bluuebunny/crossref_metadata_2025 huggingface dataset:
Serotype patterns of pneumococcal disease in adults are correlated with carriage patterns in older children
Authors: Wyllie Anne L. , Warren Joshua L. , Regev-Yochay Gili , Givon-Lavi Noga , Dagan Ron , Weinberger Daniel M.
Published: December 2019

Background

The importance of specific serotypes causing invasive pneumococcal disease (IPD) differs by age. Data on pneumococcal carriage in different age groups, along with data on serotype-specific invasiveness, could help to explain these age-related patterns and their implications for vaccination.

Methods

Using pneumococcal carriage and disease data from Israel, we evaluated the association between serotype-specific IPD in adults and serotype-specific carriage prevalence among children in different age categories, while adjusting for serotype-specific invasiveness. We used a sliding window approach to estimate carriage prevalence using different age groupings. Deviance Information Criterion was used to determine which age groupings of carriage data best fit the adult IPD data. Serotype-specific disease patterns were further evaluated by stratifying IPD data by comorbidity status.

Results

The relative frequency of serotypes causing IPD differed between adults and children, and also differed between older and younger adults and between adults with and without comorbidities. Serotypes over-represented as causes of IPD in adults were more commonly carried in older children as compared to younger children. In line with this, the serotype-specific frequency of carriage in older children (aged 36-59 months), rather than infants, best correlated with serotype-specific IPD in adults.

Conclusions

These analyses suggest that older children, rather than infants, are the main drivers of disease patterns in adults. These insights could help in optimizing vaccination strategies to reduce disease burden across all ages.

40-word summary of the article’s main point

Serotype-specific rates of invasive pneumococcal disease in adults are better correlated with serotype-specific carriage patterns in older children (36-59 months of age) than those in infants.
VPS41recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling
Authors: van der Welle R.E.N. , Jobling R. , Burns C. , Sanza P. , ten Brink C. , Fasano A. , Chen L. , Zwartkruis F.J. , Zwakenberg S. , Griffin E.F. , van der Beek J. , Veenendaal T. , Liv N. , Blaser S. , Sepulveda C. , Lozano A.M. , Yoon G. , Asensio C.S. , Caldwell G.A. , Caldwell K.A. , Chitayat D. , Klumperman J.
Published: December 2019

The vacuolar protein sorting protein 41 (VPS41) is a neuroprotective protein in models of Parkinson’s disease (PD). As part of the HOPS (Homotypic fusion and Protein Sorting) complex, VPS41 regulates fusion of lysosomes with late endosomes and autophagosomes. Independent of HOPS, VPS41 regulates transport of newly synthesized lysosomal membrane proteins and secretory proteins. Here we report two brothers with compound heterozygous mutations inVPS41(VPS41R662*andVPS41S285P), born to healthy and non-consanguineous parents. Both patients displayed transient retinal dystrophy, ataxia and dystonia, with brain MRI findings of cerebellar atrophy and a thin saber-shape corpus callosum. Patient-derived fibroblasts contained enzymatically active lysosomes that were poorly reached by endocytic cargo and failed to attract the mTORC1 complex. Consequently, transcription factor TFE3, a driver of autophagy and lysosomal genes, showed continuous nuclear localization which resulted in elevated LC3-II levels and an impaired response to nutrient starvation. CRISPR/CASVPS41HeLa knockout cells showed a similar phenotype that could be rescued by wildtype VPS41 but not by VPS41S285Por VPS41R662*. mTORC1 inhibition was also seen after knockout of HOPS subunits VPS11 or VPS18. Regulated neuropeptide secretion in PC12VPS41knockout cells was rescued by VPS41S285Pexpression, indicating that this HOPS-independent function was preserved. Co-expression of the VPS41S285Pand VPS41R662*variants in aC. elegansmodel of PD abolished the protective effect of VPS41 against α-synuclein-induced neurodegeneration. We conclude that both disease-associatedVPS41variants specifically abrogate HOPS function, which leads to a delay in endocytic cargo delivery to lysosomes, mTORC1 inhibition and irresponsiveness to autophagic clues. Our studies signify a link between HOPS function and mTORC1 signaling and imply that HOPS function is required for the neuroprotective effect of VPS41 in PD.
Alterations in Brain Morphology by MRI in Adults with Neurofibromatosis 1
Authors: Wang Su , Mautner Victor-Felix , Buchert Ralph , Flibotte Stephane , Suppa Per , Friedman Jan M. , Heran Manraj K. S.
Published: December 2019

Objective

To characterize alterations in brain morphology by MRI in adults with neurofibromatosis 1 (NF1).

Methods

Planar (2D) MRI measurements of 29 intracranial structures were compared in 389 adults with NF1 and 112 age- and sex-matched unaffected control subjects. The 2D measurements were correlated to volumetric (3D) brain measurements for 99 of the adults with NF1.

A subset of adults with NF1 (n = 70) was also assessed for clinical severity of NF1 features and neurological problems and received psychometric testing for attention deficits and IQ. Correlation analyses were performed between principal components of the intracranial measurements and clinical and psychometric features of these patients.

