bluuebunny/crossref_metadata_2025 huggingface dataset:
A CMOS–memristor hybrid system for implementing stochastic binary spike timing-dependent plasticity
Authors: Ahmadi-Farsani Javad , Ricci Saverio , Hashemkhani Shahin , Ielmini Daniele , Linares-Barranco Bernabé , Serrano-Gotarredona Teresa
Published: June 2022

This paper describes a fully experimental hybrid system in which a

4
×
4

memristive crossbar spiking neural network (SNN) was assembled using custom high-resistance state memristors with analogue CMOS neurons fabricated in 180 nm CMOS technology. The custom memristors used NMOS selector transistors, made available on a second 180 nm CMOS chip. One drawback is that memristors operate with currents in the micro-amperes range, while analogue CMOS neurons may need to operate with currents in the pico-amperes range. One possible solution was to use a compact circuit to scale the memristor-domain currents down to the analogue CMOS neuron domain currents by at least 5–6 orders of magnitude. Here, we proposed using an on-chip compact current splitter circuit based on MOS ladders to aggressively attenuate the currents by over 5 orders of magnitude. This circuit was added before each neuron. This paper describes the proper experimental operation of an SNN circuit using a

4
×
4

1T1R synaptic crossbar together with four post-synaptic CMOS circuits, each with a 5-decade current attenuator and an integrate-and-fire neuron. It also demonstrates one-shot winner-takes-all training and stochastic binary spike-timing-dependent-plasticity learning using this small system.

This article is part of the theme issue ‘Advanced neurotechnologies: translating innovation for health and well-being’.
Micro-magnetic stimulation of primary visual cortex induces focal and sustained activation of secondary visual cortex
Authors: Lee Seung Woo , Fried Shelley I.
Published: June 2022

Cortical visual prostheses that aim to restore sight to the blind require the ability to create neural activity in the visual cortex. Electric stimulation delivered via microelectrodes implanted in the primary visual cortex (V1) has been the most common approach, although conventional electrodes may not effectively confine activation to focal regions and thus the acuity they create may be limited. Magnetic stimulation from microcoils confines activation to single cortical columns of V1 and thus may prove to be more effective than conventional microelectrodes, but the ability of microcoils to drive synaptic connections has not been explored. Here, we show that magnetic stimulation of V1 using microcoils induces spatially confined activation in the secondary visual cortex (V2) in mouse brain slices. Single-loop microcoils were fabricated using platinum–iridium flat microwires, and their effectiveness was evaluated using calcium imaging and compared with that of monopolar and bipolar electrodes. Our results show that compared to the electrodes, the microcoils better confined activation to a small region in V1. In addition, they produced more precise and sustained activation in V2. The finding that microcoil-based stimulation propagates to higher visual centres raises the possibility that complex visual perception, e.g. that requiring sustained synaptic inputs, may be achievable.

This article is part of the theme issue 'Advanced neurotechnologies: translating innovation for health and well-being'.
Spatio-temporal feature extraction in sensory electroneurographic signals
Authors: Silveira C. , Khushaba R. N. , Brunton E. , Nazarpour K.
Published: June 2022

The recording and analysis of peripheral neural signal can provide insight for various prosthetic and bioelectronics medicine applications. However, there are few studies that investigate how informative features can be extracted from population activity electroneurographic (ENG) signals. In this study, five feature extraction frameworks were implemented on sensory ENG datasets and their classification performance was compared. The datasets were collected in acute rat experiments where multi-channel nerve cuffs recorded from the sciatic nerve in response to proprioceptive stimulation of the hindlimb. A novel feature extraction framework, which incorporates spatio-temporal focus and dynamic time warping, achieved classification accuracies above 90% while keeping a low computational cost. This framework outperformed the remaining frameworks tested in this study and has improved the discrimination accuracy of the sensory signals. Thus, this study has extended the tools available to extract features from sensory population activity ENG signals.

This article is part of the theme issue ‘Advanced neurotechnologies: translating innovation for health and well-being’.
bHLH heterodimer complex variations shape meristems in Arabidopsis thaliana by affecting target gene specificity
Authors: Mor Eliana , Pernisová Markéta , Minne Max , Cerutti Guillaume , Ripper Dagmar , Nolf Jonah , Andres Jennifer , Ragni Laura , Zurbriggen Matias D. , Rybel Bert De , Vernoux Teva
Published: June 2022

