bluuebunny/crossref_metadata_2025 huggingface dataset:
Model-based ordination for species with unequal niche widths
Authors: van der Veen Bert , Hui Francis K.C. , Hovstad Knut A. , Solbu Erik B. , O’Hara Robert B.
Published: October 2020

It is common practice for ecologists to examine species niches in the study of community composition. The response curve of a species in the fundamental niche is usually assumed to be quadratic. The center of a quadratic curve represents a species’ optimal environmental conditions, and the width its ability to tolerate deviations from the optimum.

Most multivariate methods assume species respond linearly to the environment of the niche, or with a quadratic curve that is of equal width and height for all species. However, it is widely understood that some species are generalists who tolerate deviations from their optimal environment better than others. Rare species often tolerate a smaller range of environments than more common species, corresponding to a narrow niche.

We propose a new method, for ordination and fitting Joint Species Distribution Models, based on Generalized Linear Mixed-Effects Models, which relaxes the assumptions of equal tolerances and equal maxima.

By explicitly estimating species optima, tolerances, and maxima, per ecological gradient, we can better predict change in species communities, and understand how species relate to each other.
Activation of the membrane-bound Nrf1 transcription factor by USP19, a ubiquitin-specific protease C-terminally tail-anchored in the endoplasmic reticulum
Authors: Hu Shaofan , Xiang Yuancai , Qiu Lu , Wang Meng , Zhang Yiguo
Published: October 2020

The membrane-bound transcription factor Nrf1 (i.e., encoded byNfe2l1) is activated by sensing glucose deprivation, cholesterol excess, proteasomal inhibition and oxidative stress, and then mediates distinct signaling responses in order to maintain cellular homeostasis. Herein, we found that Nrf1 stability and transactivity are both enhanced by USP19, a ubiquitin-specific protease tail-anchored in the endoplasmic reticulum (ER) through its C-terminal transmembrane domain. Further experiments revealed that USP19 directly interacts with Nrf1 in proximity to the ER and topologically acts as a deubiquitinating enzyme to remove ubiquitin moieties from this protein, and hence allows it to circumvent the potential proteasomal degradation. Such USP19-mediated effect takes place only after Nrf1 is retrotranslocated by p97 out of ER membranes to dislocate the cytoplasmic side. Conversely, knockout of USP19 causes significant decreases in the Nrf1 abundance and its active isoform entering the nucleus, resulting in down-regulation of its target proteasomal subunits. This led to a modest reduction ofUSP19−/−-derived tumor growth in xenograft mice, when compared with wild-type controls. Altogether, these demonstrate that USP19 serves as a novel mechanistic modulator of Nrf1, but not Nrf2, enabling Nrf1 to be rescued from putative ubiquitin-directed ER-associated degradation pathway. In turn, our additional experimental evidence has unraveled that transcriptional expression of endogenousUSP19and its promoter-driven reporter genes is differentially regulated by Nrf2, as well by Nrf1, at distinct layers within a complex hierarchical regulatory network.
“The stressed bird in the hand”: Influence of sampling design on the physiological stress response in a free-living songbird
Authors: Huber Nikolaus , Mahr Katharina , Tóth Zsófia , Szarka Endre Z. , Çınar Yusuf Ulaş , Salmón Pablo , Lendvai Ádám Z.
Published: October 2020

Despite the widely used application of standardized capture-handling protocols to collect blood and assess the physiological stress response, the effect of the actual sampling design (e.g. timing and the number of blood samples) often differs between studies, and the potential implications for the measured physiological endpoints remain understudied. We, therefore, experimentally tested the effects of repeated handling and multiple blood sampling on the stress response in wintering free-living great tits (Parus major). We modified a well-established sampling protocol of avian studies by adding either an additional blood sample or a “sham-manipulation” (i.e. handling associated with the blood sampling procedure without venepuncture), to disentangle the effects of handling stress and blood loss. We combined three different stress metrics along the endocrine-immune interface to investigate the acute short-term stress response: total corticosterone levels (CORT), the heterophil/lymphocyte ratio (H:L), and the Leukocyte Coping Capacity (LCC). Our study provided three key results: i) no relationship between CORT-levels, LCC and H:L, confirming that these three parameters represent different physiological endpoints within the stress response; ii) contrasting dynamics in response to stress by the measured parameters and iii) no difference in stress levels 30 minutes after capture due to one additional blood sampling or handling event. By optimising the sampling design, our results provide implications for animal welfare and planning experimental procedures on stress physiology in passerine species.

