bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards a Theory of Evolution as Multilevel Learning
Authors: Vanchurin Vitaly , Wolf Yuri I. , Katsnelson Mikhail I. , Koonin Eugene V. 
Published: November 2021

AbstractWe apply the theory of learning to physically renormalizable systems in an attempt to develop a theory of biological evolution, including the origin of life, as multilevel learning. We formulate seven fundamental principles of evolution that appear to be necessary and sufficient to render a universe observable and show that they entail the major features of biological evolution, including replication and natural selection. These principles also follow naturally from the theory of learning. We formulate the theory of evolution using the mathematical framework of neural networks, which provides for detailed analysis of evolutionary phenomena. To demonstrate the potential of the proposed theoretical framework, we derive a generalized version of the Central Dogma of molecular biology by analyzing the flow of information during learning (back-propagation) and predicting (forward-propagation) the environment by evolving organisms. The more complex evolutionary phenomena, such as major transitions in evolution, in particular, the origin of life, have to be analyzed in the thermodynamic limit, which is described in detail in the accompanying paper.Significance statementModern evolutionary theory gives a detailed quantitative description of microevolutionary processes that occur within evolving populations of organisms, but evolutionary transitions and emergence of multiple levels of complexity remain poorly understood. Here we establish correspondence between the key features of evolution, renormalizability of physical theories and learning dynamics, to outline a theory of evolution that strives to incorporate all evolutionary processes within a unified mathematical framework of the theory of learning. Under this theory, for example, natural selection readily arises from the learning dynamics, and in sufficiently complex systems, the same learning phenomena occur on multiple levels or on different scales, similar to the case of renormalizable physical theories.
First-order visual interneurons distribute distinct contrast and luminance information across ON and OFF pathways to achieve stable behavior
Authors: Ketkar Madhura , Gür Burak , Molina-Obando Sebastian , Ioannidou Maria , Martelli Carlotta , Silies Marion 
Published: November 2021

AbstractThe accurate processing of contrast is the basis for all visually guided behaviors. Visual scenes with rapidly changing illumination challenge contrast computation, because adaptation is not fast enough to compensate for such changes. Yet, human perception of contrast is stable even when the visual environment is quickly changing. The fruit fly Drosophila also shows nearly luminance invariant behavior for both ON and OFF stimuli. To achieve this, first-order interneurons L1, L2 and L3 all encode contrast and luminance differently, and distribute information across both ON and OFF contrast-selective pathways. Behavioral responses to both ON and OFF stimuli rely on a luminance-based correction provided by L1 and L3, wherein L1 supports contrast computation linearly, and L3 non-linearly amplifies dim stimuli. Therefore, L1, L2 and L3 are not distinct inputs to ON and OFF pathways but the lamina serves as a separate processing layer that distributes distinct luminance and contrast information across ON and OFF pathways to support behavioral performance in varying conditions.
Severity and inpatient mortality of COVID-19 pneumonia from Beta variant infection: a clinical cohort study in Cape Town, South Africa
Authors: Boloko Linda , Lifson Aimee , Little Francesca , De Wet Timothy , Papavarnavas Nectarios , Marais Gert , Hsiao Nei-yuan , Rosslee Michael-John , Doolabh Deelan , Iranzadeh Arash , Williamson Carolyn , Dlamini Sipho , Mendelson Marc , Ntusi Ntobeko , Wilkinson Robert J. , Hussey Hannah , Davies Mary-Ann , Meintjes Graeme , Wasserman Sean 
Published: November 2021