The main regions of cell proliferation in plants are the root and shoot apical meristems during primary growth and the vascular cambia as lateral meristems during secondary thickening. A number of unique regulators have been described in each of these meristems, suggesting that these different meristems might have independently evolved dedicated transcriptional networks to balance cell proliferation. Here, we show that the basic Helix Loop Helix (bHLH) transcription factor complexes formed by TARGET OF MONOPTEROS5 (TMO5), LONESOME HIGHWAY (LHW) and their close homologs are broadly expressed throughout plant development and operate as general regulators of cell proliferation in all meristems. Yet, genetic and expression analyses indicate that these complexes have specific functions in distinct meristems mediated by heterodimer complex variations between members of the TMO5 and LHW subclades. We determine that this is primarily due to their expression domains limiting the possible combinations of heterodimer complexes within a certain meristem, and to a certain extent to the absence of some members in a given meristem. We further demonstrate target gene specificity for heterodimer complexes, suggesting that spatial differences in transcriptional responses through heterodimer diversification allow a common bHLH heterodimer complex module to contribute to the control of cell proliferation in multiple meristems.
Health Care Utilization of US Medicare Beneficiaries Living with Parkinson’s Disease
Authors: Pearson Caroline , Hartzman Alex , Munevar Dianne , Feeney Megan , Dolhun Rachel , Todaro Veronica , Rosenfeld Sheera , Willis Allison , Beck James
Published: June 2022

The number of people living with Parkinson’s disease (PD) is expected to rise in the coming years. This study analyzed health care utilization patterns of Medicare beneficiaries with a PD diagnosis (ICD-10 code G20) who were enrolled in 2019. Utilization analysis included PD-related specialists and primary care physicians, therapy services, and mental health services. We found 685,116 (1.2%) Medicare beneficiaries had PD (56.3% male, 77.9% over age 70, 85.3% White, and 16.0% rural residents). Few Medicare beneficiaries with PD sought care from a movement disorder specialist (MDS) (9.1%); another 50.9% visited a general neurologist. Results reveal low utilization rates for therapy and even lower rates for mental health services. Overall healthcare utilization varied significantly by demographic group with women, people of color, and rural residents being less likely to access specialist care. Our findings emphasize the need for further research on population-specific barriers to accessing PD-related health care.
Enhanced surveillance of monkeypox in Bas-Uélé, Democratic Republic of Congo: the limitations of symptom-based case definitions
Authors: Mande Gaspard , Akonda Innocent , De Weggheleire Anja , Brosius Isabel , Liesenborghs Laurens , Bottieau Emmanuel , Ross Noam , Gembu Guy -Crispin , Colebunders Robert , Verheyen Erik , Dauly Ngonda , Leirs Herwig , Laudisoit Anne
Published: June 2022

Background

Following an outbreak of cases of vesicular-pustular rash with fever evocative of human monkeypox in Bas-Uélé province, Democratic Republic of Congo, surveillance was strengthened.

Methods

Households with at least one active generalized vesicular-pustular rash case were visited, and contact and clinical history information was collected from all household members. Whenever possible, skin lesion were screened by PCR for the monkeypox virus, followed by the varicella-zoster virus when negative for the former.

Results

PCR results were obtained for 77 suspect cases distributed in 138 households, of which 27.3% were positive for monkeypox, 58.4% for chickenpox, and 14.3% negative for both. Confirmed monkeypox cases presented more often with monomorphic skin lesions, on palms of hands, and on soles of feet. Integrating these three features into the case definition raised the specificity to 85%, but would miss 50% of true monkeypox cases. A predictive model fit on patient demographics and symptoms had 97% specificity and 80% sensitivity, but only 80% and 33% in predicting out-of-sample cases.

Conclusion

Few discriminating features were identified and the performance of clinical case definitions was suboptimal. Rapid field diagnostics are needed to optimize worldwide early detection and surveillance of monkeypox.
On the origin of Omicron’s unique Spike gene insertion
Authors: Venkatakrishnan A.J. , Anand Praveen , Lenehan Patrick J. , Suratekar Rohit , Raghunathan Bharathwaj , Niesen Michiel J.M. , Soundararajan Venky
Published: June 2022

The emergence of a heavily mutated SARS-CoV-2 variant (Omicron; B.1.1.529/BA.1/BA.2) and its rapid spread globally created public health alarms. Characterizing the mutational profile of Omicron is necessary to interpret its shared or distinctive clinical phenotypes with other SARS-CoV-2 variants. We compared the mutations of Omicron with prior variants of concern (Alpha, Beta, Gamma, Delta), variants of interest (Lambda, Mu, Eta, Iota and Kappa), and ∼1500 SARS-CoV-2 lineages constituting ∼5.8 million SARS-CoV-2 genomes. Omicron’s Spike protein has 26 amino acid mutations (23 substitutions, two deletions and one insertion) that are distinct compared to other variants of concern. Whereas the substitution and deletion mutations have appeared in previous SARS-CoV-2 lineages, the insertion mutation (ins214EPE) has not been previously observed in any other SARS-CoV-2 lineage. Here, we discuss various mechanisms through which the nucleotide sequence encoding for ins214EPE could have been acquired and highlight the plausibility of template switching via either the human transcriptome or prior viral genomes. Analysis of homology of the inserted nucleotide sequence and flanking regions suggests that this template switching event could have involved the genomes of SARS-CoV-2 variants (e.g. B.1.1 strain), other human coronaviruses that infect the same host cells as SARS-CoV-2 (e.g. HCoV-OC43 or HCoV-229E), or a human transcript expressed in a host cell that was infected by the Omicron precursor. Whether ins214EPE impacts the epidemiological or clinical properties of Omicron (e.g. transmissibility) warrants further investigation. There is also a need to understand whether human host cells are being exploited by SARS-CoV-2 as an ‘evolutionary sandbox’ for inter-viral or host-virus genomic interplay to produce new SARS-CoV-2 variants.
7-UP:generatingin silicoCODEX from a small set of immunofluorescence markers
Authors: Wu Eric , Trevino Alexandro E. , Wu Zhenqin , Swanson Kyle , Kim Honesty J. , D’Angio H. Blaize , Preska Ryan , Charville Gregory W. , Dalerba Piero D. , Duvvuri Umamaheswar , Levi Jelena , Colevas A. Dimitrios , Bedi Nikita , Chang Serena , Sunwoo John B. , Mayer Aaron T. , Zou James
Published: June 2022