Summary Statement

When testing the short-term stress response in free living passerines, both – the scientist and the bird may be better off with a 15-minute stress protocol.
Genome evolution in an agricultural pest following adoption of transgenic crops
Authors: Fritz Megan L. , Hamby Kelly A. , Taylor Katherine , DeYonke Alexandra M. , Gould Fred
Published: October 2020

Replacement of synthetic insecticides with transgenic crops for pest management has been both economically and environmentally beneficial. These benefits have often eroded as pests evolved resistance to transgenic crops, but a broad understanding of the timing and complexity of adaptive changes which lead to field-evolved resistance in pest species is lacking. Wild populations ofHelicoverpa zea, a major lepidopteran crop pest and the target of transgenic Cry toxin-expressing cotton and corn, have recently evolved widespread, damaging levels of resistance. Here, we quantified patterns of genomic change in wildH. zeacollected between 2002 and 2017 when adoption rates of Cry-expressing crops expanded in North America. Using a combination of genomic approaches, we identified significant temporal changes in allele frequency throughout the genomes of field-collectedH. zea. Many of these changes occurred concurrently with increasingly damaging levels of resistance to Cry toxins between 2012 and 2016, in a pattern consistent with polygenic selection. Surprisingly, none of the eleven previously described Cry resistance genes showed signatures of selection in wildH. zea. Furthermore, we observed evidence of a very strong selective sweep in one region of theH. zeagenome, yet this strongest change was not additively associated with Cry resistance. This first, whole genome analysis of field-collected specimens to study evolution of Cry resistance demonstrates the potential and need for a more holistic approach to examining pest adaptation to changing agricultural practices.

Significance Statement

Evolution of pest resistance to management approaches in agricultural landscapes is common and results in economic losses. Early detection of pest resistance evolution prior to significant crop damage would benefit the agricultural community. It has been hypothesized that new genomic approaches could track molecular signals of emerging resistance problems and trigger efforts to pre-empt widespread damage. We tested this hypothesis by quantifying genomic changes in the pestHelicoverpa zeaover a 15 year period concurrent with commercialization and subsequent loss of efficacy of transgenic Bt-expressing crops. Our results demonstrate the complex nature of evolution in agricultural ecosystems and provide insight into the potential for and pitfalls associated with use of genomic approaches for resistance monitoring. We discuss approaches for improvement.
Dynamic and reversible remapping of network representations in an unchanging environment
Authors: Low Isabel I. C. , Williams Alex H. , Campbell Malcolm G. , Linderman Scott W. , Giocomo Lisa M.
Published: October 2020

In response to environmental changes, the medial entorhinal cortex alters its single-cell firing properties. This flexibility in neural coding is hypothesized to support navigation and memory by dividing sensory experience into unique contextual episodes. However, it is unknown how the entorhinal circuit transitions between different representations, particularly when sensory information is not delineated into discrete contexts. Here, we describe spontaneous and abrupt transitions between multiple spatial maps of an unchanging task and environment. These remapping events were synchronized across hundreds of medial entorhinal neurons and correlated with changes in running speed. While remapping altered spatial coding in individual neurons, we show that features of the environment were statistically preserved at the population-level, enabling simple decoding strategies. These findings provoke a reconsideration of how medial entorhinal cortex dynamically represents space and broadly suggest a remarkable capacity for higher-order cortical circuits to rapidly and substantially reorganize their neural representations.
Diffusion MRI Changes in the Healthy Aging Canine Brain
Authors: Barry Erica F. , Loftus John P. , Luh Wen-Ming , de Leon Mony J. , Niogi Sumit N. , Johnson Philippa J.
Published: October 2020

White matter dysfunction and degeneration have been a topic of great interest in healthy and pathological aging. While ex vivo studies have investigated age-related changes in canines, little in vivo canine aging research exists. Quantitative diffusion MRI such as diffusion tensor imaging (DTI) has demonstrated aging and neurodegenerative white matter changes in humans. However, this method has not been applied and adapted in vivo to canine populations. This study aimed to test the hypothesis that white matter diffusion changes frequently reported in human aging are also found in aged canines. The study used Tract Based Spatial Statistics (TBSS) and a region of interest (ROI) approach to investigate age related changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD). The results show that, compared to younger animals, aged canines have significant decreases in FA in parietal and temporal regions as well as the corpus callosum and fornix. Additionally, AxD decreases were observed in parietal, frontal and midbrain regions. Similarly, an age-related increase in RD was observed in the right parietal lobe while MD decreases were found in the midbrain. These findings suggest that canine samples offer a model for healthy human aging as they exhibit similar white matter diffusion tensor changes with age.
Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis and supports restoration of the intestinal stem cell niche
Authors: Weis Victoria G. , Deal Anna C. , Mekkey Gehad , Clouse Cara , Gaffley Michaela , Whitaker Emily , Weis Jared A. , Schwartz Marshall Z. , Atala Anthony
Published: October 2020

Necrotizing enterocolitis (NEC), a life-threatening intestinal disease, is becoming a larger proportionate cause of morbidity and mortality in premature infants. To date, therapeutic options remain elusive. Based on recent cell therapy studies, we investigated the effect of a human placental-derived stem cell (hPSC) therapy on intestinal damage in an experimental NEC rat pup model. NEC was induced in newborn Sprague-Dawley rat pups for 4 days via formula feeding, hypoxia, and LPS. NEC pups received intraperitoneal (ip) injections of either saline or hPSC (NEC-hPSC) at 32 and 56 hours into NEC induction. At 4 days, intestinal macroscopic and histological damage, epithelial cell composition, and inflammatory marker expression of the ileum was assessed. Breastfed (BF) littermates were used as controls. NEC pups developed significant bowel dilation and fragility in the ileum. Further, NEC induced loss of normal villi-crypt morphology, disruption of epithelial proliferation and apoptosis, and loss of Paneth cells and LGR5+ stem cells in the crypt. hPSC treatment improved macroscopic intestinal health with reduced ileal dilation and fragility. Histologically, hPSC administration had a significant reparative effect on the villi-crypt morphology and epithelium. In addition to a trend of decreased inflammatory marker expression, hPSC-NEC pups had increased epithelial proliferation and decreased apoptosis when compared to NEC littermates. Further, the intestinal stem cell niche of Paneth cells and LGR5+ stem cells was increased with hPSC therapy. Together, these data demonstrate hPSC can promote epithelial healing of NEC intestinal damage in part through support of the intestinal stem cell niche.

