bluuebunny/crossref_metadata_2025 huggingface dataset:
Reconstruction of distinct vertebrate gastrulation modes via modulation of key cell behaviours in the chick embryo
Authors: Chuai Manli , Serrano Nájera Guillermo , Serra Mattia , Mahadevan L. , Weijer Cornelis J.
Published: October 2021

The morphology of gastrulation driving the internalisation of the mesoderm and endoderm differs dramatically among vertebrate species. It ranges from involution of epithelial sheets of cells through a circular blastopore in amphibians to ingression of mesenchymal cells through a primitive streak in amniotes. By targeting signalling pathways controlling critical cell behaviours in the chick embryo, we generated crescent- and ring-shaped mesendoderm territories in which cells can or cannot ingress. These alterations subvert the formation of the chick primitive streak into the gastrulation modes seen in amphibians, reptiles and teleost fish. Our experimental manipulations are supported by a theoretical framework linking cellular behaviors to self-organized multi-cellular flows in the accompanying paper. All together, this suggests that the evolution of gastrulation movements are largely determined by the shape of and cell behaviours in the mesendoderm territory across different species, and controlled by a relatively small number of signalling pathways.
Enhancement of hippocampal-thalamocortical temporal coordination during slow-frequency long-duration anterior thalamic spindles
Authors: Alizadeh Zahra , Azimi Amin , Ghorbani Maryam
Published: October 2021

Temporal nesting of cortical slow oscillations (SO), thalamic spindles and hippocampal ripples indicates the succession of regional neuronal interactions required for memory consolidation. However how the thalamic activity during spindles organizes hippocampal dynamics remains largely undetermined. We analyzed simultaneous recordings of anterodorsal thalamus and CA1 in mice to determine the contribution of thalamic spindles in cross-regional synchronization. Our results indicated that temporal hippocampo-thalamocortical coupling were more enhanced during slower and longer thalamic spindles. Additionally, spindles occurring closer to SO trough were more strongly coupled to ripples. We found that the temporal association between CA1 spiking/ripples and thalamic spindles was stronger following spatial exploration compared to baseline sleep. We further developed a hippocampal-thalamocortical model to explain the mechanism underlying the duration and frequency-dependent coupling of thalamic spindles to hippocampal activity. Our findings shed light on our understanding of the functional role of thalamic activity during spindles on multi-regional information transfer.
The cerebellum contributes to tonic-clonic seizures by altering neuronal activity in the ventral posteromedial nucleus (VPM) of the thalamus
Authors: Beckinghausen Jaclyn , Ortiz-Guzman Joshua , Lin Tao , Bachman Benjamin , Liu Yu , Heck Detlef H. , Arenkiel Benjamin R. , Sillitoe Roy V.
Published: October 2021

Thalamo-cortical networks are central to seizures, yet it’s unclear how these circuits initiate the seizures. Here, we test the hypothesis that a facial region of the thalamus, the VPM, is a source of convulsive, tonic-clonic seizures. We devised an in vivo optogenetic mouse model to elicit tonic-clonic seizures by driving convergent input to the VPM. With viral tracing, we show dense cerebellar and cerebral cortical afferent input to the VPM. Lidocaine microinfusions into the cerebellar nuclei selectively block seizure initiation. We perform single-unit electrophysiology recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find highly dynamic activity with biphasic properties, raising the possibility that heterogenous activity patterns promote seizures. These data reveal the VPM as a source of tonic-clonic seizures, with cerebellar input providing the predominant signals.
The first transchromosomic rat model with human chromosome 21 shows robust Down syndrome features
Authors: Kazuki Yasuhiro , Gao Feng J. , Yamakawa Miho , Hirabayashi Masumi , Kazuki Kanako , Kajitani Naoyo , Miyagawa-Tomita Sachiko , Abe Satoshi , Sanbo Makoto , Hara Hiromasa , Kuniishi Hiroshi , Ichisaka Satoshi , Hata Yoshio , Koshima Moeka , Takayama Haruka , Takehara Shoko , Nakayama Yuji , Hiratsuka Masaharu , Iida Yuich , Matsukura Satoko , Noda Naohiro , Li Yicong , Moyer Anna J. , Cheng Bei , Singh Nandini , Richtsmeier Joan T. , Oshimura Mitsuo , Reeves Roger H.
Published: October 2021

Progress in earlier detection and symptom management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available due to technical challenges. We developed the first transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein coding genes. RNA-Seq of neonatal forebrains demonstrates that TcHSA21rat not only expresses HSA21 genes but also has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a “Down syndrome karyotype” in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, a prominent feature of DS that is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.
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

Many 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

Nano-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

Slow 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

Objective

Accurate 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.