Multiplex immunofluorescence (mIF) assays multiple protein biomarkers on a single tissue section. Recently, high-plex CODEX (co-detection by indexing) systems enable simultaneous imaging of 40+ protein biomarkers, unlocking more detailed molecular phenotyping, leading to richer insights into cellular interactions and disease. However, high-plex imaging can be slower and more costly to collect, limiting its applications, especially in clinical settings. We propose a machine learning framework,7-UP,that can computationally generatein silico40-plex CODEX at single-cell resolution from a standard 7-plex mIF panel by leveraging cellular morphology. We demonstrate the usefulness of the imputed biomarkers in accurately classifying cell types and predicting patient survival outcomes. Furthermore,7-UP’simputations generalize well across samples from different clinical sites and cancer types.7-UPopens the possibility ofin silicoCODEX, making insights from high-plex mIF more widely available.
MarpolBase Expression: A Web-based, Comprehensive Platform for Visualization and Analysis of Transcriptomes in the Liverwort Marchantia polymorpha
Authors: Kawamura Shogo , Romani Facundo , Yagura Masaru , Mochizuki Takako , Sakamoto Mika , Yamaoka Shohei , Nishihama Ryuichi , Nakamura Yasukazu , Yamato Katsuyuki T. , Bowman John L. , Kohchi Takayuki , Tanizawa Yasuhiro
Published: June 2022

The liverwort Marchantia polymorpha is equipped with a wide range of molecular and genetic tools and resources that have led to its wide use to explore the evo-devo aspects of land plants. Although its diverse transcriptome data are rapidly accumulating, there is no extensive yet user-friendly tool to exploit such a compilation of data and to summarize results with the latest annotations. Here, we have developed a web-based suite of tools, MarpolBase Expression (MBEX, https://marchantia.info/mbex/), where users can visualize gene expression profiles, identify differentially expressed genes, perform co-expression and functional enrichment analyses, and summarize their comprehensive output in various portable formats. Using oil body biogenesis as an example, we demonstrated that the results generated by MBEX were consistent with the published experimental evidence and also revealed a novel transcriptional network in this process. MBEX should facilitate the exploration and discovery of the genetic and functional networks behind various biological processes in M. polymorpha, and promote our understanding of the evolution of land plants.
Intermediaries in phosphotransfer: structural features discriminating hybrid histidine kinase Rec domains from response regulator homologs
Authors: Brüderlin Mitchell , Böhm Raphael , Fadel Firas , Hiller Sebastian , Schirmer Tilman , Dubey Badri N.
Published: June 2022

In two-component systems, the information gathered by the histidine kinase (HK) is relayed to the cognate response regulator (RR). Thereby, the phosphoryl group of the autophosphorylated HK is transferred to the receiver domain of the RR to allosterically activate its effector domain. In contrast, multi-step phosphorelays comprise at least one additional Rec domain (Recinter) that is part of the HK and acts as an intermediary for phosphoryl-shuttling. While RR Rec domains have been studied extensively, little is known about Recinter domains and their potentially discriminating features. As a bona-fide Recinter domain, here we have studied the C-terminal Rec domain of the hybrid HK CckA (CckARec) from Caulobacter crescentus by X-ray crystallography and NMR spectroscopy. CckARec exhibits the canonical Rec-fold, though with a degenerated α4 helix, in which all active site residues are pre-arranged for phosphoryl-binding. BeF3- binding does not alter secondary structure nor the oligomeric state, indicating the absence of allosteric changes, the hall mark of RRs. Based on structural modeling and sequence co-variation analysis, we present a detailed picture for the intramolecular association of the CckA DHp/Rec domains and discuss the role of a FATGUY motif, a distinguishing feature of CckARec orthologs.
Characterization of the Pace-and-Drive Capacity of the Human Sinoatrial Node: a 3D in silico Study
Authors: Amsaleg Antoine , Sánchez Jorge , Mikut Ralf , Loewe Axel
Published: June 2022