New and Noteworthy

These studies demonstrate a human placental-derived stem cell (hPSC) therapeutic strategy for necrotizing enterocolitis (NEC). In an experimental model of NEC, hPSC administration improved macroscopic intestinal health, ameliorated epithelial morphology, and supported the intestinal stem cell niche. Our data suggest that hPSC are a potential therapeutic approach to attenuate established intestinal NEC damage. Further, we show hPSC are a novel research tool that can now be utilized to elucidate critical neonatal repair mechanisms to overcome NEC disease.
Evolutionary dynamics at the tumor edge reveals metabolic imaging biomarkers
Authors: Jiménez-Sánchez Juan , Bosque Jesús J. , Jiménez Londoño Germán A. , Molina-García David , Martínez Álvaro , Pérez-Beteta Julián , Ortega-Sabater Carmen , Martínez Antonio F. Honguero , García Vicente Ana M. , Calvo Gabriel F. , Pérez-García Víctor M.
Published: October 2020

Human cancers are biologically and morphologically heterogeneous. A variety of clonal populations emerge within these neoplasms and their interaction leads to complex spatio-temporal dynamics during tumor growth. We studied the reshaping of metabolic activity in human cancers by means of continuous and discrete mathematical models, and matched the results to positron emission tomography (PET) imaging data. Our models revealed that the location of increasingly active proliferative cellular spots progressively drifted from the center of the tumor to the periphery, as a result of the competition between gradually more aggressive phenotypes. This computational finding led to the development of a metric, the NPAC, based on the distance from the location of peak activity (proliferation) to the tumor centroid. The NPAC metric can be computed for human patients using 18F-FDG PET/CT images where the voxel of maximum uptake (SUVmax) is taken as the point of peak activity. Two datasets of 18F-FDG PET/CT images were collected, one from 61 breast cancer patients and another from 161 non-small-cell lung cancer patients. In both cohorts, survival analyses were carried out for the NPAC and for other classical PET/CT-based biomarkers, finding that the former had a high prognostic value, outperforming the latter. In summary, our work offers new insights into the evolutionary mechanisms behind tumor progression and provides a PET/CT-based biomarker with clinical applicability.

Significance Statement

Through the use of different in silico modeling approaches capturing tumor heterogeneity, we predicted that areas of high metabolic activity would shift towards the periphery as tumors become more malignant. To confirm the prediction and provide clinical value for the finding, we took 18F-FDG PET images of breast cancers and non-small-cell lung cancers, where we measured the distance from the point of maximum activity to the tumor centroid, and normalized it by a surrogate of the volume. We show that this metric has a high prognostic value for both malignancies and outperforms other classical PET-based metabolic biomarkers used in oncology.
Low-density lipoprotein cholesterol levels are associated with poor clinical outcomes in COVID-19
Authors: Aparisi Álvaro , Iglesias-Echeverría Carolina , Ybarra-Falcón Cristina , Cusácovich Iván , Uribarri Aitor , García-Gómez Mario , Ladrón Raquel , Fuertes Raúl , Candela Jordi , Hinojosa Williams , Dueñas Carlos , González Roberto , Nogales Leonor , Calvo Dolores , Carrasco-Moraleja Manuel , Román J. Alberto San , Amat-Santos Ignacio J. , Andaluz-Ojeda David
Published: October 2020

STRUCTURED ABSTRACT

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the sole causative agent of coronavirus infectious disease-19 (COVID-19).

Methods

We performed a retrospective single-center study of consecutively admitted patients between March 1st and May 15th, 2020, with a definitive diagnosis of SARS-CoV-2 infection. The primary end-point was to evaluate the association of lipid markers with 30-days all-cause mortality in COVID-19.

Results

A total of 654 patients were enrolled, with an estimated 30-day mortality of 22.8% (149 patients). Non-survivors had lower total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) levels during the entire course of the disease with complete resolution among survivors. Both showed a significant inverse correlation with inflammatory markers and a positive correlation with lymphocyte count. In a multivariate analysis, LDL-c ≤ 69 mg/dl (hazard ratio [HR] 1.94; 95% confidence interval [CI] 1.14-3.31), C-reactive protein > 88 mg/dl (HR 2.44; 95% CI, 1.41-4.23) and lymphopenia < 1,000 (HR 2.68; 95% CI, 1.91-3.78) at admission were independently associated with 30-day mortality. This association was maintained 7 days after admission.

