bluuebunny/crossref_metadata_2025 huggingface dataset:
Marginal ice zone dynamics: future research perspectives and pathways
Authors: Bennetts L. G. , Bitz C. M. , Feltham D. L. , Kohout A. L. , Meylan M. H.
Published: September 2022

Perspectives are discussed on future directions for the field of marginal ice zone (MIZ) dynamics, based on the extraordinary progress made over the past decade in its theory, modelling and observations. Research themes are proposed that would shift the field’s focus towards the broader implications of MIZ dynamics in the climate system. In particular, pathways are recommended for research that highlights the impacts of trends in the MIZ on the responses of Arctic and Antarctic sea ice to climate change.

This article is part of the theme issue ‘Theory, modelling and observations of marginal ice zone dynamics: multidisciplinary perspectives and outlooks’.
LEAF- 4L6715 enhances oxygenation in patients with acute respiratory distress syndrome (ARDS) due to severe COVID-19: Final results of a phase I/II clinical trial
Authors: Mertes Paul-Michel , Delabranche Xavier , Coliat Pierre , Roche Anne , Collange Olivier , Voegelin Manon , Bernard Alexandre , Dhindsa Navreet , Xu Zhenghong Hannah , Geng Bolin , Niyikiza Clet , Moyo Victor , Bourban Claire , Villa Pascal , Detappe Alexandre , Pivot Xavier
Published: September 2022

LEAF-4L6715 is a liposomal formulation encapsulating transcrocetin (TC) developed to enhance the diffusion of oxygen in the body. Here, we report the final results of the phase I/II clinical trial (NCT04378920; EUDRACT2020–001393–30) initiated to identify an optimal regimen and to assess the activity of TC in the context of acute respiratory distress syndrome (ARDS). More specifically, LEAF-4L6715 was developed to treat patients with ARDS due to severe SARS-CoV-2 infection who have a ratio of partial arterial pressure to inspired fraction of oxygen (PaO2/FiO2 ratio) <200 treated with artificial ventilation support in an intensive care unit.

A total of 37 patients were treated (across 6 dosing cohorts) with LEAF-4L6715 given as an intravenous infusion for over 90 minutes. The dose of LEAF-4L6715 was increased until the transaminase levels were elevated and 4 grade 3 events occurred among 8 patients. The recommended dosage was determined to be a fixed concentration of 300 mg administered every 12 hours. An improvement in the PaO2/FiO2 ratio and SOFA score was observed. The overall 28-day survival rate of 81%.

This study identified the recommended dose for LEAF 4L6715 and the dose-limiting toxicity and showed an overall favorable risk/benefit profile. These preliminary findings are promising for the activity of LEAF-4L6715 but will require confirmation in a randomized phase III trial.
Comparison of visual quantities in untrained deep neural networks
Authors: Lee Hyeonsu , Choi Woochul , Lee Dongil , Paik Se-Bum
Published: September 2022

The ability to compare quantities of visual objects with two distinct measures, proportion and difference, is observed in newborn animals. Nevertheless, how this function originates in the brain, even before training, remains unknown. Here, we show that neuronal tuning for quantity comparison can arise spontaneously in completely untrained deep neural networks. Using a biologically inspired model neural network, we found that units selective to proportions and differences between visual quantities emerge in randomly initialized networks and that they enable the network to perform quantity comparison tasks. Further analysis shows that two distinct tunings to proportion and difference both originate from a random summation of monotonic, nonlinear responses to changes in relative quantities. Notably, we found that a slight difference in the nonlinearity profile determines the type of measure. Our results suggest that visual quantity comparisons are primitive types of functions that can emerge spontaneously in random feedforward networks.

One sentence summary

The ability to compare visual quantities arises spontaneously in untrained deep neural networks.

Research Highlights

The ability to compare visual quantity arises spontaneously in untrained networks

Distinct tunings to measure proportion and difference of quantities are observed

Random wiring of monotonic, nonlinear activity induces quantity-comparison units

The nonlinearity pattern of the source unit determines the type of target measure
Neuronal mitochondrial morphology is significantly affected by both fixative and oxygen level during perfusion
Authors: Kim Su Yeon , Strucinska Klaudia , Osei Bertha , Han Kihoon , Kwon Seok-Kyu , Lewis Tommy L.
Published: September 2022

Neurons in the brain have a uniquely polarized structure consisting of multiple dendrites and a single axon generated from a cell body. Interestingly, intracellular mitochondria also show strikingly polarized morphologies along the dendrites and axons: in cortical pyramidal neurons (PNs) dendritic mitochondria have a long and tubular shape, while axonal mitochondria are small and circular. Mitochondria play important roles in each compartment of the neuron by generating ATP and buffering calcium, thereby affecting synaptic transmission and neuronal development. In addition, mitochondrial shape, and thereby function, is dynamically altered by environmental stresses such as oxidative stress, or in various neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Although the importance of altered mitochondrial shape has been claimed by multiple studies, methods for studying this stress-sensitive organelle have not been standardized. Here we address the pertinent steps that influence mitochondrial morphology during experimental processes. We demonstrate that fixative solutions containing only paraformaldehyde (PFA), or that introduce hypoxic conditions during the procedure induce dramatic fragmentation of mitochondria both in vitro and in vivo. This disruption was not observed following the use of glutaraldehyde addition or oxygen supplementation, respectively. Finally, using pre-formed fibril α-synuclein treated neurons, we show a difference between mitochondrial morphology when samples were fixed with PFA/glutaraldehyde or PFA/sucrose containing solutions, but not PFA alone. Our study provides optimized methods for examining mitochondrial morphology in neurons, and demonstrates that fixation conditions are critical when investigating the underlying cellular mechanisms involving mitochondria in physiological and neurodegenerative disease models.
Olfactory responses of Drosophila suzukii parasitoids to chemical cues from SWD-infested fruit
Authors: Triñanes F. , González A. , de la Vega G. J.
Published: September 2022

