bluuebunny/crossref_metadata_2025 huggingface dataset:
Sharing Massive Biomedical Data at Magnitudes Lower Bandwidth Using Implicit Neural Function
Authors: Yang Runzhao , Xiao Tingxiong , Cheng Yuxiao , Li Anan , Qu Jinyuan , Liang Rui , Bao Shengda , Wang Xiaofeng , Wang Jue , Suo Jinli , Luo Qingming , Dai Qionghai
Published: December 2022

Efficient storage and sharing of massive biomedical data would open up their wide accessibility to different institutions and disciplines. However, compressors tailored for natural photos/videos are rapidly limited for biomedical data, while emerging deep learning based methods demand huge training data and are difficult to generalize. Here we propose to conduct Biomedical data compRession with Implicit nEural Function (BRIEF) by representing the original data with compact neural networks, which are data specific and thus have no generalization issues. Benefiting from the strong representation capability of implicit neural function, BRIEF achieves 2 ∼ 3 orders of magnitude compression on diverse biomedical data at significantly higher fidelity than existing techniques. Besides, BRIEF is of consistent performance across the whole data volume, supports customized spatially-varying fidelity. BRIEF’s multi-fold advantageous features also serve reliable downstream tasks at low bandwidth. Our approach will facilitate low-bandwidth data sharing, and promote collaboration and progress in the biomedical field.
“It reminds me and motivates me”: Human-centered design and implementation of an interactive, SMS-based digital intervention to improve early retention on antiretroviral therapy: usability and acceptability among new initiates in a high-volume, public clinic in Malawi
Authors: Huwa Jacqueline , Tweya Hannock , Mureithi Maryanne , Oni Femi , Chintedza Joseph , Chiwaya Geldert , Waweru Evelyn , Kudzala Aubrey , Wasunna Beatrice , Ndhlovu Dumisani , Bisani Pachawo , Feldacker Caryl
Published: December 2022

Background

Early retention of people living with HIV (PLHIV) in antiretroviral therapy (ART) programs is critical to improve individual clinical outcomes and viral load suppression. Although many mobile health (mHealth) interventions aim to improve retention in care, there is still lack of evidence on mHealth success or failure, including from patient’s perspectives. We describe the human-centered design (HCD) process and assess patient usability and acceptability of a two-way texting (2wT) intervention to improve early retention among new ART initiates at Lighthouse Trust clinic in Lilongwe, Malawi.

Methods

An iterative HCD approach focused on patient and provider users’ needs, incorporating feedback from multidisciplinary teams to adapt 2wT for the local, public clinic context. We present mixed-methods usability and acceptability results from 100 participants, 50 at 3-months and 50 at 6-months, post 2wT enrollment, and observations of these same patients completing core tasks of the 2wT system.

Results

Among the 100 usability respondents, 95% were satisfied with visit reminders, and 88% would recommend reminders and motivational messages to friends; however, 17% were worried about confidentiality. In observation of participant task completion, 94% were able to successfully confirm visit attendance and 73% could request appointment date change. More participants in 4-6 months group completed tasks correctly compared to 1-3 months group, although not significantly different (78% vs. 66%, p=0.181). Qualitative results were overwhelmingly positive, but patients did note confusion with transfer reporting and concern that 2wT would not reach patients without mobile phones or with lower literacy.

Conclusion

The 2wT app for early ART retention appears highly usable and acceptable, hopefully creating a solid foundation for lifelong engagement in care. The HCD approach put the local team central in this process, ensuring that both patients’ and Lighthouse’s priorities, policies, and practices were forefront in 2wT optimization, raising the likelihood of 2wT success in other routine program contexts.
Identification of Spatial Proteomic Signatures of Colon Tumor Metastasis: A Digital Spatial Profiling Approach
Authors: Levy Joshua J. , Zavras John P. , Veziroglu Eren M. , Nasir-Moin Mustafa , Kolling Fred W. , Christensen Brock C. , Salas Lucas A. , Barney Rachael E. , Palisoul Scott M. , Ren Bing , Liu Xiaoying , Kerr Darcy A. , Pointer Kelli B. , Tsongalis Gregory J. , Vaickus Louis J.
Published: December 2022

