parasite’s inability to salvage CoA or intermediates of the pathway. In contrast, de novo pantothenate synthesis was only partially active in T. gondii tachyzoites, making the parasite reliant on Pan uptake. However, Pan synthesis proved to be crucial for the establishment of chronic infection, offering a promising target for intervention against the persistent stage of T. gondii.
Early diagnosis of Parkinson’s disease: A cross-species biomarker
Authors: Mallet David , Dufourd Thibault , Decourt Mélina , Carcenac Carole , Bossù Paola , Verlin Laure , Fernagut Pierre Olivier , Benoit-Marand Marianne , Spalletta Gianfranco , Barbier Emmanuel L , Carnicella Sebastien , Sgambato Véronique , Fauvelle Florence , Boulet Sabrina 
Published: October 2021

AbstractBackgroundCare management of Parkinson’s disease (PD) patients currently remains symptomatic, especially because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Detecting PD earlier therefore represents a key step for developing therapies able to delay or slow down its progression.MethodsWe investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 2 cohorts of de novo PD patients (n = 95). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics.ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence, and could represent early biomarkers of PD.Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects.ConclusionFrom our translational study which included three animal models and two PD patient cohorts, we propose a promising composite biomarker exhibiting a high level of predictivity for PD diagnosis in its early phase, before motor symptoms appearance.FundingsANR, DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Grenoble Alpes University.
Modular, synthetic chromosomes as new tools for large scale engineering of metabolism
Authors: Postma Eline D. , Hassing Else-Jasmijn , Mangkusaputra Venda , Geelhoed Jordi , de la Torre Pilar , van den Broek Marcel , Mooiman Christiaan , Pabst Martin , Daran Jean-Marc , Daran-Lapujade Pascale 
Published: October 2021

AbstractThe construction of powerful cell factories requires intensive genetic engineering for the addition of new functionalities and the remodeling of native pathways and processes. The present study demonstrates the feasibility of extensive genome reprogramming using modular, specialized de novo-assembled neochromosomes in yeast. The in vivo assembly of linear and circular neochromosomes, carrying 20 native and 21 heterologous genes, enabled the first de novo production in a microbial cell factory of anthocyanins, plant compounds with a broad range pharmacological properties. Turned into exclusive expression platforms for heterologous and essential metabolic routes, the neochromosomes mimic native chromosomes regarding mitotic and genetic stability, copy number, harmlessness for the host and editability by CRISPR/Cas9. This study paves the way for future microbial cell factories with modular genomes in which core metabolic networks, localized on satellite, specialized neochromosomes can be swapped for alternative configurations and serve as landing pads for the addition of functionalities.
TREM2-H157Y Increases Soluble TREM2 Production and Reduces Amyloid Pathology
Authors: Qiao Wenhui , Chen Yixing , Martens Yuka A. , Liu Chia-Chen , Knight Joshua , Li Fuyao , Chen Kai , Aishe Kurti , Shue Francis , Dacquel Maxwell V. , Fryer John , Zhao Na , Bu Guojun 
Published: October 2021

AbstractThe p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) has been reported to increase Alzheimer’s disease (AD) risk. This mutation in the extracellular domain of TREM2 localizes at the cleavage site, leading to enhanced shedding. Here, we generated a novel Trem2 H157Y knock-in mouse model to investigate how this H157Y mutation impacts TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathology. Consistent with previous in vitro findings, TREM2-H157Y increases the amount of soluble TREM2 (sTREM2) in the cortex and serum of mutant mice compared to the wild type controls. Interestingly, the Trem2 H157Y variant enhances synaptic plasticity without affecting microglial density and morphology. In the presence of amyloid pathology, TREM2-H157Y surprisingly accelerates Aβ clearance and reduces amyloid burden and microgliosis. Taken together, our findings support a beneficial effect of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD, we speculate TREM2-H157Y might increase AD risk through an amyloid-independent pathway, as such its effects on tauopathy and neurodegeneration merit further investigation.