Since Drosophila suzukii (Diptera: Drosophilidae; SWD) became a worldwide pest of soft-skinned fruits, multiple mitigation strategies alternative to insecticides have been explored. Among these, the search for biological control agents has prompted the assessment of drosophilid parasitoids for SWD control. Olfactometer bioassays with drosophilid parasitoids have shown that host substrate-related complex olfactory cues are relevant during host search. No information is available, however, on which fruit volatiles may be used as host-related cues. Here, we used gas chromatography coupled to electroantennography (GC-EAD) to evaluate the antennal detection of ecologically relevant fruit odours by two drosophillid parasitoids, Leptopilina boulardi (Hymenoptera: Figitidae) and Trichopria anastrephae (Hymenoptera: Diapriidae). We found that females of both wasp species are capable of detecting the main volatile compounds emitted by SWD-infested strawberries, five and ten days after oviposition by SWD females. The EAD-active fruit compounds were identified by GC-MS analysis as the common fruit esters ethyl butanoate, methyl hexanoate and ethyl hexanoate. The relative proportions of these fruit esters vary over time, with potential ecological significant for larval and pupal parasitoids. Our study is the first to report GC-EAD responses of microhymenopteran wasps of drosophilid flies. Understanding the sensory ecology of host-related chemical cues may be useful to optimize the biological control of D. suzukii by parasitoid wasps.
Assessing the risk stratification of breast cancer polygenic risk scores in two Brazilian samples
Authors: Barreiro R.A.S , Almeida TF , Gomes CS , Monfardini F , Farias AA , Tunes GC , Souza GM , Duim E , Correia JS , Coelho AVC , Caraciolo MP , Duarte YAO , Zatz M , Amaro E , Oliveira JB , Bitarello BD , Brentani H , Naslavsky MS
Published: September 2022

Polygenic risk scores (PRS) for breast cancer (BC) have a clear clinical utility in risk prediction. PRS transferability across populations and ancestry groups is hampered by population-specific factors, ultimately leading to differences in variant effects, such as linkage disequilibrium (LD) and differences in variant frequency (AF-diff). Thus, locally-sourced population-based phenotypic and genomic datasets are essential to assess the validity of PRS derived from signals detected across populations. Here, assess the transferability of a BC PRS composed of 313 risk variants (313-PRS) in two Brazilian tri-hybrid admixed ancestries (European, African and Native American) whole-genome sequenced cohorts. We computed 313-PRS in both cohorts (n=753 and n=853) versus the UK Biobank (UKBB, n=264,307) as reference. We show that although the Brazilian cohorts have a high European (EA) component, with AF-diff and to a lesser extent LD patterns like those found in EA populations, the 313-PRS distribution is inflated when compared to that of the UKBB, leading to potential overestimation of PRS-based risk if EA is taken as a standard. Interestingly, we find that case-controls lead to equivalent predictive power when compared to UKBB-EA samples with AUROC values of 0.66-0.62 compared to 0.63 for UKBB.
Decomposing Interaction and Mediating Effects of Race/Ethnicity and Circulating Cystatin C on Cognitive Status in the United States Health and Retirement Study
Authors: Higgins Cesar , Ware Erin B. , Kobayashi Lindsay C. , Fu Mingzhou , Hicken Margaret , Zawistowski Matthew , Mukherjee Bhramar , Bakulski Kelly M.
Published: September 2022

Background and objectives

Elevated circulating cystatin C is associated with cognitive impairment in non-Hispanic Whites, but its role in racial disparities in dementia is understudied. In a nationally representative sample of older non-Hispanic White, non-Hispanic Black, and Hispanic adults in the United States, we use mediation-interaction analysis to understand how racial disparities in the cystatin C physiological pathway may contribute to racial disparities in prevalent dementia.

Methods

In a pooled cross-sectional sample of the Health and Retirement Study (n=9,921), we employed Poisson regression to estimate prevalence ratios and to test the relationship between elevated cystatin C (>1.24mg/L versus <1.24mg/L) and impaired cognition, adjusted for demographics, behavioral risk factors, and other biomarkers. Self-reported racialized social categories were a proxy measure for exposure to racism. We calculated additive interaction measures and conducted four-way mediation-interaction decomposition analysis to test the moderating effect of race/ethnicity and mediating effect of cystatin C on the racial disparity.

Results

Overall, elevated cystatin C was associated with dementia (prevalence ratio [PR] = 1.4; 95%CI: 1.2, 1.8). Among non-Hispanic Black relative to non-Hispanic White participants, the relative excess risk due to interaction was 1.7 (95% CI: -0.2, 3.7), the attributable proportion was 0.2 (95%CI: 0.0, 0.5), and the synergy index was 1.4 (95% CI: 1.0, 2.0) in a fully-adjusted model. Elevated cystatin C was estimated to account for 2% (95% CI: -0%, 4%) for the racial disparity in prevalent dementia, and the interaction accounted for 9% (95% CI: -4%, 23%). Analyses for Hispanic relative to non-White participants suggested moderation by race/ethnicity, but not mediation.