Methods

A 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 Results

The 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.

Conclusions

The 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 summary

1)

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

Background

Understanding 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.

Methods

Interventional 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.

Results

Of 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.

Conclusions

Findings 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

Objectives

The 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.

Design

Retrospective multi-centre cohort study of perinatal outcomes before and during COVID-19 lockdown

Setting

Birth outcomes from all 12 public maternity hospitals in metropolitan Melbourne

Inclusion criteria

Singleton 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 measures

Odds of stillbirth, preterm birth (PTB), birth weight < 3rd centile, and iatrogenic PTB for fetal compromise, adjusting for multiple covariates.

Results

There 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).

Conclusions

Lockdown 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 registration

This 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

Adipocytes 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 Statement

Adipocyte 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

Plastic 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.
Intriguing Role of Water in Plant Hormone Perception
Authors: Zhao Chuankai , Kleiman Diego E. , Shukla Diwakar
Published: October 2021

Plant hormones are small molecules that regulate plant growth, development, and responses to biotic and abiotic stresses. Plant hormones are specifically recognized by the binding site of their receptors. In this work, we investigated the role of water displacement and reorganization at the binding site of plant receptors on the binding of eight classes of phytohormones (auxin, jasmonate, gibberellin, strigolactone, brassinosteroid, cytokinin, salicylic acid, and abscisic acid) using extensive molecular dynamics simulations and inhomogeneous solvation theory. Our findings demonstrated that displacement of water molecules by phytohormones contributes to free energy of binding via entropy gain and is associated with free energy barriers. Also, our results have shown that displacement of unfavorable water molecules in the binding site can be exploited in rational agrochemical design. Overall, this study uncovers the role of water molecules in plant hormone perception, which creates new avenues for agrochemical design to target plant growth and development.
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

Coenzyme 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.
Efficient inference for agent-based models of real-world phenomena
Authors: Jørgensen Andreas Christ Sølvsten , Ghosh Atiyo , Sturrock Marc , Shahrezaei Vahid
Published: October 2021

The modelling of many real-world problems relies on computationally heavy simulations. Since statistical inference rests on repeated simulations to sample the parameter space, the high computational expense of these simulations can become a stumbling block. In this paper, we compare two ways to mitigate this issue based on machine learning methods. One approach is to construct lightweight surrogate models to substitute the simulations used in inference. Alternatively, one might altogether circumnavigate the need for Bayesian sampling schemes and directly estimate the posterior distribution. We focus on stochastic simulations that track autonomous agents and present two case studies of real-world applications: tumour growths and the spread of infectious diseases. We demonstrate that good accuracy in inference can be achieved with a relatively small number of simulations, making our machine learning approaches orders of magnitude faster than classical simulation-based methods that rely on sampling the parameter space. However, we find that while some methods generally produce more robust results than others, no algorithm offers a one-size-fits-all solution when attempting to infer model parameters from observations. Instead, one must choose the inference technique with the specific real-world application in mind. The stochastic nature of the considered real-world phenomena poses an additional challenge that can become insurmountable for some approaches. Overall, we find machine learning approaches that create direct inference machines to be promising for real-world applications. We present our findings as general guidelines for modelling practitioners.
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

Background

Care 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.

Methods

We 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.

Results

Our 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.

Conclusion

From 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.