The sinoatrial node (SAN) is a complex structure that spontaneously depolarizes rhythmically (“pacing”) and excites the surrounding non-automatic cardiac cells (“drive”) to initiate each heart beat. However, the mechanisms by which the SAN cells can activate the large and hyperpolarized surrounding cardiac tissue are incompletely understood. Experimental studies demonstrated the presence of an insulating border that separates the SAN from the hyperpolarizing influence of the surrounding myocardium, except at a discrete number of sinoatrial exit pathways (SEP). We propose a highly detailed 3D model of the human SAN, including 3D SEPs to study the requirements for successful electrical activation of the primary pacemaking structure of the human heart. A total of 788 simulations investigate the ability of the SAN to pace and drive with different heterogeneous characteristics of the nodal tissue (gradient and mosaic models) and myocyte orientation. A sigmoidal distribution of the tissue conductivity combined with a mosaic model of SAN and atrial cells in the SEP was able to drive the right atrium (RA). Additionally, we investigated the influence of the SEPs by varying their number, length and width. SEPs created a transition zone of transmembrane voltage (TMV) and ionic currents to enable successful pace and drive. Unsuccessful simulations showed a hyperpolarized TMV (−66 mV), which blocked the L-type channels and attenuated the sodium-calcium exchanger. The fiber direction influenced the SEPs that preferentially activated the crista terminalis (CT). The location of the leading pacemaker site (LPS) shifted towards the SEP-free areas. LPSs were located closer to the SEP-free areas (3.46±1.42 mm), where the hyperpolarizing influence of the CT was reduced, compared to a larger distance from the LPS to the areas where SEPs were located (7.17±0.98 mm). This study identified the geometrical and electrophysiological aspects of the 3D SAN-SEP-CT structure required for successful pace-and-drive in silico.

SIGNIFICANCE

The human sinoatrial node (SAN) is the intrinsic natural pacemaker of the heart. Despite its remarkable robustness to failure, the electrophysiological properties, and mechanisms by which the SAN overcomes the source-sink mismatch towards the hyperpolarized surrounding cardiac tissue remains a mystery. The SAN is electrically isolated from the hyperpolarized cardiac tissue, except at a discrete number of sinoatrial exit pathways (SEP). Using in silico experiments, we explore the influence of the fiber orientation, the SEPs’ number, geometry and location on the activation of the SAN and the surrounding atrial tissue. We provide the mechanisms in a first 3D model of the human SAN-SEP structure that can successfully drive the working myocardium.
Causal effects of prefrontal transcranial magnetic stimulation on dopamine-mediated reinforcement learning in healthy adults
Authors: Biernacki Kathryn , Myers Catherine E. , Cole Sally , Cavanagh James F. , Baker Travis E.
Published: June 2022

Background

10-Hz repetitive transcranial magnetic stimulation (rTMS) to the left dorsal lateral prefrontal cortex (DLPFC) has been shown to increase dopaminergic activity in the dorsal striatum, a region strongly implicated in reinforcement learning. However, the behavioural influence of this effect remains largely unknown.

Objective

Here, we tested the causal effects of rTMS on behavioral and computational characteristics of reinforcement learning.

Methods

40 healthy individuals were randomized into Active and Sham rTMS groups. Each participant underwent one 10-Hz rTMS session (1500 pulses) in which stimulation was applied over the left DLPFC using a robotic arm. Participants then completed a reinforcement learning task sensitive to striatal dopamine functioning. Participants’ trial-to-trial training choices were modelled using a reinforcement learning model (Q-learning) that calculates separate learning rates associated with positive and negative reward prediction errors.

Results

Subjects receiving Active TMS exhibited an increased reward rate (number of correct responses per second of task activity) compared to the Sham rTMS group. Computationally, the Active rTMS group displayed a higher learning rate for correct trials (αG) compared to incorrect trials (αL). Finally, when tested with novel pairs of stimuli, the Active group displayed extremely fast reaction times, and a trend towards a higher reward rate.

Conclusions

The present study provided specific behavioral and computational accounts of altered striatal-mediated reinforcement learning induced by a proposed increase of dopamine activity by 10-Hz rTMS to the left DLPFC. Together, these findings bolster the use of TMS to target neurocognitive disturbances attributed to the dysregulation of dopaminergic-striatal circuits.
Mature rotavirus particles contain equivalent amounts of7meGpppGcap and noncapped viral positive-sense RNAs
Authors: Moreno-Contreras Joaquin , Sánchez-Tacuba Liliana , Arias Carlos F. , López Susana
Published: June 2022

Viruses have evolved different strategies to overcome their recognition by the host innate immune system. Addition of cap at their 5’RNA ends is an efficient mechanism to ensure escape from detection by the innate immune system, but also to ensure the efficient synthesis of viral proteins. Rotavirus mRNAs contain a type 1 cap structure at their 5’end that is added by the viral capping enzyme VP3. This is a multifunctional protein with all the enzymatic activities necessary to add the cap, and also functions as an antagonist of the OAS-RNase L pathway. Here, the relative abundance of capped and noncapped viral RNAs during the replication cycle of rotavirus was determined. We found that both classes of rotaviral +RNAs are encapsidated, and they were present in a 1:1 ratio in the mature infectious particles. The capping of viral +RNAs is dynamic since different ratios of capped and noncapped RNAs were detected at different times post infection. Similarly, when the relative amount of capped and uncapped viral +RNAs produced in anin vitrotranscription system was determined, we found that the proportion was very similar to that in the mature viral particles and in infected cells, suggesting that the capping efficiency of VP3 both,in vivoandin vitro,might be close to 50%. Unexpectedly, when the effect of simultaneously knocking down the expression of VP3 and RNase L on the cap status of viral +RNAs was evaluated, we found that even though at late times post infection there was an increased proportion of capped viral RNAs in infected cells, the viral particles isolated from this condition contained an equal ratio of capped and noncapped viral RNA, suggesting that there might be a selective packaging of capped-noncapped RNAs.