Conclusion

Hypolipidemia in SARS-CoV-2 infection may be secondary to an immune-inflammatory response, with complete recovery in survivors. Low LDL-c serum levels are independently associated with higher 30-day mortality in COVID-19 patients.
Clinical, laboratory, and temporal predictors of neutralizing antibodies to SARS-CoV-2 after COVID-19
Authors: Boonyaratanakornkit Jim , Morishima Chihiro , Selke Stacy , Zamora Danniel , McGuffin Sarah , Shapiro Adrienne E. , Campbell Victoria L. , McClurkan Christopher L. , Jing Lichen , Gross Robin , Liang Janie , Postnikova Elena , Mazur Steven , Chaudhary Anu , Das Marie K. , Fink Susan L. , Bryan Andrew , Greninger Alex L. , Jerome Keith R. , Holbrook Michael R. , Gernsheimer Terry B. , Wener Mark H. , Wald Anna , Koelle David M.
Published: October 2020

Background

SARS-CoV-2-specific antibodies may protect from reinfection and disease, providing the rationale for administration of plasma containing SARS-CoV-2 neutralizing antibodies (nAb) as a treatment for COVID-19. The clinical factors and laboratory assays to streamline plasma donor selection, and the durability of nAb responses, are incompletely understood.

Methods

Adults with virologically-documented SARS-CoV-2 infection in a convalescent plasma donor screening program were tested for serum IgG to SARS-CoV-2 spike protein S1 domain, nucleoprotein (NP), and for nAb.

Results

Amongst 250 consecutive persons studied a median of 67 days since symptom onset, 243/250 (97%) were seropositive on one or more assays. Sixty percent of donors had nAb titers ≥1:80. Correlates of higher nAb titer included older age (adjusted OR [AOR] 1.03/year of age, 95% CI 1.00-1.06), male sex (AOR 2.08, 95% CI 1.13-3.82), fever during acute illness (AOR 2.73, 95% CI 1.25-5.97), and disease severity represented by hospitalization (AOR 6.59, 95% CI 1.32-32.96). Receiver operating characteristic (ROC) analyses of anti-S1 and anti-NP antibody results yielded cutoffs that corresponded well with nAb titers, with the anti-S1 assay being slightly more predictive. NAb titers declined in 37 of 41 paired specimens collected a median of 98 days (range, 77-120) apart (P<0.001). Seven individuals (2.8%) were persistently seronegative and lacked T cell responses.

Conclusions

Nab titers correlated with COVID-19 severity, age, and sex. Standard commercially available SARS-CoV-2 IgG results can serve as useful surrogates for nAb testing. Functional nAb levels were found to decline and a small proportion of COVID-19 survivors lack adaptive immune responses.
Mask mandates can limit COVID spread: Quantitative assessment of month-over-month effectiveness of governmental policies in reducing the number of new COVID-19 cases in 37 US States and the District of Columbia
Authors: Maloney Michael J. , Rhodes Nathaniel J. , Yarnold Paul R.
Published: October 2020

Introduction

SARS-CoV-2 is the beta-coronavirus responsible for COVID-19. Facemask use has been qualitatively associated with reduced COVID-19 cases, but no study has quantitatively assessed the impact of government mask mandates (MM) on new COVID-19 cases across multiple US States.

Data and Methods

We utilized a non-parametric machine-learning algorithm to test the a priori hypothesis that MM were associated with reductions in new COVID-19 cases. Publicly available data were used to analyze new COVID-19 cases from 37 States and the District of Columbia (i.e., “38 States”). We conducted confirmatory All-States and State-Wise analyses, validity analyses [e.g., leave-one-out (LOO) and bootstrap resampling], and covariate analyses.

Results

No statistically significant difference in the daily number of new COVID-19 infections was discernable in the All-States analysis. In State-Wise LOO validity analysis, 11 States exhibited reductions in new COVID-19 and the reductions in four of these States (AK, MA, MN, VA) were significant in bootstrap resampling. Only the Social Capital Index predicted MM success (training p<0.028 and LOO p<0.013).

Conclusion

Results obtained when studying the impact of MM on COVID-19 cases varies as a function of the heterogeneity of the sample being considered, providing clear evidence of Simpson’s Paradox and thus of confounded findings. As such, studies of MM effectiveness should be conducted on disaggregated data. Since transmissions occur at the individual rather than at the collective level, additional work is needed to identify optimal social, psychological, environmental, and educational factors which will reduce the spread of SARS-CoV-2 and facilitate MM effectiveness across diverse settings.
Formation of flavone-based wooly fibres by glandular trichomes ofDionysia tapetodes
Authors: Bourdon Matthieu , Gaynord Josephine , Müller Karin , Evans Gareth , Wallis Simon , Aston Paul , Spring David R. , Wightman Raymond
Published: October 2020

Dionysia tapetodes, a small cushion-forming mountainous evergreen in the Primulaceae, possesses a vast surface-covering of long silky fibres forming the characteristic “wooly” farina. This contrasts with some relatedPrimulawhich instead possess a powdery farina. Using a combination of cell biology and analytical chemical techniques, we provide a detailed insight of wooly farina formation by glandular trichomes that produce a mixture of flavone and substituted flavone derivatives, including hydroxyflavones. Conversely, our analysis show that the powdery form consist almost entirely of flavone. The wooly farina inD. tapetodesis extruded through specific sites at the surface of the glandular head cell, characterised by a small complete gap in the plasma membrane, cell wall and cuticle. The data is consistent with formation and thread elongation occurring from within the cell. The putative mechanism of wool thread formation and its stability is discussed.
The sandarazols are cryptic and structurally unique plasmid encoded toxins from a rare myxobacterium
Authors: Panter Fabian , Bader Chantal D. , Müller Rolf
Published: October 2020