Discussion

Elevated cystatin C was associated with dementia prevalence. Our mediation-interaction decomposition analysis suggested that the effect of elevated cystatin C on the racial disparity might be moderated by race/ethnicity, which indicates that the racialization process affects not only the distribution of circulating cystatin C across minoritized racial groups, but also the strength of association between the biomarker and dementia prevalence. These results provide evidence that cystatin C is associated with adverse brain health and this effect is larger than expected for individuals racialized as minorities had they been racialized and treated as non-Hispanic White.
Developmental role of macrophages modelled in human pluripotent stem cell derived intestinal tissue
Authors: Song Andrew T. , Sindeaux Renata H. M. , Li Yuanyi , Affia Hicham , Agnihotri Tapan , Leclerc Severine , van Vliet Patrick Piet , Colas Mathieu , Guimond Jean-Victor , Patey Natasha , Joyal Jean-Sebastien , Haddad Elie , Barreiro Luis , Andelfinger Gregor
Published: September 2022

Macrophages populate the embryo early in gestation but their role in the developmental process remains largely unknown. In particular, specification and function of macrophages in intestinal development remain unexplored. To study this event in human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrated into the organoid, proliferated, and occupied the emerging micro-anatomical niches of epithelial crypts and ganglia. They also acquired a similar transcriptomic profile to fetal intestinal macrophages and displayed tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to regulation of metabolism and growth of the developing intestine.
Examining Litter Specific Variability in Mice and its Impact on Neurodevelopmental Studies
Authors: Valiquette Vanessa , Guma Elisa , Cupo Lani , Gallino Daniel , Anastassiadis Chloe , Snook Emily , Devenyi Gabriel A. , Chakravarty M. Mallar
Published: September 2022

Our current understanding of litter variability in neurodevelopmental studies using mouse may limit translation of neuroscientific findings. Higher variance of measures across litters than within, often termed intra-litter likeness, may be attributable to pre- and postnatal environment. This study aimed to assess the litter-effect within behavioral assessments (2 timepoints), and anatomy using T1-weighted magnetic resonance images (4 timepoints) across 72 brain region volumes (36 C57bl/6J inbred mice; 7 litters: 19F/17M). Between-litter comparisons of brain and behavioral measures and their associations were evaluated using univariate and multivariate techniques. A power analysis using simulation methods was then performed modeling neurodevelopment and evaluating trade-offs between number-of-litters, mice-per-litter, and sample size. Our results show litter-specific developmental effects, from the adolescent period to adulthood for brain structure volumes and behaviors, and their associations in adulthood. Our power simulation analysis results suggest increasing the number-of-litters in experimental design to achieve the smallest total sample size for detecting different rates of change in specific brain regions. Our results also demonstrate how litter-specific effects may influence development and that increasing the litters to the total sample size ratio should be strongly considered when designing neurodevelopmental studies.
Contractile ring mechanosensation and its anillin-dependent tuning during early embryogenesis
Authors: Hsu Christina Rou , Sangha Gaganpreet , Fan Wayne , Zheng Joey , Sugioka Kenji
Published: September 2022

The contractile ring plays crucial roles in animal morphogenesis. Previous studies have explored how tissue mechanics controls the contractile ring; however, the mechanisms by which the ring senses tissue mechanics remain largely unknown. Here, we demonstrate the mechanism of contractile ring mechanosensation and its tuning during asymmetric ring closure ofCaenorhabditis elegansembryos. High-resolution imaging of cortical flow revealed that local suppression of the ring-directed cortical flow is associated with a delay in furrowing. This suppression of cortical flow results from cortical compression. We found that the artificial inhibition of ring-directed cortical flow was sufficient to induce asymmetric ring closure in symmetrically dividing cells. Moreover, genetic analysis suggests that the positive feedback loop among ring-directed cortical flow, myosin enrichment, and ring constriction constitutes the anillin-dependent, mechanosensitive engine driving asymmetric ring closure. Our results suggest that the balance between RhoA-dependent and cortical flow-dependent myosin enrichment fine-tunes the ring’s mechanosensitivity in tissues.
Extensive Soma-Soma Plate-Like Contact Sites (Ephapses) Connect Suprachiasmatic Nucleus Neurons
Authors: Czeisler Mark É. , Shan Yongli , Schalek Richard , Berger Daniel R. , Suissa-Peleg Adi , Takahashi Joseph S. , Lichtman Jeff W.
Published: September 2022

Abstract

The hypothalamic suprachiasmatic nucleus (SCN) is the central pacemaker for mammalian circadian rhythms. As such, this ensemble of cell-autonomous neuronal oscillators with divergent periods must maintain coordinated oscillations. To investigate ultrastructural features enabling such synchronization, 805 coronal ultrathin sections of mouse SCN tissue were imaged with electron microscopy and aligned into a volumetric stack, from which selected neurons within the SCN core were reconstructed in silica. We found that clustered SCN core neurons were physically connected to each other via multiple large soma-to-soma plate-like contacts. In some cases, a sliver of a glial process was interleaved. These contacts were large, covering on average ∼21% of apposing neuronal somata. It is possible that contacts may be the electrophysiological substrate for synchronization between SCN neurons. Such plate-like contacts may explain why synchronization of SCN neurons is maintained even when chemical synaptic transmission or electrical synaptic transmission via gap junctions is blocked. Such ephaptic contact-mediated synchronization among nearby neurons may therefore underlie the wave-like oscillations of circadian core clock genes and calcium signals observed in the SCN.