SIGNIFICANCE

Rotaviruses have a genome composed of eleven segments of double stranded RNA. Whether all 5’ ends of the positive sense genomic RNA contained in the mature viral particles are modified by a cap structure is unknown. In this work, using a direct quantitative assay we characterized the relative proportion of capped and noncapped viral RNA in rotavirus infected cells and in viral particles. We found that independently of the relative proportions of cap/noncapped RNA present in rotavirus infected cells, there is a similar proportion of these two kinds of 5’-modified positive sense RNAs in the viral particles.
Designing a flow-controlled STA-MCA anastomosis based on the Hagen-Poiseuille law for preventing postoperative hyperperfusion in adult moyamoya disease
Authors: Zhang Jianjian , Fujimura Miki , Lau Tsz Yeung , Chen Jincao
Published: June 2022

OBJECTIVE

Technical improvements for preventing postoperative symptomatic cerebral hyperperfusion (CHP) during superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis for moyamoya disease (MMD) were seldom reported. The aim of this study was to investigate the significance of application of a novel flow-controlled concept which voluntarily reduces the hemodynamic difference between the donor and recipient arteries based on the Hagen-Poiseuille law when performing direct anastomoses of recipient parasylvian cortical arteries (PSCAs) with anterograde hemodynamic sources from the MCA (M-PSCAs) in adult MMD.

METHODS

Recently direct anastomoses of recipient M-PSCAs were performed on 89 symptomatic hemispheres in 82 adult MMD patients in our hospital. They were divided into the flow-controlled group and non-flow-controlled group. The patients’ basic characteristics and incidence of postoperative CHP were compared between the two groups. Risk factors for occurrence of postoperative CHP were analyzed.

RESULTS

The earlier 36 and later 53 anastomoses were respectively included in the non-flow-controlled group and flow-controlled group. The incidences of postoperative focal (22.6%) and symptomatic CHP (5.7%) in the flow-controlled group were significantly lower than those (focal, 52.8%; symptomatic, 25.0%) in the non flow-controlled group (P = 0.003 and 0.009, respectively). Multivariate analysis revealed that the flow-controlled concept used or not was significantly associated with the development of focal (P = 0.005) and symptomatic (P = 0.012) CHP.

CONCLUSIONS

The flow-controlled STA-MCA anastomosis can significantly decrease the incidence of postoperative CHP during direct anastomoses of recipient M-PSCAs in adult MMD.
Multiomic prioritisation of risk genes for anorexia nervosa
Authors: Adams Danielle M. , Reay William R. , Cairns Murray J.
Published: June 2022

Anorexia nervosa is the leading cause of mortality among psychiatric disorders worldwide. Currently no medications are approved for anorexia nervosa treatment, and thus, identification of risk factors for this disorder is pivotal to improve patient outcomes. We used models of genetically imputed expression and splicing from 17 tissues (two blood and fifteen brain regions), leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with anorexia nervosa risk. We uncovered 134 genes for which genetically predicted mRNA expression was associated with anorexia nervosa after multiple-testing correction, as well as four proteins and 16 alternatively spliced transcripts. Conditional analysis of these significantly associated genes on other proximal association signals resulted in 97 genes independently associated with anorexia nervosa. Moreover, probabilistic finemapping further refined these associations and prioritised putative causal genes. The gene WDR6, for which increased genetically predicted mRNA expression was correlated with anorexia, was strongly supported by both conditional analyses and finemapping. Pathway analysis of genes revealed by finemapping identified regulation of immune system process (overlapping genes = MST1, TREX1, PRKAR2A, PROS1) as statistically overrepresented. In summary, we leveraged multiomic datasets to genetically prioritise novel risk genes for anorexia nervosa that warrant further exploration.
Senescence rewires microenvironment sensing to facilitate anti-tumor immunity
Authors: Chen Hsuan-An , Ho Yu-Jui , Mezzadra Riccardo , Adrover Jose M. , Smolkin Ryan , Zhu Changyu , Luan Wei , Wuest Alexandra , Tian Sha , Li Xiang , Hendrickson Ronald C. , Egeblad Mikala , Alonso-Curbelo Direna , Lowe Scott W.
Published: June 2022

Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent tumor model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels cell surface proteome to alter how they sense environmental factors, as exemplified by Type II interferon gamma (IFN-γ). Compared to proliferating cells, senescent cells upregulate IFN-γ receptor, become hypersensitized to microenvironmental IFN-γ, and more robustly induce antigen presenting machinery -effects also recapitulated in human tumor cells treated with senescence-inducing drugs. Disruption of the IFN-γ sensing by senescent cells blunts their immune-mediated clearance without disabling their characteristic secretory program or immune cell recruitment. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance.