ABSTRACTBackgroundThe SARS-CoV-2 Beta variant, associated with immune escape and higher transmissibility, drove a more severe second COVID-19 wave in South Africa. Individual patient level characteristics and outcomes with the Beta variant are not well characterized.MethodsWe performed a retrospective cohort study comparing disease severity and inpatient mortality of COVID-19 pneumonia between the first and second wave periods at a referral hospital in Cape Town, South Africa. Beta variant infection was confirmed by genomic sequencing. Outcomes were analyzed with logistic regression and accelerated failure time models.Results1,182 patients were included: 571 during the first wave period and 611 from the second wave. Beta variant accounted for 97% of infections in the second wave. There was no difference in crude in-hospital mortality between wave periods (first wave 22.2%, second wave 22.1%; p = 0.9). Time to death was decreased with higher weekly hospital admissions (16%; 95% CI, 8 to 24 for every 50-patient increase), age (18%; 95% CI, 12 to 24 for every 10-year increase) and hypertension (31%; 95% CI, 12 to 46). Corticosteroid use delayed time to death by 2-fold (95% CI, 1.5 to 3.0). Admission during the second wave decreased time to death after adjustment for other predictors, but this did not reach statistical significance (24%; 95% CI, 47 to -2). There was no effect of HIV on survival.ConclusionsThere was a trend towards earlier mortality during the second COVID-19 wave driven by the Beta variant, suggesting a possible biological basis. Use of oral prednisone was strongly protective.Key pointsIn Cape Town, South Africa, the second wave of COVID-19, dominated by the Beta variant, was associated with decreased time to inpatient death after adjustment for age, comorbidities, steroid use, and admission numbers. Use of oral prednisone was strongly protective.
Calorie reformulation: A systematic review and meta-analysis examining the effect of manipulating food energy density on daily energy intake and body weight
Authors: Robinson Eric , Khuttan Mercedes , McFarland-Lesser India , Patel Zina , Jones Andrew 
Published: November 2021

AbstractBackgroundDietary energy density is thought to be a contributor to obesity, but the extent to which different magnitudes and types of reductions to food energy density decreases daily energy intake is unclear.ObjectiveTo systematically review and meta-analyse experimental studies that have examined the effect that manipulating energy density of food has on total daily energy intake.DesignA systematic review and multi-level meta-analysis of studies on human participants that used an experimental design to manipulate the energy density of foods served and measured energy intake for a minimum of one day.ResultsThirty-one eligible studies contributed 90 effects comparing the effect of higher vs. lower energy density of served food on daily energy intake to the primary meta-analysis. Lower energy density of food was associated with a large decrease in daily energy intake (SMD = -1.002 [95% CI: -0.745 to -1.266]). Findings were consistent across studies that did vs. did not manipulate macronutrient content to vary energy density. The relation between decreasing energy density and daily energy intake tended to be strong and linear, whereby compensation for decreases to energy density of foods (i.e. by eating more at other meals) was minimal. Meta-analysis of (n=5) studies indicated that serving lower energy dense food tended to be associated with greater weight loss than serving higher energy dense food, but this difference was not significant (−0.7kg, 95% CIs: -1.34, 0.04).ConclusionsDecreasing the energy density of food can substantially reduce daily energy intake and may therefore be an effective public health approach to reducing population level energy intake.
Chitin and cuticle proteins form the cuticular layer in spinning duct of silk-spinning arthropods
Authors: Wang Xin , Xie Xiaoqian , Xie Kang , Liu Qingsong , Li Yi , Tan Xiaoyin , Dong Haonan , Li Xinning , Dong Zhaoming , Xia Qingyou , Zhao Ping 
Published: November 2021

ABSTRACTChitin is found in the exoskeleton and peritrophic matrix of arthropods, but recent studies have also identified chitin in the spinning duct of silk-spinning arthropods. Here, we report the presence and function of chitin and cuticle proteins ASSCP1 and ASSCP2 in the spinning duct of silkworms. We show that chitin and these proteins are co-located in the cuticular layer of the spinning duct. Ultrastructural analysis indicates that the cuticular layer has a multilayer structure by layered stacking of the chitin laminae. After knocking down ASSCP1 and ASSCP2, the fine structure of this layer was disrupted, which had negative impacts on the mechanical properties of silk. This work clarifies the function of chitin in the spinning duct of silk-spinning arthropods. Chitin and cuticle proteins are the main components of the hard and rigid cuticular layer, providing the shearing stress during silk fibrillogenesis and regulating the final mechanical properties of silk.
OMAMO: orthology-based model organism selection
Authors: Nicheperovich Alina , Altenhoff Adrian M. , Dessimoz Christophe , Majidian Sina 
Published: November 2021