Results

Four of nine corpus callosum measurements were significantly greater in adults with NF1 than in sex- and age-matched controls. All seven brainstem measurements were significantly greater in adults with NF1 than in controls. Increased corpus callosum and brainstem 2D morphology were correlated with increased total white matter volume among the NF1 patients. No robust correlations were observed between the 2D size of these structures and clinical or neuropsychometric assessments.

Interpretation

Our findings are consistent with the hypothesis that dysregulation of brain myelin production is an important manifestation of NF1 in adults.
An integrative machine learning approach to discovering multi-level molecular mechanisms of obesity using data from monozygotic twin pairs
Authors: Kibble Milla , Khan Suleiman A. , Ammad-ud-din Muhammad , Bollepalli Sailalitha , Palviainen Teemu , Kaprio Jaakko , Pietiläinen Kirsi H. , Ollikainen Miina
Published: December 2019

We combined clinical, cytokine, genomic, methylation and dietary data from 43 young adult monozygotic twin pairs (aged 22 – 36, 53% female), where 25 of the twin pairs were substantially weight discordant (delta BMI > 3kg/ m2). These measurements were originally taken as part of the TwinFat study, a substudy of The Finnish Twin Cohort study. These five large multivariate data sets (comprising 42, 71, 1587, 1605 and 63 variables, respectively) were jointly analysed using an integrative machine learning method called Group Factor Analysis (GFA) to offer new hypotheses into the multi-molecular-level interactions associated with the development of obesity. New potential links between cytokines and weight gain are identified, as well as associations between dietary, inflammatory and epigenetic factors. This encouraging case study aims to enthuse the research community to boldly attempt new machine learning approaches which have the potential to yield novel and unintuitive hypotheses. The source code of the GFA method is publically available as the R package GFA.
Seroprevalence of the hepatitis E virus among blood donors in the Qassim Region, Saudi Arabia
Authors: Alhatlani Bader Y. , Aljabr Waleed A. , Almarzouqi Mohammed S. , Alhatlani Sami M. , Alzunaydi Rayan N. , Alsaykhan Abeer S. , Almaiman Sulaiman H. , Aleid Ahmed A. , Alsughayir Ammar H. , Bishawri Yara E. , Almusallam Abdulrahman A.
Published: December 2019

The aim of this study was to evaluate the seroprevalence of hepatitis E virus (HEV), a major public health issue worldwide with the potential for transmission via blood transfusion, in blood donors in the Qassim Region, Saudi Arabia. Serum samples (n = 1,078) were collected from volunteer blood donors from January to April 2019 and tested for the presence of anti-HEV IgG and IgM by indirect enzyme-linked immunosorbent assays. Overall, the seroprevalence of anti-HEV IgG and IgM among blood donors was 5.7% and 1.3%, respectively. Additionally, the seropositive rates of anti-HEV IgG and IgM were significantly higher in non-Saudi donors (22.1% and 7.8%) than in Saudi donors (3% and 0.2%). The seroprevalence of anti-HEV IgG increased with age; however, there was no correlation between gender and anti-HEV IgG and/or IgM. The seroprevalence of HEV among blood donors in the Qassim Region was lower than previous estimates for other regions of the country. Further studies covering a wider geographical area are needed to validate and expand the findings and to determine the importance of HEV screening in the region.
Massively parallel, time-resolved single-cell RNA sequencing with scNT-Seq
Authors: Qiu Qi , Hu Peng , Govek Kiya W. , Camara Pablo G. , Wu Hao
Published: December 2019

Single-cell RNA sequencing offers snapshots of whole transcriptomes but obscures the temporal dynamics of RNA biogenesis and decay. Here we present single-cell new transcript tagging sequencing (scNT-Seq), a method for massively parallel analysis of newly-transcribed and pre-existing RNAs from the same cell. This droplet microfluidics-based method enables high-throughput chemical conversion on barcoded beads, efficiently marking metabolically labeled newly-transcribed RNAs with T-to-C substitutions. By simultaneously measuring new and old transcriptomes, scNT-Seq reveals neuronal subtype-specific gene regulatory networks and time-resolved RNA trajectories in response to brief (minutes) versus sustained (hours) neuronal activation. Integrating scNT-Seq with genetic perturbation reveals that DNA methylcytosine dioxygenases may inhibit stepwise transition from pluripotent embryonic stem cell state to intermediate and totipotent two-cell-embryo-like (2C-like) states by promoting global RNA biogenesis. Furthermore, pulse-chase scNT-Seq enables transcriptome-wide measurements of RNA stability in rare 2C-like cells. Time-resolved single-cell transcriptomic analysis thus opens new lines of inquiry regarding cell-type-specific RNA regulatory mechanisms.
Incipient resistance to an effective pesticide results from genetic adaptation and the canalization of gene expression
Authors: Yin Xiaoshen , Martinez Alexander S. , Perkins Abigail , Sparks Morgan M. , Harder Avril M. , Willoughby Janna R. , Sepúlveda Maria S. , Christie Mark R.
Published: December 2019