Soil dwelling bacteria such as myxobacteria defend themselves by using secondary metabolites to inhibit growth of competing microorganisms. In this work we describe a new plasmid found inSandaracinussp. MSr10575 named pSa001 spanning 209.7 kbp that harbors a cryptic secondary metabolite biosynthesis gene cluster (BGC). Activation of this BGC by homologous recombination mediated exchange of the native promoter sequence against a vanillate inducible system led to production and subsequent isolation and structure elucidation of novel secondary metabolites, the sandarazols A-G. The sandarazol structure contains intriguing features such as an α-chlorinated ketone, an epoxyketone and a (2R)-2-amino-3- (N,N-dimethylamino)-propionic acid building block. In depth investigation of the underlying biosynthetic machinery led to a concise biosynthetic model for the new compound family, including several uncommon biosynthesis steps. The chlorinated congener sandarazol C shows an IC50value of 0.5 µM against HCT 116 cells and a MIC of 14 µM againstMycobacterium smegmatis, which points at the sandarazol’s potential function as defensive secondary metabolites or toxins. The sandara-zols’ BGC location on pSa001 is one of the very few example of large multimodular BGCs on a replicative plasmid, whose existence points at the mechanism of horizontal gene transfer events of entire multimodular BGCs to exchange chemical warfare capabilities between bacterial species.
The mouse cortico-basal ganglia-thalamic network
Authors: Foster Nicholas N. , Korobkova Laura , Garcia Luis , Gao Lei , Becerra Marlene , Sherafat Yasmine , Peng Bo , Li Xiangning , Choi Jun-Hyeok , Gou Lin , Zingg Brian , Azam Sana , Lo Darrick , Khanjani Neda , Zhang Bin , Stanis Jim , Bowman Ian , Cotter Kaelan , Cao Chunru , Yamashita Seita , Tugangui Amanda , Li Anan , Jiang Tao , Jia Xueyan , Feng Zhao , Aquino Sarvia , Dan Gordon , Fayzullina Marina , Mun Hyun-Seung , Ustrell Sarah , Boesen Tyler , Santarelli Anthony , Zhu Muye , Benavidez Nora L. , Song Monica , Johnson David L. , Xu Hanpeng , Bienkowski Michael S. , Yang X. William , Gong Hui , Wickersham Ian , Luo Qingming , Lim Byung Kook , Zhang Li I. , Hintiryan Houri , Dong Hongwei
Published: October 2020

The cortico-basal ganglia-thalamic loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behavior, and the natural history of many neurological and neuropsychiatric diseases. Classically, the basal ganglia is conceptualized to contain three primary information output channels: motor, limbic, and associative. However, given the roughly 65 cortical areas and two dozen thalamic nuclei that feed into the dorsal striatum, a three-channel view is overly simplistic for explaining the myriad functions of the basal ganglia. Recent works from our lab and others have subdivided the dorsal striatum into numerous functional domains based on convergent and divergent inputs from the cortex and thalamus. To complete this work, we generated a comprehensive data pool of ∼700 injections placed across the striatum, external globus pallidus (GPe), substantia nigra pars reticulata (SNr), thalamic nuclei, and cortex. We identify 14 domains of SNr, 36 in the GPe, and 6 in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify 6 parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information with complex patterns of convergence and divergence through every elemental node of the entire cortico-basal ganglia loop. These experiments reveal multiple important novel features of the cortico-basal ganglia network motif. The prototypical sub-network structure is characterized by a highly interconnected nature, with cortical information processing through one or more striatal nodes, which send a convergent output to the SNr and a more parallelized output to the GPe; the GPe output then converges with the SNr. A domain of the thalamus receives the nigral output, and is interconnected with both the striatal domains and the cortical areas that filter into its nigral input source. This study provides conceptual advancement of our understanding of the structural and functional organization of the classic cortico-basal ganglia network.
Environmental stressors induced strong small-scale phenotypic differentiation in a wide-dispersing marine snail
Authors: Bonel Nicolás , Pointier Jean-Pierre , Alda Pilar
Published: October 2020

Heterogeneous environments pose a particular challenge for organisms because the same phenotype is unlikely to perform best regardless of the variety of encountered stressors. To understand how species meet this challenge, we investigated the extent to which contrasting environmental pressures induced ecological and phenotypic responses in a natural population of a wide-dispersing marine snail at a small spatial scale. We analyzed several traits ofHeleobia australis(Rissooidea: Cochliopidae) collected from heterogeneous, but highly connected, habitats from the intertidal area of the Bahía Blanca estuary, Argentina. We also conducted molecular analyses by amplifying the COI gene in individuals sampled from each habitat. We found that sympatric subpopulations ofH. australisexhibited a strong phenotypic divergence in shell characters and body weight in response to thermal, saline, and dehydration stress, crab predation risk, and parasitic castrators. We proved that this differentiation occurred even early in life as most of the characters observed in juveniles mirrored those found in adults. We also found a divergence in penis size in snails collected from each habitat and raised in common garden laboratory conditions. The molecular analyses confirmed that the individuals studied constituted a single species despite the strong phenotypic differences among subpopulations. The small-scale phenotypic differentiation suggests thatH.australisexperienced a fine-grained environment where conditions imposed by different sources of stress favored the expression of beneficial traits. We discuss the role of plasticity in shaping adaptive phenotypic responses that increase the likelihood of persistence of subpopulations facing environmental stress conditions.
A triresidue motif in the GLUTAMATE RECEPTOR-LIKE 3.3 C-tail interacts with IMPAIRED SUCROSE INDUCTION 1 and controls long distance wound signaling
Authors: Wu Qian , Stolz Stéphanie , Kumari Archana , Glauser Gaétan , Farmer Edward E.
Published: October 2020