Fundings

ANR, 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

The 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

The 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.
Protein complex prediction with AlphaFold-Multimer
Authors: Evans Richard , O’Neill Michael , Pritzel Alexander , Antropova Natasha , Senior Andrew , Green Tim , Žídek Augustin , Bates Russ , Blackwell Sam , Yim Jason , Ronneberger Olaf , Bodenstein Sebastian , Zielinski Michal , Bridgland Alex , Potapenko Anna , Cowie Andrew , Tunyasuvunakool Kathryn , Jain Rishub , Clancy Ellen , Kohli Pushmeet , Jumper John , Hassabis Demis
Published: October 2021

While the vast majority of well-structured single protein chains can now be predicted to high accuracy due to the recent AlphaFold [1] model, the prediction of multi-chain protein complexes remains a challenge in many cases. In this work, we demonstrate that an AlphaFold model trained specifically for multimeric inputs of known stoichiometry, which we call AlphaFold-Multimer, significantly increases accuracy of predicted multimeric interfaces over input-adapted single-chain AlphaFold while maintaining high intra-chain accuracy. On a benchmark dataset of 17 heterodimer proteins without templates (introduced in [2]) we achieve at least medium accuracy (DockQ [3] ≥ 0.49) on 13 targets and high accuracy (DockQ ≥ 0.8) on 7 targets, compared to 9 targets of at least medium accuracy and 4 of high accuracy for the previous state of the art system (an AlphaFold-based system from [2]). We also predict structures for a large dataset of 4,446 recent protein complexes, from which we score all non-redundant interfaces with low template identity. For heteromeric interfaces we successfully predict the interface (DockQ ≥ 0.23) in 70% of cases, and produce high accuracy predictions (DockQ ≥ 0.8) in 26% of cases, an improvement of +27 and +14 percentage points over the flexible linker modification of AlphaFold [4] respectively. For homomeric inter-faces we successfully predict the interface in 72% of cases, and produce high accuracy predictions in 36% of cases, an improvement of +8 and +7 percentage points respectively.
Olfactory-driven beta band entrainment of limbic circuitry during neonatal development
Authors: Kostka Johanna K. , Hanganu-Opatz Ileana L.
Published: October 2021

Cognitive processing relies on the functional refinement of the limbic circuitry during the first two weeks of life. During this developmental period, when most sensory systems are still immature, the sense of olfaction acts as “door to the world”, providing the main source of environmental inputs. However, it is unknown whether early olfactory processing shapes the activity in the limbic circuitry during neonatal development. Here, we address this question by combining simultaneous in vivo recordings from the olfactory bulb (OB), lateral entorhinal cortex (LEC), hippocampus (HP), and prefrontal cortex (PFC) with olfactory stimulation as well as opto- and chemogenetic manipulations of mitral/tufted cells (M/TCs) in the OB of non-anesthetized neonatal mice. We show that the neonatal OB synchronizes the limbic circuity in the beta frequency range. Moreover, it drives neuronal and network activity in LEC, as well as subsequently, HP and PFC via long-range projections from mitral cells (MCs) to HP-projecting LEC neurons. Thus, OB activity shapes the communications within limbic circuits during neonatal development.
Amplitude discrimination is predictably affected by echo frequency filtering in wideband echolocating bats
Authors: Tuninetti Amaro , Simmons Andrea Megela , Simmons James A.
Published: October 2021

Big brown bats emit wideband frequency modulated (FM) ultrasonic pulses for echolocation. They perceive target range from echo delay and target size from echo amplitude. Their sounds contain two prominent down-sweeping harmonic sweeps (FM1, ∼55-22 kHz; FM2, ∼100-55 kHz), which are affected differently by propagation out to the target and back to the bat. FM2 is attenuated more than FM1 during propagation. Bats anchor target ranging asymmetrically on the low frequencies in FM1, while FM2 only contributes if FM1 is present as well. These experiments tested whether the bat’s ability to discriminate target size from the amplitude of echoes is affected by selectively attenuating upper or lower frequencies. Bats were trained to perform an echo amplitude discrimination task with virtual echo targets 83 cm away. While echo delay was held constant and echo amplitude was varied to estimate threshold, either lower FM1 frequencies or higher FM2 frequencies were attenuated. The results parallel effects seen in echo delay experiments; bats’ performance was significantly poorer when the lower frequencies in echoes were attenuated, compared to higher frequencies. The bat’s ability to distinguish between virtual targets at the same simulated range from echoes arriving at the same delay indicates a high level of focused attention for perceptual isolation of one and suppression of the other.
Weight Perturbation Learning Performs Similarly or Better than Node Perturbation on Broad Classes of Temporally Extended Tasks
Authors: Züge Paul , Klos Christian , Memmesheimer Raoul-Martin
Published: October 2021