The resistance of bacteria, disease vectors, and pest species to chemical controls has vast ecological, economic, and societal costs. In most cases, resistance is only detected after spreading throughout an entire population. Detecting resistance in its incipient stages, by comparison, provides time to implement preventative strategies. Incipient resistance can be detected by coupling standard toxicology assays with large-scale gene expression experiments. We apply this approach to a system where an invasive parasite, sea lamprey (Petromyzon marinus), has been treated with the highly-effective pesticide 3-trifluoromethyl-4-nitrophenol (TFM) for 60 years. Toxicological experiments revealed that lamprey from treated populations did not have higher survival to TFM exposure than lamprey from their native range, demonstrating that full-fledged resistance has not yet evolved. In contrast, we find hundreds of genes differentially expressed in response to TFM in the population with the longest history of exposure, many of which relate to TFM’s primary mode of action, the uncoupling of oxidative phosphorylation and subsequent depletion of ATP. Three genes critical to oxidative phosphorylation,ATP5PB, PLCB1, andNDUFA9, were nearly fixed for alternative alleles in comparisons of SNPs between native and treated populations (FST> 5 SD from the mean).ATP5PBencodes subunit b of ATP synthase and an additional subunit,ATP5F1B, was canalized for high expression in treated populations, but remained plastic in response to TFM treatment in individuals from the native range. These combined genomic and transcriptomic results demonstrate that an adaptive, genetic response to TFM is driving incipient resistance in a damaging pest species.
Cell type- and stage-specific expression of Otx2 is coordinated by a cohort of transcription factors and multiplecis-regulatory modules in the retina
Authors: Chan Candace , Lonfat Nicolas , Zhao Rong , Davis Alexander , Li Liang , Wu Man-Ru , Lin Cheng-Hui , Ji Zhe , Cepko Constance L. , Wang Sui
Published: December 2019

Transcription factors (TFs) are often used repeatedly during development and homeostasis to control distinct processes in the same and/or different cellular contexts. Considering the limited number of TFs in the genome and the tremendous number of events that need to be regulated, re-use of TFs is an advantageous strategy. However, the mechanisms that control the activation of TFs in different cell types and at different stages of development remain unclear. The neural retina serves as a model of the development of a complex tissue. We used this system to analyze how expression of the homeobox TF, Orthodenticle homeobox 2 (Otx2), is regulated in a cell type- and stage-specific manner during retinogenesis. We identified sevenOtx2 cis-regulatory modules (CRMs), among which the O5, O7 and O9 CRMs mark three distinct cellular contexts of Otx2 expression. These include mature bipolar interneurons, photoreceptors, and retinal progenitor/precursor cells. We discovered that Otx2, Crx and Sox2, which are well-known TFs regulating retinal development, bind to and activate the O5, O7 or O9 CRMs respectively. The chromatin status of these three CRMs was found to be distinct in vivo in different retinal cell types and at different stages, as revealed by ATAC-seq and DNase-seq analyses. We conclude that retinal cells utilize a cohort of TFs with different expression patterns, and multiple CRMs with different chromatin configurations, to precisely regulate the expression of Otx2 in a cell type- and stage-specific manner in the retina.
Interaction of an abiraterone with calf thymus DNA: Investigation with spectroscopic technique and modeling studies
Authors: Wani Tanveer A. , Alsaif Nawaf , Bakheit Ahmed H. , Zargar Seema , Al-Mehizia Abdurrahman A. , Khan Azmat Ali
Published: December 2019

Binding of toxic ligands to DNA could result in undesirable biological processes, such as carcinogenesis or mutagenesis. Binding mode of Abiraterone (ABR), a steroid drug and ctDNA(calf thymus DNA was investigated in this study using fluorescence and ultraviolet–visible spectroscopy. The probable prediction of binding and the type of interaction forces involved in the arrangement between ABR and ctDNA were explored through spectroscopic and molecular docking studies. The results indicated the binding of ABR to ctDNA in the minor groove. The binding constants were in the range of 1.35 × 106– 0.36× 106L mol-1at the studied temperatures. Fluorescence and spectrophotometric data suggested static quenching between ctDNA and ABR The endothermic values of thermodynamic parameters ΔH= -82.8 kJ mol−1; ΔS= - 161 J mol−1K−1suggested that hydrogen bonding is the main force involved in binding ctDNA and ABR. In experimental studies the free binding energy at 298K was −34.9 kJ mol−1with the relative binding energy ≈ −29.65 kJ mol−1of docked structure. The Ksv obtained for ABR-KI was similar to that for ABR-ctDNA -KI demonstrating no protection by ctDNA against quenching effect of KI. Thus, suggesting involvement of groove binding between ABR and ctDNA. No change in the fluorescence intensity of ABR-ctDNA was observed in presence of NaCl. Thus, ruling out the involvement of electrostatic interaction. These studies could serve as new insights in understanding the mechanisms of toxicity, resistance and side effects of ABR.
Low costs of adaptation to dietary restriction
Authors: Moger-Reischer Roy Z. , Snider Elizabeth V. , McKenzie Kelsey L. , Lennon Jay T.
Published: December 2019