AbstractSummaryThe conservation of pathways and genes across species has allowed scientists to use non-human model organisms to gain a deeper understanding of human biology. However, the use of traditional model systems such as mice, rats, and zebrafish is costly, time-consuming and increasingly raises ethical concerns, which highlights the need to search for less complex model organisms. Existing tools only focus on the few well-studied model systems, most of which are complex animals. To address these issues, we have developed Orthologous Matrix and Model Organisms, a software and a website that provide the user with the best simple organism for research into a biological process of interest based on orthologous relationships between the human and the species. The outputs provided by the database were supported by a systematic literature review.Availability and implementationhttps://omabrowser.org/omamo/, https://github.com/DessimozLab/omamoContactchristophe.dessimoz@unil.ch and sina.majidian@unil.ch
The Impact of Multivesicular Release on the Transmission of Sensory Information by Ribbon Synapses
Authors: James Ben , Piekarz Pawel , Moya-Diaz José , Lagnado Leon 
Published: November 2021

AbstractThe statistics of vesicle release determine how information is transferred at the synapse but the classical Poisson model of independent fusion does not hold at the first stages of vision and hearing. There, ribbon synapses encoding analogue signals can coordinate the release of two or more vesicles as a single event. The implications of such multivesicular release (MVR) for spike generation are not known. Here we investigate the hypothesis that MVR might provide advantages over Poisson synapses. We used leaky integrate-and-fire models incorporating the statistics of release measured experimentally from glutamatergic synapses of retinal bipolar cells and compared these with models assuming Poisson inputs constrained to operate at the same average rates. We find that MVR can increase the number of spikes generated per vesicle while reducing interspike intervals and latency to first spike. The combined effect was to increase the efficiency of information transfer (bits per spike) over a range of conditions mimicing retinal ganglion cells of different size. MVR was most advantageous in neurons with short time-constants and reliable synaptic inputs, when a lower degree of convergence was required to trigger spikes. In the special case of a single input driving a neuron with short time-constant, as occurs at the first synapse in hearing, MVR increased information transfer whenever spike generation required more than one vesicle. This study demonstrates how presynaptic integration of vesicles by MVR has the potential to compensate for less effective summation post-synaptically to increase the efficiency with which sensory information is transmitted.
Joint inference of exclusivity patterns and recurrent trajectories from tumor mutation trees
Authors: Luo Xiang Ge , Kuipers Jack , Beerenwinkel Niko 
Published: November 2021

AbstractCancer progression is an evolutionary process shaped by both deterministic and stochastic forces. Multi-region and single-cell sequencing of tumors enable high-resolution reconstruction of the mutational history of each tumor and highlight the extensive diversity across tumors and patients. Resolving the interactions among mutations and recovering recurrent evolutionary processes may offer greater opportunities for successful therapeutic strategies. To this end, we present a novel probabilistic framework, called TreeMHN, for the joint inference of exclusivity patterns and recurrent trajectories from a cohort of intra-tumor phylogenetic trees. Through simulations, we show that TreeMHN outperforms existing alternatives that can only focus on one aspect of the task. By analyzing datasets of blood, lung, and breast cancers, we find the most likely evolutionary trajectories and mutational patterns, consistent with and enriching our current understanding of tumorigenesis. Moreover, TreeMHN facilitates the prediction of tumor evolution and provides probabilistic measures on the next mutational events given a tumor tree, a prerequisite for evolution-guided treatment strategies.
PD-L1-expressing astrocytes act as a gate-keeper for neuroinflammation in the central nervous system of mice with traumatic brain injury
Authors: Gao Xiang , Li Wei , Syed Fahim , Yuan Fang , Li Ping , Yu Qigui 
Published: November 2021

AbstractBackgroundTissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain. While appropriate acute and transient neuroimmune and neuroinflammatory responses facilitate the repair and adaptation of injured brain tissues, prolonged and excessive neuroimmune and neuroinflammatory responses exacerbate brain damage. The mechanisms that control the intensity and duration of neuroimmune and neuroinflammatory responses in TBI largely remain elusive.MethodsWe used the controlled cortical impact (CCI) model of TBI to study the role of immune checkpoints (ICPs), key regulators of immune homeostasis, in the regulation of neuroimmune and neuroinflammatory responses in the brainin vivo.ResultsWe found thatde novoexpression of PD-L1, a potent inhibitory ICP, was robustly and transiently induced in reactive astrocytes, but not in microglial cells, neurons, or oligodendrocyte progenitor cells (OPCs). These PD-L1+reactive astrocytes were highly enriched to form a dense zone around the TBI lesion. Blockade of PD-L1 signaling enlarged brain tissue cavity size, increased infiltration of inflammatory Ly-6CHighmonocytes/macrophages (M/Mϕ) but not tissue-repairing Ly-6CLow/F4/80+M/Mϕ, and worsened TBI outcomes in mice. PD-L1 gene knockout enhanced production of CCL2 that interacted with its cognate receptor CCR2 on Ly-6CHighM/Mϕto chemotactically recruit these cells into inflammatory sites. Mechanically, PD-L1 signaling in astrocytes likely exhibits dual inhibitory activities for the prevention of excessive neuroimmune and neuroinflammatory responses to TBI through(1)the PD-1/PD-L1 axis to suppress the activity of brain-infiltrating PD-1+immune cells such as PD-1+T cells, and(2)PD-L1 reverse signaling to regulate the timing and intensity of astrocyte reactions to TBI.ConclusionsPD-L1+astrocytes act as a gatekeeper to the brain to control TBI-related neuroimmune and neuroinflammatory responses, thereby opening a novel avenue to study the role of ICP-neuroimmune axes in the pathophysiology of TBI and other neurological disorders.
miR-122 affects both the initiation and maintenance of Hepatitis C Virus infections
Authors: Panigrahi Mamata , Thibault Patricia A , Wilson Joyce A 
Published: November 2021

ABSTRACTA liver-specific microRNA, miR-122, anneals to the HCV genomic 5’ terminus and is essential for virus replication in cell culture. However, bicistronic HCV replicons and full length RNAs with specific mutations in the 5’ UTR can replicate, albeit to low levels, without miR-122. In this study, we have identified that HCV RNAs lacking the structural gene region or having EMCV IRES-regulated translation had reduced requirements for miR-122. In addition, we found that a smaller proportion of cells supported miR-122-independent replication when compared a population of cells supporting miR-122-dependent replication, while viral protein levels per positive cell were similar. Further, the proportion of cells supporting miR-122-independent replication increased with the amount of viral RNA delivered, suggesting that establishment of miR-122-independent replication in a cell is affected by amount of viral RNA delivered. HCV RNAs replicating independent of miR-122 were not affected by supplementation with miR-122, suggesting that miR-122 is not essential for maintenance of a miR-122-independent HCV infection. However, miR-122 supplementation had a small positive impact on miR-122-dependent replication suggesting a minor role in enhancing ongoing virus RNA accumulation. We suggest that miR-122 functions primarily to initiate an HCV infection but has a minor influence on its maintenance, and we present a model in which miR-122 is required for replication complex formation at the beginning of an infection, and also supports new replication complex formation during ongoing infection and after infected cell division.IMPORTANCEThe mechanism by which miR-122 promotes the HCV life cycle is not well understood, and a role in directly promoting genome amplification is still debated. In this study, we have shown that miR-122 increases the rate of viral RNA accumulation and promotes the establishment of an HCV infection in a greater number of cells than in the absence of miR-122. However, we also confirm a minor role in promoting ongoing virus replication and propose a role in the initiation of new replication complexes throughout a virus infection. This study has implications for the use of anti-miR-122 as potential HCV therapy.
Sexual reproduction contributes to the evolution of resistance breaking isolates of the spinach pathogen Peronospora effusa
Authors: Skiadas Petros , Klein Joël , Monnens Thomas Quiroz , Elberse Joyce , de Jonge Ronnie , Van den Ackerveken Guido , Seidl Michael F. 
Published: November 2021