Over 150,000 Americans are diagnosed with colorectal cancer (CRC) every year, and annually over 50,000 individuals will die from CRC, necessitating improvements in screening, prognostication, disease management, and therapeutic options. CRC tumors are removed en bloc with surrounding vasculature and lymphatics. Examination of regional lymph nodes at the time of surgical resection is essential for prognostication. Developing alternative approaches to indirectly assess recurrence risk would have utility in cases where lymph node yield is incomplete or inadequate. Spatially dependent, immune cell-specific (e.g., Tumor Infiltrating Lymphocytes– TILs), proteomic, and transcriptomic expression patterns inside and around the tumor - the tumor immune microenvironment (TIME) - can predict nodal/distant metastasis and probe the coordinated immune response from the primary tumor site. The comprehensive characterization of TILs and other immune infiltrates is possible using highly multiplexed spatial omics technologies, such as the GeoMX Digital Spatial Profiler (DSP). In this study, machine learning and differential co-expression analyses helped identify biomarkers from DSP-assayed protein expression patterns inside, at the invasive margin, and away from the tumor, associated with extracellular matrix remodeling (e.g., GZMB, fibronectin), immune suppression (e.g., FOXP3), exhaustion and cytotoxicity (e.g., CD8), PD-L1 expressing dendritic cells, neutrophil proliferation, amongst other concomitant alterations. Further investigation of these biomarkers may reveal independent risk factors of CRC metastasis that can be formulated into low-cost, widely available assays.
Molecular methods for diagnosis of monkeypox: A mini-review
Authors: de Oliveira Thomasi Rodrigo Michelini , Silva Correa Thais da , do Carmo Dalise Silva , Rodrigues Déborah Fernandes , da Silva Correa Luiz Vinicius , Xavier Sandra Rodrigues , Silva Liria Souza , da Silva Jonatas Oliveira , Santos Michelli dos , Silva Dantas Alessandra da , da Paz Mariana Campos , Chávez Fumagalli Miguel Angel , Giunchetti Rodolfo Cordeiro , Ferraz Coelho Eduardo Antônio , Machado Juliana Martins , Galdino Alexsandro Sobreira
Published: December 2022

Background

Monkeypox is a global public health issue caused by the monkeypox virus (MPXV), a virus belonging to the Orthopoxvirus genus. As of October 28 2022, a total of 77,115 laboratory-confirmed cases and 3,610 probable cases, including 36 deaths, were reported, with 9,070 cases reported in Brazil, the second most affected country. The need to develop national technologies for the rapid diagnosis of emerging diseases for mass testing of the population is evident, as observed in the current SARS-CoV-2 pandemic. With that in mind, this article provides an overview of current methods, techniques, and their applications in the molecular detection of monkeypox.

Methods

The relevant documents or papers covered in this study were selected by a search in international bibliographic databases. The search terms used in the databases were aimed at summarizing existing knowledge on molecular diagnostic methods, such as: monkeypox; MPX, MPXV, qPCR, PCR, PCR-ELISA, and Diagnosis and Detection searched separately or together using the Boolean operator “AND” either in the title or abstract. The searches took place in September 2022, and the corresponding articles were selected between 2012 and 2022.

Results

We found 256 documents in total and twelve studies addressing the molecular diagnosis of monkeypox were classified as possible sources for this review.

Conclusion

This paper presents new perspectives and an overview of current methods, technologies, and applications in the molecular diagnosis of monkeypox. It is evident there is a pressing need to develop national technologies for the rapid diagnosis of emerging diseases for mass testing of the population. It is extremely important to have national detection kits with greater diagnostic capacity to assist in developing effective public policies in countries affected by this disease.
Prior expectation enhances sensorimotor behavior by modulating population tuning and subspace activity in the sensory cortex
Authors: Park JeongJun , Kim Seolmin , Kim HyungGoo R. , Lee Joonyeol
Published: December 2022

Prior knowledge facilitates our perception and goal-directed behaviors in the dynamic world, particularly when sensory input is lacking or noisy. However, the neural mechanisms underlying the improvement in sensorimotor behaviors by prior expectations remain unknown. In this study, we examine the neural activity in the middle temporal (MT) area of visual cortex while monkeys perform a smooth pursuit eye movement task with prior expectation of the visual target’s motion direction. Prior expectations discriminately reduce the MT neural responses depending on their preferred directions, only when the sensory evidence is weak. This response reduction effectively sharpens neural population direction tuning. Simulations with a realistic MT population demonstrate that sharpening the tuning explains both the biases and variabilities in smooth pursuit, thus suggesting that neural computations in the sensory area alone can underpin the integration of prior knowledge and sensory evidence. State-space analysis further supports this by revealing neural signals of prior expectation in the MT population activity that correlate with behavioral changes.
Stimulus information guides the emergence of behavior related signals in primary somatosensory cortex during learning
Authors: Panniello Mariangela , Gillon Colleen J , Maffulli Roberto , Celotto Marco , Panzeri Stefano , Richards Blake A , Kohl Michael M
Published: December 2022