Dietary restriction (DR) is the most successful and widespread means of extending organismal lifespan. However, the evolutionary basis of life extension under DR remains uncertain. The traditional evolutionary explanation is that when organisms experience DR, they allocate endogenous resources to survival and postpone reproduction until conditions improve. However, this life-extension strategy should be maladaptive if DR continues for multiple generations due to tradeoffs between longevity and reproduction. To test this prediction, we subjected the budding yeastSaccharomyces cerevisiaeto 1,800 generations of evolution on restricted (i.e., DR) vs. non-restricted diets. Adaptation to a non-restricted diet improved reproductive fitness by 57% on that diet, but provided a much smaller (14%) advantage on a restricted diet. In contrast, adaptation to DR resulted in an approximately 35% increase in reproductive fitness on both restricted and non-restricted diets. Importantly, the life-extending effect of DR did not decrease following long-term evolution on the restricted diet. Thus, contrary to theoretical expectations, we found no evidence that the life-extending DR response became maladaptive during multigenerational DR. Our results suggest the DR response may have a low cost and that this phenomenon may have evolved for reasons that extend beyond the benefits of postponing reproduction.
Distinct evolutionary trajectories of V1R clades across mouse species
Authors: Miller Caitlin H , Campbell Polly , Sheehan Michael J
Published: December 2019

Background

Many animals rely heavily on olfaction to navigate their environment. Among rodents, olfaction is crucial for a wide range of social behaviors. The vomeronasal olfactory system in particular plays an important role in mediating social communication, including the detection of pheromones and recognition signals. Currently, very few vomeronasal receptors have known ligands, which severely limits our understanding of chemosensory-driven social communication. In this study we examine patterns of vomeronasal type-1 receptor (V1R) evolution in the house mouse and related species within the genusMus. By exploring the evolution of these receptors, we provide insight into the functional roles of receptor subtypes as well as the dynamics of gene family evolution.

Results

We generated transcriptomes from the vomeronasal organs of 5Musspecies, and produced high quality V1R repertoires for each species. We find that V1R clades in the house mouse and relatives exhibit distinct evolutionary trajectories. Some clades are highly conserved, while others reveal patterns of rapid evolutionary change. We identify putative species-specific gene expansions, including a dramatic clade D expansion in the house mouse. While gene gains are abundant, we detect very few gene losses. We describe a novel V1R clade and highlight candidate receptors for future de-orphanization. Based on clade-level evolutionary patterns, we identify receptor families that are strong candidates for detecting social signals and predator cues. Our results further support the view that V1Rs are important for detecting the physiological status of conspecifics, particularly female estrus cues.

Conclusion

Analysis of clade-level evolution is critical for understanding species’ chemosensory adaptations. This study provides clear evidence that V1R clades are characterized by distinct evolutionary trajectories. As receptor evolution is shaped by ligand identity, these results provide a framework for examining the functional roles of different receptors.
Personalized genealogical history inferred from biobank-scale IBD segments
Authors: Naseri Ardalan , Tang Kecong , Geng Xin , Shi Junjie , Zhang Jing , Liu Xiaoming , Zhang Shaojie , Zhi Degui
Published: December 2019

When modern biobanks collect genotype information for a significant fraction of a population, dense genetic connections of a person can be traced using identity by descent (IBD) segments. These connections offer opportunities to characterize individuals in the context of the underlying populations. Here, we conducted an individual-centric analysis of IBDs among the UK Biobank participants that represent 0.7% of the UK population. On average, one UK individual shares IBDs over 5 cM with 14,000 UK Biobank participants, which we refer to as “cousins”. Using these segments, approximately 80% of a person’s genome can be reconstructed. Also, using changes of cousin counts sharing IBDs at different lengths, we identified a group, potentially British Jews, who has a distinct pattern of familial expansion history. Finally, using the enrichment of cousins in one’s neighborhood, we identified regional variations of personal preference favoring living closer to one’s extended families. In summary, our analysis revealed genetic makeup, personal genealogical history, and social behaviors at population scale, opening possibilities for further studies of individual’s genetic connections in biobank data.
Single molecule studies reveal that p53 tetramers dynamically bind response elements containing one or two half sites
Authors: Ly Elina , Kugel Jennifer F. , Goodrich James A.
Published: December 2019

The tumor suppressor protein p53 is at the nexus of cell fate decisions, including apoptosis, senescence, and cell cycle arrest. p53 is a tetrameric transcription factor that binds to DNA response elements to regulate transcription of its target genes, a process activated by cellular stress. p53 response elements consist of two decameric half-sites, and most data suggest one p53 dimer in the tetramer binds to each half-site. Despite a broad literature describing p53 binding to DNA, unanswered questions remain, due in part to the need for more quantitative and structural studies with the full length protein. Here we describe a single molecule fluorescence system to visualize full length p53 tetramers binding to DNA in real time. The data reveal a dynamic interaction with many p53 binding and dissociation events occurring on single DNA molecules over minutes. We found that p53 tetramers bound to response elements containing only a single half site. The kinetic stability of tetramer/DNA complexes depended on the number of half sites and the helical phasing between them, with the most stable complexes forming on DNA containing two adjacent half sites. The forward rate of binding was not strongly impacted when one half site was mutated. These studies provide real time kinetic measurements of full length p53 tetramers binding to single molecules of DNA, and reveal new insight into the mechanisms by which this nucleoprotein complex forms.
Learning steers the ontogeny of an efficient hunting sequence in zebrafish larvae
Authors: Lagogiannis Konstantinos , Diana Giovanni , Meyer Martin P
Published: December 2019