Biological constraints often impose restrictions for plausible plasticity rules such as locality and reward-based rather than supervised learning. Two learning rules that comply with these restrictions are weight (WP) and node (NP) perturbation. NP is often used in learning studies, in particular as a benchmark; it is considered to be superior to WP and more likely neurobiologically realized, as the number of weights and therefore their perturbation dimension typically massively exceeds the number of nodes. Here we show that this conclusion no longer holds when we take two biologically relevant properties into account: First, tasks extend in time. This increases the perturbation dimension of NP but not WP. Second, tasks are low dimensional, with many weight configurations providing solutions. We analytically delineate regimes where these properties let WP perform as well as or better than NP. Furthermore we find that the changes in weight space directions that are irrelevant for the task differ qualitatively between WP and NP and that only in WP gathering batches of subtasks in a trial decreases the number of trials required. This may allow to experimentally distinguish which of the two rules underlies a learning process. Our insights suggest new learning rules, which combine for specific task types the advantages of WP and NP. If the inputs are similarly correlated, temporally correlated perturbations improve NP. Using numerical simulations, we generalize the results to networks with various architectures solving biologically relevant and standard network learning tasks. Our findings, together with WP’s practicability suggest WP as a useful benchmark and plausible model for learning in the brain.
REV7/FANCV Binds to CHAMP1 and Promotes Homologous Recombination Repair
Authors: Li Feng , Sarangi Prabha , Feng Hanrong , Moreau Lisa , Nguyen Huy , Clairmont Connor , D’Andrea Alan D.
Published: October 2021

A critical determinant of DNA repair pathway choice is the HORMA protein REV7, a small abundant adaptor which binds to various DNA repair proteins through its C-terminal seatbelt domain. The REV7 seatbelt binds to the REV3 polymerase to form the Polymerase ζ complex, a positive regulator of translesion synthesis (TLS) repair. Alternatively, the REV7 seatbelt binds to SHLD3 in the Shieldin complex, a positive regulator of NHEJ repair. Recent studies have identified another novel REV7 seatbelt-binding protein, CHAMP1 (Chromosome Alignment-Maintaining Phosphoprotein, though its role in DNA repair is unknown. Here, we show that the REV7-CHAMP1 complex promotes homologous recombination (HR) repair by sequestering REV7 from the Shieldin complex. CHAMP1 competes directly with the SHLD3 subunit of the Shieldin complex for a limited pool of C-REV7, thereby inhibiting the REV7-mediated recruitment of the SHLD2 and SHLD1 effector subunits to DNA double strand breaks. CHAMP1 thereby channels DNA repair away from error-prone NHEJ and towards the competing error-free HR pathway. Similarly, CHAMP1 competes with the REV3 component of the POLζ complex, thereby reducing the level of mutagenic TLS repair. CHAMP1 interacts with POGZ in a heterochromatin complex further promoting HR repair. Importantly, in human tumors, CHAMP1 overexpression promotes HR, confers PARP inhibitor resistance, and correlates with poor prognosis. Thus, by binding to either REV3, SHLD3, or CHAMP1 through its seatbelt, the REV7 protein can promote either TLS repair, NHEJ repair, or HR repair respectively.
Fluorescence Activation Mechanism and Imaging of Drug Permeation with New Sensors for Smoking-Cessation Ligands
Authors: Nichols Aaron L. , Blumenfeld Zack , Fan Chengcheng , Luebbert Laura , Blom Annet E. M. , Cohen Bruce N. , Marvin Jonathan S. , Borden Philip M. , Kim Charlene H. , Muthusamy Anand K. , Shivange Amol V. , Knox Hailey J. , Campello Hugo Rego , Wang Jonathan H. , Dougherty Dennis A. , Looger Loren L. , Gallagher Timothy , Rees Douglas C. , Lester Henry A.
Published: October 2021

Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug sensing fluorescent reporters (“iDrugSnFRs”) for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives – 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by > 30 fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.
Defining Moults in Migratory Birds: A Sequence-based Approach
Authors: Pyle Peter
Published: October 2021