ArabidopsisClade 3GLUTAMATE RECEPTOR-LIKE(GLRs) genes are primary players in wound-induced electrical signaling and jasmonate-activated defense responses. As cation-permeable ion channels, previous studies have focused on resolving their gating properties and structures. However, little is known regarding to the regulatory mechanism of these channel proteins. Here, we report that the C-tail of GLR3.3 contains key elements that control its function in long distance wound signaling. GLR3.3 without its C-tail failed to rescue theglr3.3amutant. To further investigate the underlying mechanism, we performed a yeast two-hybrid screen. IMPAIRED SUCROSE INDUCTION 1 (ISI1) was identified as an interactor with both the C-tail and the full-length GLR3.3in planta. Reduced functionisi1mutants had enhanced electrical activity and jasmonate-regulated defense responses. Furthermore, we found that a triresidue motif RFL (R884, F885 and L886) in the GLR3.3 C-tail is essential for interacting with ISI1. RFL mutation abolished GLR3.3 function in electrical signaling and jasmonate-mediated defense gene activation. Our study shows the importance of the C-tail in GLR3.3 function, and reveals parallels with the ipnotropic glutamate receptor regulation in animal cells.
Extinct species identification from Upper Pleistocene bone fragments not identifiable from their osteomorphological studies by proteomics analysis
Authors: Bray Fabrice , Flament Stéphanie , Abrams Grégory , Bonjean Dominique , Modica Kévin Di , Rolando Christian , Tokarski Caroline , Auguste Patrick
Published: October 2020

The ancient preserved molecules offer the opportunity to gain a better knowledge on the biological past. In recent years, bones proteomics has become an attractive method to study the animal biological origin, extinct species and species evolution as an alternative to DNA analysis which is limited by DNA amplification present in ancient samples and its contamination. However, the development of a proteomic workflow remains a challenge. The analysis of fossils must consume a low quantity of material to avoid damaging the samples. Another difficulty is the absence of genomic data for most of the extinct species. In this study, a proteomic methodology was applied to mammalian bones of 130,000 years old from the earlier Upper Pleistocene site of Scladina Cave (Belgium). Starting from 5 milligram samples, our results show a large majority of detected peptides matching collagen I alpha 1 and alpha 2 proteins with a sequence coverage up to 60%. Using sequence homology with modern sequences, a biological classification was successfully achieved and the associated taxonomic ranks to each bone were identified consistently with the information gained from osteomorphological studies and palaeoenvironmental and palaeodietary data. Among the taxa identified are the Felidae family, Bovinae subfamily, Elephantidae family and the Ursus genus. Amino acid substitutions on the collagens were identified providing new information on extinct species sequences and also helping in taxonomy-based clustering. Considering samples with no osteomorphological information, such as two bone retouchers, proteomics successfully identified the bovidae and ursidae families providing new information to the paleontologists on these objects. Combining osteomorphology studies and amino acid variations identified by proteomics, one retoucher was identified to be potentially from theUrsus spelaeusspecies.
SACSANN: identifying sequence-based determinants of chromosomal compartments
Authors: Prost Julie A , Cameron Christopher JF , Blanchette Mathieu
Published: October 2020

Genomic organization is critical for proper gene regulation and based on a hierarchical model, where chromosomes are segmented into megabase-sized, cell-type-specific transcriptionally active (A) and inactive (B) compartments. Here, we describe SACSANN, a machine learning pipeline consisting of stacked artificial neural networks that predicts compartment annotation solely from genomic sequence-based features such as predicted transcription factor binding sites and transposable elements. SACSANN provides accurate and cell-type specific compartment predictions, while identifying key genomic sequence determinants that associate with A/B compartments. Models are shown to be largely transferable across analogous human and mouse cell types. By enabling the study of chromosome compartmentalization in species for which no Hi-C data is available, SACSANN paves the way toward the study of 3D genome evolution. SACSANN is publicly available on GitHub:https://github.com/BlanchetteLab/SACSANN
Uncertainty is Maintained and Used in Working Memory
Authors: Yoo Aspen H. , Acerbi Luigi , Ma Wei ji
Published: October 2020