The success of goal-directed behaviours relies on the coordinated execution of a sequence of component actions. In young animals, such sequences may be poorly coordinated, but with age and experience, behaviour progressively adapts to efficiently exploit the animal’s ecological niche. How experience impinges on the developing neural circuits of behaviour is an open question. As a model system, larval zebrafish (Danio rerio) hold enormous potential for studying both the development of behaviour and the underlying circuits, but no relevant experience-dependent learning paradigm has yet been characterized. To address this, we have conducted a detailed study of the effects of experience on the ontogeny of hunting behaviour in larval zebrafish. We report that larvae with prior prey experience consume considerably more prey than naive larvae. This is mainly due to increased capture success that is also accompanied by a modest increase in hunt rate. We identified two components of the hunting sequence that are jointly modified by experience. At the onset of the hunting sequence, the orientation strategy of the turn towards prey is modified such that experienced larvae undershoot prey azimuth. Near the end of the hunt sequence, we find that experienced larvae are more likely to employ high-speed capture swims initiated from longer distances to prey. Combined, these modified turn and capture manoeuvrers can be used to predict the probability of capture success and suggest that their development provides advantages specific to larvae feeding on live-prey. Our findings establish an ethologically relevant paradigm in zebrafish for studying how the brain is shaped by experience to drive the ontogeny of efficient behaviour.
Short-term Effects of Vagus Nerve Stimulation on Learning and Evoked Activity in Auditory Cortex
Authors: Lai Jesyin , David Stephen V.
Published: December 2019

Chronic vagus nerve stimulation (VNS) can facilitate learning of sensory and motor behaviors. VNS is believed to trigger release of neuromodulators, including norepinephrine and acetylcholine, which can mediate cortical plasticity associated with learning. Most previous work has studied effects of VNS over many days, and less is known about how acute VNS influences neural coding and behavior over the shorter term. To explore this question, we measured effects of VNS on learning of an auditory discrimination over 1-2 days. Ferrets implanted with cuff electrodes on the vagus nerve were trained by classical conditioning on a tone frequency-reward association. One tone was associated with reward while another tone, was not. The frequencies and reward associations of the tones were changed every two days, requiring learning of a new relationship. When the tones (both rewarded and non-rewarded) were paired with VNS, rates of learning increased on the first day following a change in reward association. To examine VNS effects on auditory coding, we recorded single- and multi-unit neural activity in primary auditory cortex (A1) of passively listening animals following brief periods of VNS (20 trials/session) paired with tones. Because afferent VNS induces changes in pupil size associated with fluctuations in neuromodulation, we also measured pupil during recordings. After pairing VNS with a neuron’s best-frequency (BF) tone, responses in a subpopulation of neurons were reduced. Pairing with an off-BF tone or performing VNS during the inter-trial interval had no effect on responses. We separated the change in A1 activity into two components, one that could be predicted by fluctuations in pupil and one that persisted after VNS and was not accounted for by pupil. The BF-specific reduction in neural responses remained, even after regressing out changes that could be explained by pupil. In addition, the size of VNS-mediated changes in pupil predicted the magnitude of persistent changes in the neural response. This interaction suggests that changes in neuromodulation associated with arousal gate the long-term effects of VNS on neural activity. Taken together, these results support a role for VNS in auditory learning and help establish VNS as a tool to facilitate neural plasticity.
Inhibitory control of active expiration by the Bötzinger complex in rats
Authors: Flor Karine C. , Barnett William H. , Karlen-Amarante Marlusa , Molkov Yaroslav , Zoccal Daniel B.
Published: December 2019

The expiratory neurons of the Bötzinger complex (BötC) provide inhibitory inputs to the respiratory network, which, during eupnea, are critically important for respiratory phase transition and duration control. Herein, we investigated how the BötC neurons interact with the expiratory oscillator located in the parafacial respiratory group (pFRG) and control the abdominal activity during active expiration. Using the decerebrated, arterially perfusedin siturat preparations, we recorded the neuronal activity and performed pharmacological manipulations of the BötC and pFRG during hypercapnia or after the exposure to short-term sustained hypoxia – conditions that generate active expiration. The experimental data were integrated in a mathematical model to gain new insights in the inhibitory connectome within the respiratory central pattern generator. Our results reveal a complex inhibitory circuitry within the BötC that provides inhibitory inputs to the pFRG thus restraining abdominal activity under resting conditions and contributing to abdominal expiratory pattern formation during active expiration.
Engineering recurrent neural networks from task-relevant manifolds and dynamics
Authors: Pollock Eli , Jazayeri Mehrdad
Published: December 2019

Many cognitive processes involve transformations of distributed representations in neural populations, creating a need for population-level models. Recurrent neural network models fulfill this need, but there are many open questions about how their connectivity gives rise to dynamics that solve a task. Here, we present a method for finding the connectivity of networks for which the dynamics are specified to solve a task in an interpretable way. We apply our method to a working memory task by synthesizing a network that implements a drift-diffusion process over a ring-shaped manifold. We also use our method to demonstrate how inputs can be used to control network dynamics for cognitive flexibility and explore the relationship between representation geometry and network capacity. Our work fits within the broader context of understanding neural computations as dynamics over relatively low-dimensional manifolds formed by correlated patterns of neurons.