SIGNIFICANCE

Our work identifies a novel interplay between tissue remodeling and tissue sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance anti-tumor immunity.
Protective human anti-poxvirus monoclonal antibodies are generated from rare memory B cells isolated by multicolor antigen tetramers
Authors: Gu Xiuling , Zhang Yufan , Jiang Wei , Wang Dongfang , Lu Jiao , Gu Guanglei , Qin Cheng-Feng , Fang Min
Published: June 2022

Smallpox, an epidemic disease caused by Orthopoxvirus variola, was eradicated worldwide through immunization. The immunization against smallpox was discontinued in 1980. However, incidences of monkeypox virus infection in humans have occurred sporadically, and there is also great fear that engineered forms of poxvirus could be used as biological weapons. Therefore, monoclonal antibodies against poxvirus are in urgent need for the detection and treatment of poxvirus infection. The vaccinia virus extracellular envelope protein A33 is a potential candidate for subunit vaccine. We used multi-fluorescence-labeled tetrameric A33 antigen to identify rare poxvirus specific memory B cells from PBMC of volunteers with vaccinia virus immunization more than 40 years ago. Despite extremely low frequencies of the poxvirus specific memory B cells, we successfully sorted A33 tetramer-labeled single memory B cells and reconstructed antibodies with single-cell RT-PCR of the B-cell receptor. Among the monoclonal antibodies, one clone H2 exhibited high specificity and affinity with A33. H2 efficiently inhibited viral infection and spread in cells. Passive immunotherapy of H2 in mice protected mice from lethal infection when administered either prophylactically or therapeutically. These results suggest the potential of the anti-A33 human antibody-based detection and therapeutics for poxvirus infection.
Pseudoalignment facilitates assignment of error-prone Ultima Genomics reads
Authors: Booeshaghi A. Sina , Pachter Lior
Published: June 2022

We analyze single-cell RNA-seq data sequenced with Ultima Genomics technology and find high error rates in and near homopolymers. To compensate for these errors, we explore the use of pseudoalignment for read assignment, and find that it can perform better than standard read alignment. Our pseudoalignment read assignment for Ultima Genomics data is available as part of the kallisto-bustools kb-python package available at https://github.com/pachterlab/kb_python.
Meta-analysis reveals obesity associated gut microbial alteration patterns and reproducible contributors of functional shift
Authors: Chanda Deep , De Debojyoti
Published: June 2022

Cohort-specific 16S rRNA sequence-based studies associating gut microbiota with obesity are often marred with contradictory findings regarding community structure and composition leading to “reproducibility crisis” of the signals. Moreover, taxonomic drivers of the obesity-linked gut microbial functional imbalances and their replicability also remains unexplored which should be useful for in-depth understanding of obese host-gut microbiota interaction and, strategizing therapeutics. We addressed these questions through unbiased meta-analysis and further machine-learning validation of 692 curated fecal whole metagenomic sequence datasets from diverse geographical locations. Further, obesity-linked pathway shifts were traced back to their specific drivers by integrating the species and pathway profiles through genomic content of the species. We found reproducible depletion of diversity in obese gut microbiome without any pattern in Firmicutes/Bacteroidetes ratio. Additionally, we also identified obesity-linked robust and reproducible gut microbial species and pathway features. Contributors of these pathway features identified as both dataset-specific and shared across the datasets.
Capturing the liquid-crystalline phase transformation: Implications for protein targeting to sterol ester-rich lipid droplets
Authors: Braun R. Jay , Swanson Jessica M.J.
Published: June 2022

Lipid droplets are essential organelles that store and traffic neutral lipids. The phospholipid monolayer surrounding their neutral lipid core engages with a highly dynamic proteome that changes according to cellular and metabolic conditions. Recent work has demonstrated that when the abundance of sterol esters increases above a critical concentration, such as under conditions of starvation or high LDL exposure, the lipid droplet core can undergo an amorphous to liquid-crystalline phase transformation. Herein we study the consequences of this transformation on the physical properties of lipid droplets that are thought to regulate protein association. Using simulations of different sterol-ester concentrations we have captured the liquid-crystalline phase transformation at the molecular level, highlighting the alignment of sterol esters in alternating orientations to form concentric layers. We demonstrate how ordering in the core permeates into the neutral lipid/phospholipid interface, changing the magnitude and nature of neutral lipid intercalation and inducing ordering in the phospholipid monolayer. Increased phospholipid packing is concomitate with altered surface properties, including smaller area per phospholipid and substantially reduced packing defects. Additionally, the ordering of sterol esters in the core causes less hydration in more ordered regions. We discuss these findings in the context of their expected consequences for preferential protein recruitment to lipid droplets under different metabolic conditions.
Induction of senescence renders cancer cells highly immunogenic
Authors: Marín Inés , Boix Olga , García Andrea , Sirois Isabelle , Caballe Adrià , Zarzuela Eduardo , Ruano Irene , Stephan-Otto Attolini Camille , Prats Neus , López-Domínguez José Alberto , Kovatcheva Marta , Garralda Elena , Muñoz Javier , Caron Etienne , Abad María , Gros Alena , Pietrocola Federico , Serrano Manuel
Published: June 2022

Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy.