Significance

Three-dimensional reconstruction of SCN tissue via serial electron microscopy revealed a novel structural feature of SCN neurons that may account for inter-neuronal synchronization that persists even when usual mechanisms of neuronal communication are blocked. We found that SCN core neurons are connected by multiple soma-soma contact specializations, ultrastructural elements that could enable synchronization of tightly packed neurons organized in clustered networks. This extensive network of plate-like soma-soma contacts among clustered SCN neurons may provide insight into how ∼20,000 autonomous neuronal oscillators with a broad range of intrinsic periods remain synchronized in the absence of ordinary communication modalities, thereby conferring the resilience required for the SCN to function as the mammalian circadian pacemaker.
Spread the word about freshwater mussels’ conservation: Increasing awareness and willingness to support conservation-oriented policies through social media
Authors: Ferreira-Rodríguez Noé
Published: September 2022

Research on social media users has examined the immediate effects of popular social networking sites on vote intention, but studies have not to the potential use of these sites in conservation programs. By conducting an online survey, which included a short-term Before-After-Control-Impact experiment, the author noted an overall increase in respondents’ ecological knowledge after exposure to a dissemination campaign. More importantly, exposure to information through social media affected peoples’ willingness to change their vote intention to support conservation-oriented policies. The current study results suggest that key stakeholders in biodiversity conservation (i.e., researchers, managers, and conservationists) adopting an active role to increase biodiversity valuation may lead to a new form of ecological knowledge acquisition in modern societies.
Attenuation of neural responses in subthalamic nucleus during internally guided voluntary movements in Parkinson’s disease
Authors: Filyushkina Veronika , Belova Elena , Usova Svetlana , Tomskiy Alexey , Sedov Alexey
Published: September 2022

The proposed models of segregated functional loops describe the organization of motor control over externally triggered (ET) and internally guided (IG) movements. The dopamine deficiency in Parkinson’s disease (PD) is considered to cause a disturbance in the functional loop regulating IG movements. At the same time, the neural mechanisms of movement performance and the role of basal ganglia in motor control remains unclear.

The aim of this study was to compare neuronal responses in subthalamic nucleus (STN) during ET and IG movements in PD. We found and analyzed 26 sensitive neurons in 12 PD patients who underwent surgery for implantation of electrodes for deep brain stimulation. We also analyzed the local field potentials (LFP) of the STN of 6 patients in the postoperative period. Patients were asked to perform voluntary movements (clenching and unclenching the fist) evoked by verbal command (ET) or self-initiated (IG).

We showed heterogeneity of neuronal responses and did not find sensitive neurons associated with only one type of movement. Most cells were characterized by leading responses, indicating that the STN has an important role in movement initiation. At the same time, we found attenuation of motor responses during IG movement versus stable responses during ET movemements. LFP analysis also showed attenuation of beta desynchronization during multiple IG movements.

We propose that stable neuronal response to ET movements is associated with reboot of the motor program for each movement, while attenuation of responses to IG movement is associated with single motor program launching for multiple movements.
iPSC-derived astrocytes to model phenotype-specific differential neuroinflammatory and metabolic responses in X-linked adrenoleukodystrophy
Authors: Parasar Parveen , Kaur Navtej , Poisson Laila M , Singh Jaspreet
Published: September 2022

X-linked adrenoleukodystrophy (X-ALD) is an inherited progressive metabolic disorder caused by pathogenic variants in theABCD1gene, which leads to accumulation of very long chain fatty acids in body fluids and tissues including brain and spinal cord. In the absence of a clear genotype-phenotype correlation the molecular mechanisms of the severe cerebral adrenoleukodystrophy (cALD) and the milder adrenomyeloneuropathy (AMN) phenotypes remain unknown. Given our previous evidence of role of astrocytes in the neuroinflammatory response in X-ALD we investigated the metabolic and molecular profiles of astrocytes derived from induced pluripotent stem cells (iPSC). The iPSCs were in turn generated from skin fibroblasts from healthy controls and patients with AMN or cALD. AMN and cALD astrocytes exhibited lack ofABCD1and accumulation of very long chain fatty acids, a hallmark of X-ALD disease. Further, cALD astrocytes harbor significantly higher phosphorylation of STAT3, increased Toll-like receptor expression and higher chemokine and cytokine expression. In this first report of miRNA sequencing in X-ALD astrocytes, we observed that miR-9 expression was associated with increasing disease severity phenotype. CRISPR-Cas9 knock-in ofABCD1ABCD1gene expression differentially affected the expression of key molecular, metabolic and microRNA targets in AMN and cALD astrocytes. Extensive characterization of the AMN and cALD iPSC-derived astrocyte model demonstrates critical aspects of X-ALD inflammatory disease in response toABCD1ABCD1mutation and can be further utilized for exploring the contribution of astrocytes to differential inflammatory response in cALD.
Localizing the Sources of Modulations of the P3m Component by Task Difficulty
Authors: Boetzel Cindy , Kasten Florian H. , Herrmann Christoph S.
Published: September 2022