Author Summary

Neurons in the brain form intricate networks that can produce a vast array of activity patterns. To support goal-directed behavior, the brain must adjust the connections between neurons so that network dynamics can perform desirable computations on behaviorally relevant variables. A fundamental goal in computational neuroscience is to provide an understanding of how network connectivity aligns the dynamics in the brain to the dynamics needed to track those variables. Here, we develop a mathematical framework for creating recurrent neural network models that can address this problem. Specifically, we derive a set of linear equations that constrain the connectivity to afford a direct mapping of task-relevant dynamics onto network activity. We demonstrate the utility of this technique by creating and analyzing a set of network models that can perform a simple working memory task. We then extend the approach to show how additional constraints can furnish networks whose dynamics are controlled flexibly by external inputs. Finally, we exploit the flexibility of this technique to explore the robustness and capacity limitations of recurrent networks. This network synthesis method provides a powerful means for generating and validating hypotheses about how task-relevant computations can emerge from network dynamics.
Evolutionary genomics of structural variation in Asian rice (Oryza sativa) and its wild progenitor (O. rufipogon)
Authors: Kou Yixuan , Liao Yi , Toivainen Tuomas , Lv Yuanda , Tian Xinmin , Emerson J.J , Gaut Brandon S. , Zhou Yongfeng
Published: December 2019

Structural variants (SVs) are a largely unstudied feature of plant genome evolution, despite the fact that SVs contribute substantially to phenotypes. In this study, we discovered structural variants (SVs) across a population sample of 358 high-coverage, resequenced genomes of Asian rice (Oryza sativa) and its wild ancestor (O. rufipogon). In addition to this short-read dataset, we also inferred SVs from whole-genome assemblies and long-read data. Comparisons among datasets revealed different features of genome variability. For example, genome alignment identified a large (~4.3 Mb) inversion in indica rice varieties relative to an outgroup, and long-read analyses suggest that ~9% of genes from this outgroup are hemizygous. We focused, however, on the resequencing sample to investigate the population genomics of SVs. Clustering analyses with SVs recapitulated the rice cultivar groups that were also inferred from SNPs. However, the site-frequency spectrum of each SV type -- which included inversions, duplications, deletions, translocations and mobile element insertions -- was skewed toward lower frequency variants than synonymous SNPs, suggesting that SVs are predominantly deleterious. The strength of these deleterious effects varied among SV types, with inversions especially deleterious, and across transposable element (TE) families. Among TEs SINE andmarinerinsertions were especially deleterious, due to stronger selection against their insertions. We also used SVs to study domestication by contrasting between rice andO. rufipogon. Cultivated genomes contained ~25% more derived SVs thanO. rufipogon, suggesting these deleterious SVs contribute to the cost of domestication. We also used SVs to study the effects of positive selection on the rice genome. Generally, the search for domestication genes were enriched for known candidates, suggesting some utility for SVs towards this purpose. More importantly, we detected hundreds to thousands of genes gained and lost during domestication, many of which are predicted to contribute to traits of agronomic interest.
Investigating mechanisms of polarized light sensitivity in the small white butterflyPieris rapae
Authors: Blake Adam J. , Hahn Gina S. , Grey Hayley , Kwok Shelby , McIntosh Deby , Gries Gerhard
Published: December 2019

There is an ever increasing number of arthropod taxa shown to have polarization sensitivity throughout their compound eyes. However, the mechanisms underlying arthropod perception of polarized reflections from objects such as plants are not well understood. The small white butterfly,Pieris rapae, has been demonstrated to exploit foliar polarized reflections, specifically the degree of linear polarization (DoLP), to recognize host plants. The well-described visual system ofP. rapaeincludes several photoreceptor types (red, green, blue) that are sensitive to polarized light. Yet, the mechanism underlying the behavioral responses ofP. rapaeto stimuli with differentDoLPsremains unknown. To investigate potential mechanisms, we designed several two-choice behavioral bioassays, displaying plant images on paired LCD monitors which allowed for independent control of polarization, color and intensity. We found that shifts in image intensity had a similar effect onP. rapaepreferences for stimuli dissimilar inDoLPand dissimilar in color, suggestingDoLPdifferences are perceived as color. When aDoLPchoice was offered between plant images manipulated in a manner to minimizing the response of blue, red, or blue and red photoreceptors,P. rapaeshifted its preference forDoLP, suggesting a role for red, green and blue polarization-sensitive photoreceptors. Modeling ofP. rapaephotoreceptor responses to test stimuli suggests that differentialDoLPis not perceived solely as a color difference. Our combined results suggest thatP. rapaefemales process and interpret polarization reflections in a way different from that described for other polarization-sensitive taxa.
A mathematical model exhibiting the effect of DNA methylation on the stability boundary in cell-fate networks
Authors: Chen Tianchi , Al-Radhawi M. Ali , Sontag Eduardo D.
Published: December 2019