STATEMENT OF SIGNIFICANCE

Our study shows that senescent cells are endowed with a high immunogenic potential, superior to the gold standard of immunogenic cell death. The induction of senescence in cancer cells can be exploited to develop efficient and protective CD8-dependent anti-tumor immune responses.
The role of inflammation in the prospective associations between early childhood sleep problems and ADHD at 10 years: Findings from a UK birth cohort study
Authors: Muñoz Isabel Morales , Upthegrove Rachel , Lawrence Kate , Kooij Sandra , Gregory Alice M , Marwaha Steven
Published: June 2022

Background

Several underlying mechanisms potentially account for the link between sleep and attention deficit and hyperactivity disorder (ADHD), including inflammation. However, studies so far have been cross-sectional. We investigate (i) the association between early childhood sleep and probable ADHD diagnosis in childhood; and (ii) whether childhood circulating inflammatory markers mediate any associations.

Methods and Findings

Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were available for 7658 10-years-old children. Parent-reported sleep duration, night awakening frequency, and regular sleep routines were collected at 3.5 years. The Development and Wellbeing Assessment (DAWBA) was administered to capture children with clinically relevant ADHD symptoms, or probable ADHD diagnosis. Further, blood samples were collected at 9 years, from which two inflammatory markers were obtained [i.e. interleukin-6 (IL-6) and C-reactive protein (CRP)]. Logistic regressions were applied to investigate the associations between sleep variables at 3.5 years and probable ADHD diagnosis at 10 years. Further, path analysis was applied to examine the mediating role of inflammation at 9 years (i.e. as measured by CRP and IL-6) in the associations between early sleep and ADHD at 10 years. We found that less regular sleep routines (OR=0.51, 95%CI=0.28-0.93, p=0.029), shorter nighttime sleep (OR=0.70, 95%CI=0.56-0.89, p=0.004), and higher night awakening (OR=1.27, 95I%CI=1.06-1.52, p=0.009) at 3.5 years were associated with higher odds of probable ADHD at 10 years. Further, IL-6 at 9 years mediated the association between irregular sleep routines and ADHD (bias-corrected estimate, -0.002; p=0.005); and between night awakening and ADHD (bias-corrected estimate, 0.002; p=0.003).

Conclusions

Several sleep problems in early childhood constitute a risk factor for probable ADHD diagnosis at 10 years. These associations may be mediated by inflammation, as measured by IL-6. These results open a new research vista to the pathophysiology of ADHD and highlight sleep and inflammation as potential preventative targets for ADHD.
A fast non-parametric test of association for multiple traits
Authors: Garrido-Martín Diego , Calvo Miquel , Reverter Ferran , Guigó Roderic
Published: June 2022

The increasing availability of multidimensional phenotypic data in large cohorts of genotyped individuals requires efficient methods to identify genetic effects on multiple traits. Permutational multivariate analysis of variance (PERMANOVA) offers a powerful non-parametric approach. However, it relies on permutations to assess significance, which hinders the analysis of large datasets. Here, we derive the limiting null distribution of the PERMANOVA test statistic, providing a framework for the fast computation of asymptotic p values. We show that the asymptotic test presents controlled type I error and high power, comparable to or higher than parametric approaches. We illustrate the applicability of our method in a number of use-cases. Using the GTEx cohort, we perform the first population-biased splicing QTL mapping study across multiple tissues. We identify thousands of genetic variants that affect alternative splicing differently depending on ethnicity, including potential disease markers. Using the UK Biobank cohort, we perform the largest GWAS to date of MRI-derived volumes of hippocampal subfields. Most of the identified loci have not been previously related to the hippocampus, but many are associated to cognition or brain disorders, thus contributing to understand the intermediate traits through which genetic variants impact complex organismal phenotypes.
Optimisation of the core subset for the APY approximation of genomic relationships
Authors: Pocrnic Ivan , Lindgren Finn , Tolhurst Daniel , Herring William O. , Gorjanc Gregor
Published: June 2022

Background

By entering the era of mega-scale genomics, we are facing many computational issues with standard genomic evaluation models due to their dense data structure and cubic computational complexity. Several scalable approaches have have been proposed to address this challenge, like the Algorithm for Proven and Young (APY). In APY, genotyped animals are partitioned into core and non-core subsets, which induces a sparser inverse of genomic relationship matrix. The partitioning into subsets is often done at random. While APY is a good approximation of the full model, the random partitioning can make results unstable, possibly affecting accuracy or even reranking animals. Here we present a stable optimisation of the core subset by choosing animals with the most informative genotype data.