Cortical neurons in primary sensory cortex carry not only sensory but also behavior-related information. However, it remains unclear how these types of information emerge and are integrated with one another over learning and what the relative contribution of activity in individual cells versus neuronal populations is in this process. Current evidence supports two opposing views of learning-related changes: 1) sensory information increases in primary cortex or 2) sensory information remains stable in primary cortex but its readout efficiency in association cortices increases. Here, we investigate these questions in primary sensory cortex during learning of a sensory task. Over the course of weeks, we imaged neuronal activity at different depths within layers 2 and 3 of the mouse vibrissal primary somatosensory cortex (vS1) before, during, and after training on a whisker-based object-localization task. We leveraged information theoretical analysis to quantify stimulus and behavior-related information in vS1 and estimate how much neural activity encoding sensory information is used to inform perceptual choices as sensory learning progresses. We also quantified the extent to which these types of information are supported by an individual neuron or population code. We found that, while sensory information rises progressively from the start of training, choice information is only present in the final stages of learning and is increasingly supported by a population code. Moreover, we demonstrate that not only the increase in available information, but also a more efficient readout of such information in primary sensory cortex mediate sensory learning. Together, our results highlight the importance of primary cortical neurons in perceptual learning.
Behavioral encoding across timescales by region-specific dopamine dynamics
Authors: Jørgensen Søren H. , Ejdrup Aske L. , Lycas Matthew D. , Posselt Leonie P. , Madsen Kenneth L. , Tian Lin , Dreyer Jakob K. , Herborg Freja , Sørensen Andreas T. , Gether Ulrik
Published: December 2022

The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions and reward-related behavior. It remains poorly understood how dopamine release dynamics across different temporal scales in these regions are coupled to behavioral outcomes. Here, we employ the dopamine sensor dLight1.3b together with multi-region fiber photometry and machine learning-based analysis to decode dopamine dynamics across striatum during self-paced exploratory behavior in mice. Our data show a striking coordination of rapidly fluctuating signal in the DS, carrying information across dopamine levels, with a slower signal in the VS, consisting mainly of slow-paced transients. Importantly, these release dynamics correlated with discrete behavioral motifs, such as turns, running and grooming on a subsecond-to-minutes time scale. Disruption of dopamine dynamics with cocaine caused randomization of action selection sequencing and disturbance of DS-VS coordination. The data suggest that distinct dopamine dynamics of DS and VS jointly encode behavioral sequences during unconstrained activity with DS modulating the stringing together of actions and VS the signal to initiate and sustain the selected action.

Significance Statement

New genetically encoded dopamine sensors offer unprecedented temporal resolution for measurement of dopamine release dynamics across different brain regions over extended periods. In this study, we use the dopamine sensor dLight1.3b to decipher the role of dopamine release dynamics in the dorsal (DS) and ventral striatum (VS) of mice during simple, self-paced exploratory behavior. By AI-based splitting of behavioral kinematics into individual motifs, we link differential but highly cooperative dopamine release dynamics of DS and VS with movements on a subsecond-to-minutes time scales. In addition to coupling region-specific dopamine dynamics to behavioral sequences, our study demonstrates the strength of a machine learning-based data analysis pipeline that can be readily applied to other neurotransmitters for which genetically encoded biosensors are available.
Genome charaterization based on the Spike-614 and NS8-84 loci of SARS-CoV-2 reveals two major onsets of the COVID-19 pandemic
Authors: Hu Xiaowen , Mu Yaojia , Deng Ruru , Yi Guohui , Yao Lei , Zhang Jiaming
Published: December 2022