1

The P3m is a late component of the event-related field (ERF) and is assumed to reflect the allocation of resources in various cognitive domains. The amplitude of the P3m can be affected by several task parameters, like stimulus probability, inter-stimulus interval and task difficulty. The task difficulty can alter the P3m amplitude, depending on which mechanisms are involved. The sources of the P3m are located in several brain areas, suggesting a widespread network generating the P3m. Which of these sources of the P3m give rise to the task-difficulty induced amplitude modulation are not well investigated. However, localizing these sources could pave the way for intervention studies with non-invasive brain stimulation methods, which might be suitable to modulate the pathologically altered P3m emerging in various psychiatric and neurodevelopmental disorders. We designed a MEG-study with a visual oddball-like task with two different task difficulties to 1) show decreased P3m amplitudes induced by increased task difficulty and 2) estimate the sources of this P3m modulation. Additionally, the influence of the increased task difficulty on behavioral outcomes were analyzed. The P3m amplitude decreased significantly in the hard condition compared to easy condition. Furthermore, the hit rate for standard trials decreased significantly, while the reaction times increased for both, targets and standards. For this specific visual oddball-like task, the sources of the task difficulty dependent P3m amplitude modulation are located in the centro-parietal regions.
Quantitative comparison of CRISPR-Cas9-mediated mutation efficiency between mice and MEFs using digital PCR assays
Authors: Lee Kwangjun , Lee Choogon
Published: September 2022

The creation of mutant mice has been invaluable for advancing biomedical science, but is too time- and resource-intensive for investigating the full range of mutations and polymorphisms. Cell culture models are therefore an invaluable complement to mouse models, especially for cell-autonomous pathways like the circadian clock. In this study, we quantitatively assessed the use of CRISPR to create cell models in MEFs as compared to mouse models. We generated two point mutations in the clock genesPer1andPer2in mice and in MEFs using the same sgRNAs and repair templates for HDR and quantified the frequency of the mutations by digital PCR. The frequency was about an order of magnitude higher in mouse zygotes compared to that in MEFs. However, the mutation frequency in MEFs was still high enough for clonal isolation by simple screening of a few dozen individual cells. ThePermutant cells that we generated provide important new insights into the role of the PAS domain in regulating PER phosphorylation, a key aspect of the circadian clock mechanism. Accurate quantification of the mutation frequency in bulk MEF populations provides a critical basis for optimizing CRISPR protocols and time/resource planning for generating cell models for further studies.
Development of a new cold hardiness prediction model for grapevine using phased integration of acclimation and deacclimation responses
Authors: Kovaleski Al P. , North Michael G. , Martinson Timothy E. , Londo Jason P.
Published: September 2022

Cold injury limits distribution of perennial agricultural crops, though replacement of plants and other management practices may allow for some damage tolerance. However, winter damage to crops such as grapevines (Vitisspp.) can result in losses in yield the following year if buds are damaged, but over many years when vines must be replaced and reach maturity before fruiting. Despite risks, grapevines are cultivated at the edge of permissible climate and rely on cold hardiness monitoring programs to determine when cold damage mitigation and management practices are required. These monitoring programs represent a critical, but laborious process for tracking cold hardiness. To reduce the need for continuous monitoring, a model (WAUS.2) using cold hardiness data collected over many years from Washington state, USA, growers was published in 2014. Although the WAUS.2 model works well regionally, it underperforms in other regions. Therefore, the objective of this work was to develop a new model (NYUS.1) that incorporates recent knowledge of cold hardiness dynamics for better prediction outcomes. Cold hardiness data fromV. labruscana‘Concord’, andV. vinifera‘Cabernet Sauvignon’ and ‘Riesling’ from Geneva, NY, USA were used. Data were separated in calibration (~2/3) and validation (~1/3) datasets. The proposed model uses three functions to describe acclimation, and two functions to describe deacclimation, with a total of nine optimized parameters. A shared chill response between acclimation and deacclimation provides a phased integration where acclimation responses decrease over the course of winter and are overcome by deacclimation. The NYUS.1 model outperforms the WAUS.2 model, reducing RMSE by up to 37% depending on cultivar. The NYUS.1 model also tends to be more conservative in its prediction, slightly underpredicting cold hardiness, as opposed to the overprediction from the WAUS.2 model. Some optimized parameters were shared between cultivars, suggesting conserved physiology was captured by the new model.

Highlights

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Multi-year cold hardiness data from three grapevine cultivars were used for modeling

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Cold hardiness was modeled based on daily temperature and accumulated chill

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Phased acclimation and deacclimation processes result in cold hardiness predictions

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The new model was compared to the currently available model for grapevines

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The model proposed here outperforms the currently available model
Using machine learning to predict protein-protein interactions between a zombie ant fungus and its carpenter ant host
Authors: Will Ian , Beckerson William C. , de Bekker Charissa
Published: September 2022