AbstractPeronospora effusa causes downy mildew, the economically most important disease of cultivated spinach worldwide. To date, 19 P. effusa races have been denominated based on their capacity to break spinach resistances, but their genetic diversity and the evolutionary processes that contribute to race emergence are unknown. Here, we performed the first systematic analysis of P. effusa races showing that those emerge by both asexual and sexual reproduction. Specifically, we studied the diversity of 26 P. effusa isolates from 16 denominated races based on mitochondrial and nuclear comparative genomics. Mitochondrial genomes based on long-read sequencing coupled with diversity assessment based on short-read sequencing uncovered two mitochondrial haplogroups, each with distinct genome organization. Nuclear genome-wide comparisons of the 26 isolates revealed that ten isolates from six races could clearly be divided into three asexually evolving groups, in concordance with their mitochondrial phylogeny. The remaining isolates showed signals of reticulated evolution and discordance between nuclear and mitochondrial phylogenies, suggesting that these evolved through sexual reproduction. Increased understanding of this pathogen’s reproductive modes will provide the framework for future studies into the molecular mechanisms underlying race emergence and into the P. effusa-spinach interaction, thus assisting in sustainable production of spinach through knowledge-driven resistance breeding.Significance statementMany microbial plant pathogens depend on the successful colonization of their hosts to complete their life cycle, thereby damaging food crops worldwide. The most effective way of disease control is to deploy genetic disease resistances. However, the extensive use of resistant crop varieties exerts strong selective pressure on microbial plant pathogens to adapt in order to escape resistance. Through yet unknown mechanisms, the spinach pathogen Peronospora effusa can rapidly break the resistance of newly introduced varieties, often within a single growing season. Thus, there is an urgent need to better understand the mechanisms driving adaptation in P. effusa. This information will lead the way to knowledge-driven resistance breeding. Here, we capture for the first time the genetic variation of 26 P. effusa, 16 of which can break a different combination of host resistances. We demonstrate that P. effusa isolates evolve by both asexual and sexual reproduction, and thereby provide the framework to study the molecular mechanisms of the interactions between P. effusa and spinach.
CDK5 mediated phosphorylation of cytosolic phospholipase A2 regulates its activity and neuroinflammation in Parkinson’s Disease
Authors: Paul Sangita , Fatihi Saman , Sharma Srishti , Kutum Rintu , Fields Raymond , Pant Harish C , Thukral Lipi , Binukumar BK 
Published: November 2021

AbstractHyperactivation of cyclin-dependent kinase 5 (CDK5) by p25, contributes to neuroinflammation causing neurodegeneration in Parkinson’s Disease (PD) and Alzheimer diseases (AD). However, the mechanism by which CDK5 induces neuroinflammation in the PD brain is largely unexplored. Here, we show that CDK5 phosphorylates cytosolic phospholipase A2 (cPLA2) at Thr-268 and Ser-505 sites lead to its activation and generation of eicosanoid products. Mutational studies using site-directed mutagenesis and molecular simulations show that the architecture of the protein changes upon each single-point mutation. Interestingly, double-mutations also led to severe decline in the activity of cPLA2 and disruption of its translocation to the plasma membrane. Further, the brain lysates of transgenic PD mouse models show hyperactivation of CDK5 resulting in enhanced phosphorylation of Thr-268 and Ser-505 of cPLA2 and its heightened activity confirming the findings observed in the cell culture model of PD. These phosphorylation sites of cPLA2 and CDK5 could be explored as the future therapeutic targets against neuroinflammation in PD. Further, conjoint transcriptomic analysis of the publicly available human PD datasets strengthens the hypothesis that genes of the arachidonic acid, prostaglandin synthesis and inflammatory pathways are significantly upregulated in case of the PD patients as compared to that of healthy controls.