The global COVID-19 pandemic has lasted for three years since its outbreak, however its origin is still unknown. Here, we analyzed the genotypes of 3.14 million SARS-CoV-2 genomes based on the amino acid 614 of the Spke (S) and the amino acid 48 of NS8 (nonstructural protein 8), and identified 16 linkage haplotypes. The GL haplotype (S_614G and NS8_48L) was the major haplotype driving the global pandemic and accounted for 99.2% of the sequenced genomes, while the DL haplotype (S_614D and NS8_48L) caused the pandemic in China in the spring of 2020 and accounted for approximately 60% of the genomes in China and 0.45% of the global genomes. The GS (S_614G and NS8_48S), DS (S_614D and NS8_48S) and NS (S_614N and NS8_48S) haplotypes accounted for 0.26%, 0.06%, and 0.0067% of the genomes, respectively. The main evolutionary trajectory of SARS-CoV-2 is DS→DL→GL, whereas the other haplotypes are minor byproducts in the evolution. Surprisingly, the newest haplotype GL had the oldest time of most recent common ancestor (tMRCA), which was May 1 2019 by mean, while the oldest haplotype had the newest tMRCA with a mean of October 17, indicating that the ancestral strains that gave birth to GL had been extinct and replaced by the more adapted newcomer at the place of its origin, just like the sequential rise and fall of the delta and omicron variants. However, they arrived and evolved into toxic strains and ignited a pandemic in China where the GL strains did not exist at the end of 2019. The GL strains had spread all over the world before they were discovered, and ignited the global pandemic, which had not been noticed until the pandemic was declared in China. However, the GL haplotype had little influence in China during the early phase of the pandemic due to its late arrival as well as the strict transmission controls in China. Therefore, we propose two major onsets of the COVID-19 pandemic, one was mainly driven by the haplotype DL in China, the other was driven by the haplotype GL globally.
In situquantification of osmotic pressure within living embryonic tissues
Authors: Vian Antoine , Pochitaloff Marie , Yen Shuo-Ting , Kim Sangwoo , Pollock Jennifer , Liu Yucen , Sletten Ellen , Campàs Otger
Published: December 2022

Mechanics is known to play a fundamental role in many cellular and developmental processes. Beyond active forces and material properties, osmotic pressure is believed to control essential cell and tissue characteristics. However, it remains very challenging to performin situandin vivomeasurements of osmotic pressure. Here we introduce doubleemulsion droplet sensors that enable local measurements of osmotic pressure intra- and extra-cellularly within 3D multicellular systems, including living tissues. After generating and calibrating the sensors, we measured the osmotic pressure in blastomeres of early zebrafish embryos as well as in the interstitial fluid between the cells of the blastula by monitoring the size of droplets previously inserted in the embryo. Our results show a balance between intracellular and interstitial osmotic pressures, with values of approximately 0.7 MPa, but a large pressure imbalance between the inside and outside of the embryo. The ability to measure osmotic pressure in 3D multicellular systems (developing embryos, organoids, etc.) will help understand its role in fundamental biological processes.
The impact of quality control on cortical morphometry comparisons in autism
Authors: Bedford Saashi A. , Ortiz-Rosa Alfredo , Schabdach Jenna M. , Costantino Manuela , Tullo Stephanie , Piercy Tom ,   Lifespan Brain Chart Consortium, Lai Meng-Chuan , Lombardo Michael V. , Di Martino Adriana , Devenyi Gabriel A. , Chakravarty M. Mallar , Alexander-Bloch Aaron F. , Seidlitz Jakob , Baron-Cohen Simon , Bethlehem Richard A.I.
Published: December 2022

Structural magnetic resonance imaging (MRI) quality is known to impact and bias neuroanatomical estimates and downstream analysis, including case-control comparisons. However, despite this, limited work has systematically evaluated the impact of image and image-processing quality on these measures, or compared different quality control (QC) methods and metrics. The growing size of typical neuroimaging datasets presents an additional challenge to QC, which is typically extremely time and labour intensive. Two of the most important aspects of MRI quality are motion, which is known to have a substantial impact on cortical measures in particular, and the accuracy of processed outputs, which have been shown to impact neurodevelopmental trajectories. Here, we present a tool, FSQC, that enables quick and efficient yet thorough assessment of both of these aspects in outputs of the FreeSurfer processing pipeline. We validate our method against other existing QC metrics, including the automated FreeSurfer Euler number, and two other manual ratings of raw image quality. We show strikingly similar spatial patterns in the relationship between each QC measure and cortical thickness; relationships for cortical volume and surface area are largely consistent across metrics, though with some notable differences. We next demonstrate that thresholding by QC score attenuates but does eliminate the impact of quality on cortical estimates. Finally, we explore different ways of controlling for quality when examining differences between autistic individuals and neurotypical controls in the ABIDE dataset, demonstrating that inadequate control for quality can alter results of case-control comparisons.
Plasma GFAP associates with secondary Alzheimer’s pathology in Lewy body disease
Authors: Cousins Katheryn A.Q. , Irwin David J. , Chen-Plotkin Alice , Shaw Leslie M. , Arezoumandan Sanaz , Lee Edward B. , Wolk David A. , Weintraub Daniel , Spindler Meredith , Deik Andres , Grossman Murray , Tropea Thomas F.
Published: December 2022