Parasitic fungi produce proteins that modulate virulence, alter host physiology, and trigger host responses. These proteins, classified as a type of “effector,” often act via protein-protein interactions (PPIs). The fungal parasiteOphiocordyceps camponoti-floridani(zombie ant fungus) manipulatesCamponotus floridanus(carpenter ant) behavior to promote transmission. The most striking aspect of this behavioral change is a summit disease phenotype where infected hosts ascend and attach to an elevated position. Plausibly, interspecific PPIs drive aspects ofOphiocordycepsinfection and host manipulation. Machine learning PPI predictions offer high-throughput methods to produce mechanistic hypotheses on how this behavioral manipulation occurs. Using D-SCRIPT to predict host-parasite PPIs, we found ca. 6,000 interactions involving 2,083 host proteins and 129 parasite proteins, which are encoded by genes upregulated during manipulated behavior. We identified multiple overrepresentations of functional annotations among these proteins. The strongest signals in the host highlighted neuromodulatory G-protein coupled receptors and oxidation-reduction processes. We also detectedCamponotusstructural and gene-regulatory proteins. In the parasite, we found enrichment ofOphiocordycepsproteases and frequent involvement of novel small secreted proteins with unknown functions. From these results, we provide new hypotheses on potential parasite effectors and host targets underlying zombie ant behavioral manipulation.
Cik1 and Vik1 Accessory Proteins Confer Distinct Functions to the Kinesin-14, Kar3
Authors: Bergman Zane J , Wong Jonathan J , Drubin David G , Barnes Georjana
Published: September 2022

The budding yeast Saccharomyces cerevisiae has a closed mitosis in which the mitotic spindle and cytoplasmic microtubules (MTs) used to segregate chromosomes remain separated by the nuclear envelope throughout the cell cycle. Kar3, the yeast kinesin-14, has unique roles in both compartments and has been implicated in capturing unattached kinetochores, stabilizing crosslinked interpolar microtubules (MT), and creating intranuclear and cytoplasmic MT arrays at the spindle pole body for kinetochore capture and karyogamy, respectively. Here, we show that two proteins, Cik1 and Vik1, that form heterodimers with Kar3, regulate its localization and function within the cell and along MTs in a cell cycle-dependent manner. Using a cell cycle synchronized, yeast MT dynamics reconstitution assay in cell lysate, we found that Kar3Vik1 induces MT catastrophes in S phase and metaphase and limits MT polymerization in G1 and anaphase. In contrast, Kar3Cik1 is a catastrophe and pause promoter in G1, while increasing catastrophes in metaphase and anaphase. Adapting this assay to track single-molecules, we saw that Kar3Cik1 is necessary for tracking MT plus-ends in S phase and metaphase, but, surprisingly, not during anaphase. These experiments demonstrate how the binding partners of Kar3 modulate its diverse functions both spatially and temporally.

SUMMARY STATEMENT

We show through biochemical reconstitution experiments and live-cell imaging that the functions and localization of the budding yeast kinesin-14, Kar3, are dictated by which of its two accessory protein binding partners, Cik1 or Vik1, it binds to and by the cell cycle stage.
Subcellular distribution of PP1 isoforms in holoenzyme complexes
Authors: Mehta Virja , Chamousset Delphine , Law Jennifer , Ooi Sarah , Campuzano Denise , Nguyen Vincent , Boisvert François-Michel , Moorhead Greg B. , Trinkle-Mulcahy Laura
Published: September 2022

Unlike its counterpart Ser/Thr kinases, the predominant Ser/Thr protein phosphatase 1 (PP1) is a promiscuous enzyme that gains its subcellular localization and substrate specificity from a large panel of regulatory proteins with which it associates in predominantly dimeric complexes. Inhibition of specific PP1-mediated dephosphorylation events relies on targeting the regulatory rather than the catalytic subunit, which in turn relies on a comprehensive understanding of the holoenzyme complexes that underlie its distribution throughout the cell. Proteomic, bioinformatic and biochemical screens have assembled lists of putative regulatory proteins, which have been studied to varying degrees. We took a non-biased approach to link steady-state localization to complexes, using a combination of fluorescence imaging, cellular fractionation and quantitative affinity purification/mass spectrometry (AP/MS) to map interactomes for PP1ɑ/β/ɣ in 3 human cell lines. Comparing the distribution of each isoform between the pool of identified regulatory subunits highlighted key signaling pathways and identified c20orf27 as a novel PP1 regulatory protein. Steady-state association of a large fraction of PP1 with the evolutionarily conserved SDS22 was demonstrated, as was redistribution at the entry to mitosis. This is consistent with recent work suggesting that SDS22 acts as a PP1 sink from which it can be recruited as needed. Moving forward, this approach can be used to assess the redistribution of PP1 during other cellular processes or in response to perturbations or disease states, facilitating identification of the relevant complexes and the design of strategies to target them therapeutically.
A Programmable Model for Exploring the Functional Logic of the Drosophila Mushroom Body
Authors: Lazar Aurel A. , Turkcan Mehmet Kerem , Zhou Yiyin
Published: September 2022

We advance a model of the Mushroom Body of the Drosophila brain based on the recently published fruit fly brain connectome. We quantify the effect of the connectivity from antennal lobe projection neurons to Kenyon Cells (KCs) and the effect of feedback between KCs and the anterior paired lateral (APL) neuron on the representation of odorants at the KC level. We then characterize odorant representation in the mushroom body output neurons (MBONs) as a function of semantics represented by the dopaminergic neurons (DANs). Finally, we evaluate the performance of associative learning in the MB that endows pure odorants with DAN semantics.
Spectral slope and Lempel-Ziv complexity as robust markers of brain states during sleep and wakefulness
Authors: Höhn Christopher , Hahn Michael A. , Lendner Janna D. , Hoedlmoser Kerstin
Published: September 2022