1

What are the contents of working memory? In both behavioral and neural computational models, a working memory representation is typically described by a single number, namely a point estimate of a stimulus. Here, we asked if people also maintain the uncertainty associated with a memory, and if people use this uncertainty in subsequent decisions. We collected data in a two-condition orientation change detection task; while both conditions measured whether people used memory uncertainty, only one required maintaining it. For each condition, we compared an optimal Bayesian observer model, in which the observer uses an accurate representation of uncertainty in their decision, to one in which the observer does not. We find that this “Use Uncertainty” model fits better for all participants in both conditions. In the first condition, this result suggests that people use uncertainty optimally in a working memory task when that uncertainty information is available at the time of decision, confirming earlier results. Critically, the results of the second condition suggest that this uncertainty information was maintained in working memory. We test model variants and find that our conclusions do not depend on our assumptions about the observer’s encoding process, inference process, or decision rule. Our results provide evidence that people have uncertainty that reflects their memory precision on an item-specific level, maintain this information over a working memory delay, and use it implicitly in a way consistent with an optimal observer. These results challenge existing computational models of working memory to update their frameworks to represent uncertainty.
The guidance and adhesion protein FLRT2 dimerizesin cisvia dual Small-X3-Small transmembrane motifs
Authors: Jackson Verity , Hermann Julia , Tynan Christopher J. , Rolfe Daniel J. , Corey Robin A. , Duncan Anna L. , Noriega Maxime , Chu Amy , Kalli Antreas C. , Yvonne Jones E. , Sansom Mark S. P. , Martin-Fernandez Marisa L. , Seiradake Elena , Chavent Matthieu
Published: October 2020

Fibronectin Leucine-rich Repeat Transmembrane (FLRT 1-3) proteins are a family of broadly expressed single-spanning transmembrane receptors that play key roles in development. Their extracellular domains mediate homotypic cell-cell adhesion and heterotypic protein interactions with other receptors to regulate cell adhesion and guidance. Thesein transFLRT interactions determine the formation of signaling complexes of varying complexity and function. Whether FLRTs also interact at the surface of the same cell,in cis, remains unknown. Here, molecular dynamics simulations reveal two dimerization motifs in the FLRT2 transmembrane helix. Single particle tracking experiments show that these ‘Small-X3-Small’ motifs synergize with a third dimerization motif encoded in the extracellular domain to permit thecisassociation and co-diffusion patterns of FLRT2 receptors on cells. These results may point to a competitive switching mechanism betweenin cisandin transinteractions which suggests that homotypic FLRT interaction mirrors the functionalities of classic adhesion molecules.

Fields

Structural Biology and Biophysics / Computational Biology
Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 2
Authors: Antonarakis Stylianos E. , Holoubek Ales , Rapti Melivoia , Rademaker Jesse , Meylan Jenny , Iwaszkiewicz Justyna , Zoete Vincent , Ansar Muhammad , Borel Christelle , Menzel Olivier , Kuželová Kateřina , Santoni Federico A.
Published: October 2020

Knobloch syndrome is an autosomal recessive phenotype mainly characterized by retinal detachment and encephalocele caused by biallelic pathogenic variants in theCOL18A1gene. However, there are patients clinically diagnosed as Knobloch syndrome with unknown molecular etiology not linked toCOL18A1. We studied an historical pedigree (published in 1998) designated as KNO2 (Knobloch type 2 syndrome with intellectual disability, autistic behavior, retinal degeneration, encephalocele). Whole exome sequencing of the two affected siblings and the normal parents resulted in the identification of a PAK2 non-synonymous substitution p.(Glu435Lys) as a causative variant. The variant was monoallelic and apparentlyde novoin both siblings indicating a likely germline mosaicism in one of the parents; the mosaicism however could not be observed after deep sequencing of blood parental DNA. PAK2 encodes a member of a small group of serine/threonine kinases; these P21-activating kinases (PAKs) are essential in signal transduction and cellular regulation (cytoskeletal dynamics, cell motility, death and survival signaling, and cell cycle progression). Structural analysis of the PAK2 p.(Glu435Lys) variant which is located in the kinase domain of the protein predicts a possible compromise in the kinase activity. Functional analysis of the p.(Glu435Lys) PAK2 variant in transfected HEK293T cells results in a partial loss of the kinase activity. PAK2 has been previously suggested as an autism related gene. Our results show that PAK2 induced phenotypic spectrum is broad and not fully understood. We conclude that the KNO2 syndrome in the studied family is dominant and caused by a deleterious variant in the PAK2 gene.
BiSulfite Bolt: A BiSulfite Sequencing Analysis Platform
Authors: Farrell Colin , Thompson Michael , Tosevska Anela , Oyetunde Adewale , Pellegrini Matteo
Published: October 2020

Background

Bisulfite sequencing is commonly employed to measure DNA methylation. Processing bisulfite sequencing data is often challenging due to the computational demands of mapping a low complexity, asymmetrical library and the lack of a unified processing toolset to produce an analysis ready methylation matrix from read alignments. To address these shortcomings, we have developed BiSulfite Bolt (BSBolt); a fast and scalable bisulfite sequencing analysis platform. BSBolt performs a pre-alignment sequencing read assessment step to improve efficiency when handling asymmetrical bisulfite sequencing libraries.

Findings

We evaluated BSBolt against simulated and real bisulfite sequencing libraries. We found that BSBolt provides accurate and fast bisulfite sequencing alignments and methylation calls. We also compared BSBolt to several existing bisulfite alignment tools and found BSBolt outperforms Bismark, BSSeeker2, BISCUIT, and BWA-Meth based on alignment accuracy and methylation calling accuracy.