Two broad nomenclatures have emerged to describe moult strategies in birds, the “life-cycle” system which describes moults relative to present-day breeding and other life-history events and the Humphrey-Parkes (H-P) system which reflects the evolution of moults along ancestral lineages. Using either system, challenges have arisen defining strategies in migratory species with more than one moult per year. When all or part of two moults occur in non-breeding areas they may fail to be recognized as two moults or have been discriminated temporally, whether feathers are replaced in fall, winter, or spring. But in some cases feather replacement can span the non-breeding period, and this has resulted in an inability to identify inserted moults and to compare moult strategies between species. Furthermore, recent analyses on factors influencing the extent of the postjuvenile or preformative moults have either confined this moult to the summer grounds or presumed that it can be suspended and resumed on winter grounds, which has lead to quite divergent results. Evolutionarily, the timing, extent, and location of moults are very plastic whereas the sequence in which feathers are replaced is comparatively fixed. As, such, I propose taking an evolutionary approach to define moults on the basis of feather-replacement sequences as opposed to timing or location of replacement, including strategies in which moults can overlap temporally. I provide examples illustrating the functionality of a sequence-based definition in three migratory North American passerines that can undergo feather replacement twice in non breeding areas, and I demonstrate how this system can effectively apply to moults in many other passerine and non-passerine species. I recommend that authors studying the evolutionary drivers of moult strategies in migratory birds adopt a sequence-based approach or carefully consider replacement strategies both prior to and following autumn migration.
Population ecology of seabirds in Mexican Islands at the California Current System
Authors: Sánchez Federico Méndez , Guzmán Yuliana Bedolla , Mayoral Evaristo Rojas , Aguirre-Muñoz Alfonso , Koleff Patricia , Vargas Alejandro Aguilar , Santana Fernando Álvarez , Arnaud Gustavo , Ornelas Alicia Aztorga , Beltrán Morales Luis Felipe , Yáñez Maritza Bello , García Humberto Berlanga , Hernández Esmeralda Bravo , Tapia Ana Cárdenas , Vera Aradit Castellanos , Sauceda Miguel Corrales , Canizales Ariana Duarte , Blanco Alejandra Fabila , Lizárraga María Félix , Robledo Anely Fernández , Montoya Julio Hernández , Ríos Alfonso Hernández , Elías Eduardo Iñigo , Rosas Ángel Méndez , Mayoral Braulio Rojas , Carlos Fernando Solís , Ortega-Rubio Alfredo
Published: October 2021

The Baja California Pacific Islands (BCPI) is a seabird hotspot in the southern California Current System supporting 129 seabird breeding populations of 23 species and over one million birds annually. These islands had a history of environmental degradation because of invasive alien species, human disturbance, and contaminants that caused the extirpation of 27 seabird populations. Most of the invasive mammals have been eradicated and breeding colonies have been restored with social attraction techniques. We have systematic information for most of the breeding populations since 2008. To assess population trends, we analyzed data and present results for 19 seabird species on ten island groups. The maximum number of breeding pairs for each nesting season was used to estimate the population growth rate (λ) for each species at every island colony. We performed a nonparametric bootstrapping to assess whether seabird breeding populations are increasing or decreasing. San Benito, Natividad, and San Jerónimo are the top three islands in terms of abundance of breeding pairs. The most widespread species is Cassin’s Auklet with 14 colonies. Twenty-three populations of 13 species are significantly increasing while eight populations of six species are decreasing. We did not find statistical significance for 30 populations, however, 20 have λ>1 which suggest they are growing. Seven of the 18 species for which we estimated a regional population trend are significantly increasing, including three surface-nesting species: Brown Pelican, Elegant Tern and Laysan Albatross, and four burrow-nesting species: Ainley’s and Ashy Storm-Petrels, and Craveri’s and Guadalupe Murrelet. Our results suggest that the BCPI support healthy and growing populations of seabirds that have shown to be resilient to extreme environmental conditions such as the “Blob”, and that such resilience has been strengthen from conservation and restoration actions such as the eradication of invasive mammals and social attraction techniques.