Cell-fate networks are traditionally studied within the framework of gene regulatory networks. This paradigm considers only interactions of genes through expressed transcription factors and does not incorporate chromatin modification processes. This paper introduces a mathematical model that seamlessly combines gene regulatory networks and DNA methylation, with the goal of quantitatively characterizing the contribution of epigenetic regulation to gene silencing. The “Basin of Attraction percentage” is introduced as a metric to quantify gene silencing abilities. As a case study, a computational and theoretical analysis is carried out for a model of the pluripotent stem cell circuit as well as a simplified self-activating gene model. The results confirm that the methodology quantitatively captures the key role that methylation plays in enhancing the stability of the silenced gene state.
Protein Docking and Steered Molecular Dynamics Reveal Alternative Regulatory Sites on the SERCA Calcium Transporter
Authors: Alford Rebecca F. , Smolin Nikolai , Young Howard S. , Gray Jeffrey J. , Robia Seth L.
Published: December 2019

The transport activity of the calcium ATPase SERCA is modulated by an inhibitory interaction with a 52-residue transmembrane peptide, phospholamban (PLB). Biochemical and structural studies have revealed the primary inhibitory site on SERCA, but PLB has been hypothesized to interact with alternative sites on SERCA that are distinct from the inhibitory site. The present study was undertaken to test these hypotheses and explore structural determinants of SERCA regulation by PLB. Steered molecular dynamics (SMD) and membrane protein-protein docking experiments were performed to investigate the apparent affinity of PLB interactions with candidate sites on SERCA. We modeled the relative binding of PLB to several different conformations of SERCA, representing different enzymatic states sampled during the calcium transport catalytic cycle. Overall, the SMD and docking experiments suggest that the canonical binding site is preferred, but also provide evidence for alternative sites that are favorable for certain conformational states of SERCA.
Simple, Functional, Inexpensive Cell Extract forin vitroPrototyping of Proteins with Disulfide Bonds
Authors: Dopp Jared L. , Reuel Nigel F.
Published: December 2019

In vitroexpression of proteins fromE. coliextract is a useful method for prototyping and production of cytotoxic or unnatural products. However, proteins that have multiple disulfide bonds require custom extract that, to date, requires careful addition of exogenous isomerase enzymes or the use of expensive commercial kits. This cost and complexity currently limit access to some groups who wish to rapidly prototype proteins with disulfide bonds. Herein, we present a simple solution that does not require addition of supplemental enzymes. We use a commercially available SHuffle T7 ExpresslysYstrain ofE. colithat expresses both T7 RNAP and DsbC isomerase enzymes. We experimentally determine optimal growth conditions (IPTG induction and harvest times) to balance overall productivity and efficiency of disulfide bond formation using a luciferase (fromGaussia princeps) that contains five disulfide bonds as our reporter protein. We also demonstrate the ability for rapid prototyping by screening the activity of four luciferase candidates against ten luciferin analogues. To display the broad applicability of the extract, three other enzymes containing ≥3 disulfide bonds (hevamine, endochitinase A, and periplasmic AppA) were also expressed from minimal genetic templates that had undergone rolling circle amplification and confirmed via activity assays.
Data-driven algorithm for the diagnosis of behavioral variant frontotemporal dementia
Authors: Manera Ana L. , Dadar Mahsa , van Swieten John , Borroni Barbara , Sanchez-Valle Raquel , Moreno Fermin , LaForce Robert , Graff Caroline , Synofzik Matthis , Galimberti Daniela , Rowe James , Masellis Mario , Tartaglia Maria Carmela , Finger Elizabeth , Vandenberghe Rik , de Mendonça Alexandre , Tagliavini Fabrizio , Santana Isabel , Butler Chris , Gerhard Alex , Danek Adrian , Levin Johannes , Otto Markus , Frisoni Giovanni , Ghidoni Roberta , Sorbi Sandro , Rohrer Jonathan D , Ducharme Simon , Collins D. Louis ,   Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI),   GENetic Frontotemporal dementia Initiative (GENFI)
Published: December 2019

INTRODUCTION

Brain structural imaging is paramount for the diagnosis of behavioral variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis.

METHODS

A total of 515 subjects from two different bvFTD databases (training and validation cohorts) were included to perform voxel-wise deformation-based morphometry analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from morphometric differences in isolation and together with bedside cognitive scores.

RESULTS

Average ten-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In a separate validation cohort of genetically confirmed bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added cognitive scores.

DISCUSSION

The random forest classifier developed can accurately predict bvFTD at the individual subject level.
Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR)
Authors: Dong Rui , Libby Kendra A. , Blaeschke Franziska , Marson Alexander , Vale Ronald D. , Su Xiaolei
Published: December 2019

The chimeric antigen receptor (CAR) directs T cells to target and kill specific cancer cells. Despite the success of CAR T therapy in clinics, the intracellular signaling pathways that lead to CAR T cell activation remain unclear. Using CD19 CAR as a model, we report that, similar to the endogenous T cell receptor (TCR), antigen-engagement triggers the formation of CAR microclusters that transduce downstream signaling. However, CAR microclusters do not coalesce into a stable central supramolecular activation cluster (cSMAC). Moreover, LAT, an essential scaffold protein for TCR signaling, is not required for microcluster formation, immunological synapse formation, and actin remodeling following CAR activation. Meanwhile, CAR T cells still require LAT for the normal production of the cytokine IL-2. Together, these data show that CAR T cells can bypass LAT for a subset of downstream signaling outputs, thus revealing a rewired signaling pathway as compared to native T cells.
Microbial microdroplet culture system (MMC): an integrated platform for automated, high–throughput microbial cultivation and adaptive evolution
Authors: Jian Xingjin , Guo Xiaojie , Wang Jia , Tan Zheng Lin , Xing Xin-hui , Wang Liyan , Zhang Chong
Published: December 2019