Conclusion

BSBolt offers streamlined processing of bisulfite sequencing data through an integrated toolset that offers support for simulation, alignment, methylation calling, and data aggregation. BSBolt is implemented as a python package and command line utility for flexibility when building informatics pipelines. BSBolt is available athttps://github.com/NuttyLogic/BSBoltunder an MIT license.
Clustering-based positive feedback between a kinase and its substrate enables effective T-cell receptor signaling
Authors: Dine Elliot , Reed Ellen H. , Toettcher Jared E.
Published: October 2020

Protein clusters and condensates are pervasive in mammalian signaling. Yet how the signaling capacity of higher-order assemblies differs from simpler forms of molecular organization is still poorly understood. Here, we present an optogenetic approach to switch between light-induced clusters and simple protein heterodimers with a single point mutation. We apply this system to study how clustering affects signaling from the kinase Zap70 and its substrate LAT, proteins that normally form membrane-localized clusters during T cell activation. We find that light-induced clusters of LAT and Zap70 trigger potent activation of downstream signaling pathways even in non-T cells, whereas one-to-one dimers do not. We provide evidence that clusters harbor a local positive feedback loop between three components: Zap70, LAT, and Src-family kinases that bind to phosphorylated LAT and further activate Zap70. Overall, our study provides evidence for a specific role of protein condensates in cell signaling, and identifies a simple biochemical circuit that can robustly sense protein oligomerization state.

Highlights

-

A general system for studying the role of protein clusters versus dimers.

-

Membrane clusters of the kinase Zap70 and its substrate LAT trigger potent downstream signaling.

-

Clustering Zap70 with LAT is required for full activation of Zap70 kinase activity.

-

A positive feedback loop connects phosphorylated LAT to Zap70 activation via Src-family kinases.
Detection of a historic reservoir of bedaquiline / clofazimine resistance associated variants inMycobacterium tuberculosis
Authors: Nimmo Camus , Ortiz Arturo Torres , Pang Juanita , Acman Mislav , Tan Cedric C.S. , Millard James , Padayatchi Nesri , Grant Alison , O’Donnell Max , Pym Alex , Brynildsrud Ola B , Eldholm Vegard , Grandjean Louis , Didelot Xavier , Balloux François , van Dorp Lucy
Published: October 2020

Drug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains ofMycobacterium tuberculosis(Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by off-target resistance-associated variants (RAVs) in themmpR5gene (Rv0678), the regulator of an efflux pump, which can also confer cross-resistance to clofazimine, another TB drug. We compiled a dataset of 3,682Mtbgenomes, including 150 carrying variants inmmpR5that have been associated to borderline (henceforth intermediate) or confirmed resistance to bedaquiline. We identified eight cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic reconstruction points to multiple emergence events and circulation of RAVs inmmpR5, some estimated to predate the introduction of bedaquiline. However, epistatic interactions can complicate bedaquiline drug-susceptibility prediction from genetic sequence data. Indeed, in one clade of isolates where the RAV Ile67fs is estimated to have emerged prior to the antibiotic era, co-occurrence of mutations inmmpL5are found to neutralise bedaquiline resistance. The presence of a pre-existing reservoir ofMtbstrains carrying bedaquiline RAVs prior to its clinical use augments the need for rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.
CardioPy: An open-source heart rate variability toolkit for single-lead EKG
Authors: Gottshall Jackie L. , Recoder Natasha , Schiff Nicholas D.
Published: October 2020

Background and Objective

Heart rate variability (HRV) is a promising clinical marker of health and disease. Although HRV methodology is relatively straightforward, accurate detection of R-peaks remains a significant methodological challenge; this is especially true for single-lead EKG signals, which are routinely collected alongside EEG monitoring and for which few software options exist. Most developed algorithms with favorable R-peak detection profiles require significant mathematical and computational proficiency for implementation, providing a significant barrier for clinical research. Our objective was to address these challenges by developing a simple, free, and open-source software package for HRV analysis of single-lead EKG signals.

Methods

CardioPy was developed in python and optimized for short-term (5-minute) single-lead EKG recordings. CardioPy’s R-peak detection trades full automation and algorithmic complexity for an adaptive thresholding mechanism, manual artifact removal and parameter adjustment. Standard time and frequency domain analyses are included, such that CardioPy may be used as a stand-alone HRV analysis package. An example use-case of HRV across wakefulness and sleep is presented and results validated against the widely used Kubios HRV software.

Results

HRV analyses were conducted in 66 EKG segments collected from five healthy individuals. Parameter optimization was conducted or each segment, requiring ~1-3 minutes of manual inspection time. With optimization, CardioPy’s R-peak detection algorithm achieved a mean sensitivity of 100.0% (SD 0.05%) and positive predictive value of 99.8% (SD 0.20%). HRV results closely matched those produced by Kubios HRV, both by eye and by quantitative comparison; CardioPy power spectra explained an average of 99.7% (SD 0.50%) of the variance present in Kubios spectra. HRV analyses showed significant group differences between brain states; SDNN, low frequency power, and low frequency-to-high frequency ratio were reduced in slow wave sleep compared to wakefulness.

Conclusions

CardioPy provides an accessible and transparent tool for HRV analyses. Manual parameter optimization and artifact removal allow granular control over data quality and a highly reproducible analytic pipeline, despite additional time requirements. Future versions are slated to include automatic parameter optimization and a graphical user interface, further reducing analysis time and improving accessibility.