Spectral slope and Lempel-Ziv complexity are affected in many neurophysiological disorders and are modulated by sleep, anesthesia, and aging. Yet, few studies have explored the relationship between these two parameters. We evaluated the impact of sleep stage and task-engagement (resting, attention and memory) on spectral slope and Lempel-Ziv complexity in a narrow- (30 – 45Hz) and broadband (1 – 45Hz) frequency range in 28 healthy males (21.54 ± 1.90 years) over three recordings. Only in the broadband range, the slope steepens and complexity decreases continuously from wakefulness to N3. However, REM sleep is best discriminated by the narrowband slope. Importantly, slope and complexity also differentiate between tasks during wakefulness. While the narrowband complexity decreases across tasks, the slope is flattening with task engagement in both frequency ranges. In general, broadband slope and complexity are strongly positively correlated, but we observe a dissociation between them in the narrowband range. Critically, only the narrowband slope is associated with better Go/Nogo task performance. Our results demonstrate that slope and complexity are both powerful indices of sleep depth, task engagement and cognitive performance. While the broadband range is better suited to discriminate between brain states, especially the narrowband slope is a unique marker of task performance.
DipM controls multiple autolysins and mediates two regulatory feedback loops promoting cell constriction in C. crescentus
Authors: Izquierdo-Martinez Adrian , Miguel-Ruano Vega , Hernández-Tamayo Rogelio , Biboy Jacob , Batuecas María T. , Billini Maria , Glatter Timo , Vollmer Waldemar , Graumann Peter L. , Hermoso Juan A. , Thanbichler Martin
Published: September 2022

Proteins containing a catalytically inactive LytM-type endopeptidase domain have emerged as important regulators of cell wall-degrading enzymes in bacteria. Although these so-called LytM factors are wide-spread among species, the range of functions they fulfill and their precise modes of action are still incompletely understood. In this work, we study the LytM factor DipM, a protein required for proper cell division in the model species C. crescentus. We show that the LytM domain of DipM interacts directly with multiple autolysins, including the lytic transglycosylases SdpA and SdpB, the amidase AmiC and the putative carboxypeptidase CrbA, and stimulates the activities of SdpA and AmiC. The crystal structure of the LytM domain of DipM reveals conserved features, including a distinctive groove. Modeling studies suggest that this groove could represent the docking site of AmiC. The architecture of the binding interface in the DipM-AmiC complex is very similar to that observed for the LytM domain of EnvC in complex with its autoinhibitory restraining arm, suggesting a conserved role of the groove in the interaction of LytM factors with their (auto-)regulatory targets. In line with this hypothesis, a mutation in the groove abolishes DipM function. Interestingly, single-molecule tracking studies reveal that the recruitment of DipM and its regulatory targets SdpA and SdpB to the division site is mutually interdependent, with DipM establishing a self-reinforcing cycle that gradually increases lytic transglycosylase activity at the cell center as division progresses. At the same time, the DipM-dependent activation of AmiC leads to the production of denuded peptidoglycan, generating a spatial cue that attracts FtsN to the division site and thus, in turn, again promotes the recruitment of DipM. Collectively, these findings show that DipM is a central regulator that acts at the intersection of different peptidoglycan remodeling pathways and coordinates the activities of various classes of autolysins to promote cell constriction and daughter cell separation.
Nuclear basket protein ZC3HC1 and its yeast homolog Pml39p feature an evolutionary conserved bimodular construction essential for initial binding to NPC-anchored homologs of scaffold protein TPR
Authors: Gunkel Philip , Iino Haruki , Krull Sandra , Cordes Volker C.
Published: September 2022

Proteins ZC3HC1 and TPR are construction elements of the nuclear pore complex (NPC)-attached nuclear basket (NB). NB-location of ZC3HC1 depends on TPR already occurring NPC-anchored, whereas additional TPR polypeptides are appended to the NB by ZC3HC1. The current study examined the molecular properties of ZC3HC1 that enable it to bind to the NB and TPR. We report the identification and definition of a nuclear basket-interaction domain (NuBaID) ofHsZC3HC1 comprising two similarly built modules, both essential for the binding to the NB’s NPC-anchoredHsTPR. Furthermore, we describe such a bimodular construction as evolutionarily conserved and exemplify the kinship ofHsZC3HC1 by the NB- andDdTPR-interacting homolog ofDictyostelium discoideumand by characterizing protein Pml39 as the ZC3HC1 homolog inSaccharomyces cerevisiae. Among several properties shared by the different species’ homologs, we unveil the integrity of the bimodular NuBaID ofScPml39p as being essential for binding to the yeast’s NBs and its TPR homologsScMlp1p andScMlp2p, and we further present Pml39p as enabling interlinkage of Mlp1p subpopulations. In addition to phyla-specific features, we delineate the three species’ common NuBaID as the characterizing structural entity of a one-of-a-kind protein found not in all but likely most taxa of the eukaryotic realm.
Circadian and environmental signal integration in a natural population ofArabidopsis
Authors: Nishio Haruki , Cano-Ramirez Dora L. , Muranaka Tomoaki , de Barros Dantas Luíza Lane , Honjo Mie N. , Sugisaka Jiro , Kudoh Hiroshi , Dodd Antony N.
Published: September 2022