Conventional microbial cell cultivation techniques are typically labor intensive, low throughput, and poor parallelization, rendering them inefficient. The development of automated, modular microbial cell micro–cultivation systems, particularly those employing droplet microfluidics, has gained attention for their high–throughput, parallel and highly efficient cultivation capabilities. Here, we report the development of a microbial microdroplet culture system (MMC), which is an integrated platform for automated, high–throughput cultivation and adaptive evolution of microorganisms. We demonstrated that the MMC yielded both accurate and reproducible results for the manipulation and detection of droplets. The superior performance of MMC for microbial cell cultivation was validated by comparing the growth curves of six microbial strains grown in MMC, conventional shake flasks or well plates. The highest incipient growth rate for all six microbial cell lines was achieved using MMC. We also conducted an 18–day process of adaptive evolution of a methanol–essentialEscherichia colistrain in MMC and obtained two strains exhibiting higher growth rates compared with the parent strain. Our study demonstrates the power of MMC to provide an efficient and reliable approach for automated, high–throughput microbial cultivation and adaptive evolution.
Categorical signaling of the strongest stimulus by an inhibitory midbrain nucleus
Authors: Schryver Hannah M. , Straka Malgorzata , Mysore Shreesh P.
Published: December 2019

The isthmi pars magnocellularis (Imc), a group of inhibitory neurons in the vertebrate midbrain tegmentum, orchestrates stimulus competition and spatial selection in the optic tectum (OT). Here, we investigate the properties of relative-strength dependent competitive interactions within the barn owl Imc. Imc neurons exhibit switch-like as well as gradual response profiles as a function of relative stimulus strength, do so for competing stimuli both within and across sensory modalities, and signal the strongest stimulus in a dynamically flexible manner. Notably, Imc signals the strongest stimulus more categorically (with greater precision), and earlier than the OT. Paired recordings at spatially aligned Imc and OT sites reveal that although some properties of stimulus competition are correlated, others are set independently. Our results demonstrate that the Imc is itself an active site of competition, and may be the first site in the midbrain selection network at which stimulus competition is resolved.
Cannabidivarin for the treatment of HIV-associated neuropathic pain: a randomized, blinded, controlled clinical trial
Authors: Eibach Luca , Scheffel Simone , Cardebring Madeleine , Lettau Marie , Celik Ozgur , Morguet Andreas , Roehle Robert , Stein Christoph
Published: December 2019

Background: HIV remains a major burden to the health care system and neuropathic pain is the most common neurological complication of HIV-infection. Since current treatment strategies often lack satisfying pain relief, cannabinoids are discussed as a new option. We investigated Cannabidivarin as treatment for HIV-associated neuropathic pain.
Methods: We conducted a randomized, double-blind, placebo-controlled cross-over study. Patients underwent two successive treatment phases (4 weeks each) and were treated with Cannabidivarin (400mg/d) or placebo in a randomized order. A 3-week wash-out phase was designed to eliminate potential carry-overeffects and patients were followed up for 3 weeks after the end of the second treatment phase. The primary endpoint was pain intensity on an 11-point numeric rating scale and was recorded in a diary. Secondary endpoints were additional pain medication, pain characteristics and quality of life.
Results: We included 32 (31 male) patients. The mean pain intensity under Cannabidivarin was by 0.62 points higher compared to placebo (p=0.16; 95% CI -0.27 to 1.51). Cannabidivarin did not influence the amount of additional pain medication, pain characteristics or quality of life. No suspected unexpected adverse reactions occurred during the trial.
Discussion: Cannabidivarin was safe but failed to reduce neuropathic pain intensity in HIV-patients. This may be explained by a lack of cannabinoid receptor activation, as indicated by preclinical experiments. Further studies on larger sample sizes are needed.
Neural modelling of the semantic predictability gain under challenging listening conditions
Authors: Rysop Anna , Schmitt Lea-Maria , Obleser Jonas , Hartwigsen Gesa
Published: December 2019

When speech intelligibility is reduced, listeners exploit constraints posed by semantic context to facilitate comprehension. The left angular gyrus (AG) has been argued to drive this semantic predictability gain. Taking a network perspective, we ask how the connectivity within language-specific and domain-general networks flexibly adapts to the predictability and intelligibility of speech. During continuous functional magnetic resonance imaging (fMRI), participants repeated sentences, which varied in semantic predictability of the final word and in acoustic intelligibility. At the neural level, highly predictable sentences led to stronger activation of left-hemispheric semantic regions including subregions of the AG (PGa, PGp) and posterior middle temporal gyrus when speech became more intelligible. The behavioural predictability gain of single participants mapped onto the same regions but was complemented by increased activity in frontal and medial regions. Effective connectivity from PGa to PGp increased for more intelligible sentences. In contrast, inhibitory influence from pre-supplementary motor area to left insula was strongest when predictability and intelligibility of sentences were either lowest or highest. This interactive effect was negatively correlated with behavioural predictability gain. Together, these results suggest that successful comprehension in noisy listening conditions relies on an interplay of semantic regions and concurrent inhibition of cognitive control regions when semantic cues are available.