Methods

We derived a novel algorithm for optimising the core subset based on the conditional genomic relationship matrix or the conditional SNP genotype matrix. We compared accuracy of genomic predictions with different core subsets on simulated and real pig data. The core subsets were constructed (1) at random, (2) based on the diagonal of genomic relationship matrix, (3) at random with weights from (2), or (4) based on the novel conditional algorithm. To understand the different core subset constructions, we have visualised population structure of genotyped animals with the linear Principal Component Analysis and the non-linear Uniform Manifold Approximation and Projection.

Results

All core subset constructions performed equally well when the number of core animals captured most of variation in genomic relationships, both in simulated and real data. When the number of core animals was not optimal, there was substantial variability in results with the random construction and no variability with the conditional construction. Visualisation of population structure and chosen core animals showed that the conditional construction spreads core animals across the whole domain of genotyped animals in a repeatable manner.

Conclusions

Our results confirm that the size of the core subset in APY is critical. The results further show that the core subset can be optimised with the conditional algorithm that achieves a good and repeatable spread of core animals across the domain of genotyped animals.
Reshaping the dynamics of follicle-stimulant hormone receptor models in polyunsaturated lipid bilayers. Calculation of conformational free energy landscapes of α-helical domains from all-atom MD simulations
Authors: Jardón-Valadez Eduardo , Ulloa-Aguirre Alfredo , Portillo-Bobadilla Tobías , Villavicencio-Pulido Geiser
Published: June 2022

G-coupled-protein receptors (GPCR) are conspicuous target molecules for novel therapeutic drugs due to their role as mediators of cellular responses. Structural biology of GPCR revealed that intracellular signaling stimulated by extracellular ligands involves subtle conformational changes of the receptor during activation. Nonetheless, transitions among intermediates evolve in an intricate and rough free energy landscape of the conformational space. Experimental evidence suggests that the membrane environment is an active modulator of the receptor dynamics; therefore, the lipid composition may facilitate conformational transitions towards productive signaling states. In this study, we setup molecular dynamics simulations to examine the conformational dynamics of the transmembrane domains, in the context of a membrane of polyunsaturated phospholipid molecules, for a homology model of the human follicle-stimulating-hormone receptor (FSHR) and the crystal structure of the Lumi intermediate of the squid rhodopsin (LSRh). The conformational dynamics of the α−helical domains of LSRh was consistent with interactions stabilizing the crystal structure, which remained well preserved in the membrane environment. In contrast, conformations in the FSHR model evolved towards stable states in the membrane environment. To assess the relevance of the conformational dynamics in the FSHR model, dihedral restraints were imposed for the helical domains on top of the force field. This strategy was implemented to reoptimize the interhelical interactions probably overlooked in the modeling process. The conformational dynamics in the helical domains was evaluated by the TM-score, contact maps, principal components analysis of Cα atoms at the helical domains, and projections of the conformational free energy on principal components. The roughness of the conformational landscape in the FSHR model without dihedral restraints, suggested that alternative interhelical conformational states were populated, whereas imposing restraints led to a dominant conformational state. Template-based models of GPCR, with reoptimized interhelical interactions using dihedral restraints, may enhance the identification of binding sites for potential therapeutic drugs.
Predicting supply chain risks through big data analytics: role of risk alert tool in mitigating business disruption
Authors: Park Minseok , Singh Nitya Prasad
Published: June 2022

Purpose

As organizations globalize, they are facing twin challenges of (1) how to develop actionable intelligence from the vast amount of data flowing into their organization and (2) how to effectively manage the increasing risks to their supply chain. Therefore, the purpose of this paper is to bring these two issues on a single platform to understand how firms can effectively predict supply chain risk by developing and using BDA capabilities, through an automated risk alert tool.

Design/methodology/approach

The authors used a questionnaire-based survey methodology supported by secondary data to collect information related to managerial perceptions on how firms can develop a risk alert tool by improving BDA capabilities. A database of 213 senior and middle-level managers was developed and used to test the proposed hypothesis. Using econometric techniques, the authors identify the conditions necessary for such an automated risk management tool to be effective.

Findings

The results suggest that if organizations focus on developing an effective IT infrastructure supported by a strong BDA capability, they will be able to leverage these capabilities to develop an effective risk management tool. Moderating influences of Upstream and Downstream Supply Chain IT Infrastructure capabilities were also observed on different types of BDA capabilities within a firm. In conclusion, it was argued that the effectiveness of a risk alert tool is dependent on how well firms harness big data analytics capability.

Originality/value

The value of the research stems from the fact that it uses managerial surveys to identify specific BDA capabilities that can enable firms to develop risk resilience capabilities. In addition, the article is one of the few empirical studies that aims to identify how firms can use BDA capabilities within a supply chain context to develop an automated risk alert tool. The article, therefore, contributes to the literature that identifies the value of BDA capabilities within the context of supply chain risk management.