Plants sense and respond to environmental cues during 24 h fluctuations in their environment. This requires the integration of internal cues such as circadian timing with environmental cues such as light and temperature to elicit cellular responses through signal transduction. However, the integration and transduction of circadian and environmental signals within plants growing in natural environments remains poorly understood. To gain insights into the 24 h dynamics of environmental signalling in nature, we performed a field study of signalling from the nucleus to chloroplasts in a natural population ofArabidopsis halleri.Using advanced modelling approaches to interpret the data, we identified that the circadian clock and temperature are key regulators of this pathway under natural conditions. We identified potential time-delay steps between pathway components, and diel fluctuations in the response of the pathway to temperature cues that are reminiscent of the process of circadian gating. This approach of combining studies of gene expression in the field with modelling allowed us to identify the dynamic integration and transduction of environmental cues, in plant cells, under naturally fluctuating diel cycles.
Development of the Centralized Interactive Phenomics Resource (CIPHER) Standard for Electronic Health Data-Based Phenomics Knowledgebase
Authors: Honerlaw Jacqueline , Ho Yuk-Lam , Fontin Francesca , Gosian Jeffrey , Maripuri Monika , Murray Michael , Sangar Rahul , Galloway Ashley , Zimolzak Andrew J. , Whitbourne Stacey B. , Casas Juan P. , Ramoni Rachel B. , Gagnon David R. , Cai Tianxi , Liao Katherine P. , Gaziano J. Michael , Muralidhar Sumitra , Cho Kelly
Published: September 2022

The development of phenotypes using electronic health records is a resource intensive process. Therefore, the cataloging of phenotype algorithm metadata for reuse is critical to accelerate clinical research. The Department of Veterans Affairs Office of Research and Development has developed a phenomics knowledgebase library, CIPHER (Centralized Interactive Phenomics Research), which improves upon existing phenomics library models to help advance innovation in clinical research by using the CIPHER phenotype collection standard. The CIPHER standard was iteratively developed with phenomics experts and has been used to capture over 5,000 phenotypes. We describe the development of the CIPHER standard for phenotype metadata collection, its current application to the largest healthcare system in the United States, and the future expansion of the CIPHER knowledgebase as a public resource for phenotyping.
Structural insights into the elevator-type transport mechanism of a bacterial ZIP metal transporter
Authors: Zhang Yao , Jiang Yuhan , Gao Kaifu , Sui Dexin , Yu Peixuan , Su Min , Wei Guowei , Hu Jian
Published: September 2022

The Zrt-/Irt-like protein (ZIP) family consists of ubiquitously expressed divalent metal transporters critically involved in maintaining systemic and cellular homeostasis of zinc, iron, and manganese. Here, we present a study on a prokaryotic ZIP from Bordetella bronchiseptica (BbZIP) by combining structural biology, evolutionary covariance, computational modeling, and a variety of biochemical assays to tackle the issue of the transport mechanism which has not been established for the ZIP family. The apo state structure in an inward-facing conformation revealed a disassembled transport site, altered inter-helical interactions, and importantly, a rigid body movement of a 4-transmembrane helix (TM) bundle relative to the other TMs. The computationally generated and biochemically validated outward-facing conformation model revealed a slide of the 4-TM bundle, which carries the transport site(s), by approximately 8 Å toward the extracellular side against the static TMs which mediate dimerization. These findings allowed us to conclude that BbZIP is an elevator-type transporter.
The western redcedar genome reveals low genetic diversity in a self-compatible conifer
Authors: Shalev Tal J. , Gamal El-Dien Omnia , Yuen Macaire M.S. , Shengqiang Shu , Jackman Shaun D. , Warren René L. , Coombe Lauren , van der Merwe Lise , Stewart Ada , Boston Lori B. , Plott Christopher , Jenkins Jerry , He Guifen , Yan Juying , Yan Mi , Guo Jie , Breinholt Jesse W. , Neves Leandro G. , Grimwood Jane , Rieseberg Loren H. , Schmutz Jeremy , Birol Inanc , Kirst Matias , Yanchuk Alvin D. , Ritland Carol , Russell John H. , Bohlmann Joerg
Published: September 2022

We assembled the 9.8-Gbp genome of western redcedar (WRC;Thuja plicata), an ecologically and economically important conifer species of the Cupressaceae. The genome assembly, derived from a uniquely inbred tree produced through five generations of self-fertilization (selfing), was determined to be 86% complete by BUSCO analysis, one of the most complete genome assemblies for a conifer. Population genomic analysis revealed WRC to be one of the most genetically depauperate wild plant species, with an effective population size of approximately 300 and no significant genetic differentiation across its geographic range. Nucleotide diversity, π, is low for a continuous tree species, with many loci showing zero diversity, and the ratio of π at zero- to fourfold degenerate sites is relatively high (approximately 0.33), suggestive of weak purifying selection. Using an array of genetic lines derived from up to five generations of selfing, we explored the relationship between genetic diversity and mating system. Although overall heterozygosity was found to decline faster than expected during selfing, heterozygosity persisted at many loci, and nearly 100 loci were found to deviate from expectations of genetic drift, suggestive of associative overdominance. Nonreference alleles at such loci often harbor deleterious mutations and are rare in natural populations, implying that balanced polymorphisms are maintained by linkage to dominant beneficial alleles. This may account for how WRC remains responsive to natural and artificial selection, despite low genetic diversity.