Objective

Within Lewy body spectrum disorders (LBSD) with α-synuclein pathology (αSyn), concomitant Alzheimer’s disease (AD) pathology is common and is predictive of clinical outcomes, including cognitive impairment and decline. Plasma phosphorylated tau 181 (p-tau181) is sensitive to AD neuropathologic change (ADNC) in clinical AD, and plasma glial fibrillary acidic protein (GFAP) is associated with the presence of β-amyloid plaques. While these plasma biomarkers are well tested in clinical and pathological AD, their diagnostic and prognostic performance for concomitant AD in LBSD is unknown.

Methods

In autopsy-confirmed αSyn-positive LBSD, we tested how plasma p-tau181and GFAP differed across αSyn with concomitant ADNC (αSyn+AD; n=19) and αSyn without AD (αSyn; n=30). Severity of burden was scored on a semi-quantitative scale for several pathologies (e.g., β-amyloid and tau), and scores were averaged across sampled brainstem, limbic, and neocortical regions.

Results

Linear models showed that plasma GFAP was significantly higher in αSyn+AD compared to αSyn (β=0.31, 95%CI=0.065 – 0.56,p=0.015), after covarying for age at plasma, plasma-to-death interval and sex; plasma p-tau181was not (p=0.37). Next, linear models tested associations of AD pathological features with both plasma analytes, covarying for plasma-to-death, age at plasma, and sex. GFAP was significantly associated with brain β-amyloid (β=15, 95%CI=6.1 – 25,p=0.0018) and tau burden (β=12, 95%CI=2.5 – 22,p=0.015); plasma p-tau181was not associated with either (bothp>0.34).

Interpretation

Findings indicate that plasma GFAP may be sensitive to concomitant AD pathology in LBSD, especially accumulation of β-amyloid plaques.
Adequacy of using a residual nasal swab specimen from a rapid influenza diagnostic test to perform PCR and whole genome sequencing
Authors: Temte Jonathan L. , Bell Cristalyne , Goss Maureen D. , Reisdorf Erik , Tamerius John , Reddy Sushruth , Barlow Shari , Temte Emily , Wedig Mary , Shult Peter A.
Published: December 2022

Background

Rapid influenza diagnostic tests (RIDT) demonstrate varying sensitivities, often necessitating reverse transcriptase polymerase chain reaction (RT-PCR) to confirm results. The two methods generally require separate specimens. Using the same anterior nasal swab for both RIDT and molecular confirmation would reduce cost and waste and increase patient comfort.

Objective

The aim of this study was to determine if RIDT residual nasal swab (rNS) specimens are adequate for RT-PCR and whole genome sequencing (WGS).

Study design

We performed RT-PCR and WGS on paired rNS and nasopharyngeal or oropharyngeal (NP/OP) swab specimens that were collected from primary care patients across all ages. We randomly selected 199 and 40 paired specimens for RT-PCR and WGS, respectively, from the 962 paired surveillance specimens collected during the 2014-2015 influenza season.

Results

Sensitivity and specificity for rNS specimens were 81.3% and 96.7%, respectively, as compared to NP/OP specimens. The mean cycle threshold (Ct) value for the NP/OP specimen was significantly lower when the paired specimens were both positive than when the NP/OP swab was positive and the nasal swab was negative (25.5 vs 29.5; p<0.001). WGS was successful in 67.5% of the rNS specimens and 55.0% of the NP/OP specimens.

Conclusion

It is feasible to use a single anterior nasal swab for RIDT followed by RT-PCR or WGS. This approach may be appropriate in situations where training and supplies are limited. Additional studies are needed to determine if residual nasal swabs from other rapid diagnostic tests produce similar results.
Entrenching social norms in Community-led total sanitation for sustainability of open defecation free status: A survey of Suna West Sub-County, Migori County, Kenya
Authors: Aluoch Naomi R. , Asweto Collins O. , Onyango Patrick O.
Published: December 2022

Background

Community-led total sanitation (CLTS) has been used to stir sanitation-related behaviour change and attain open defecation free (ODF) status. CLTS interventions suffer high rates of reversion such that their gains are unsustainable in most contexts including Suna West sub-County, Kenya.

Objective

This study aimed at determining the role of sanitation hygiene practices and social norms on open defecation free status in Suna West Sub County.

Methodology

Survey study design was employed using questionnaire and observation checklist to collect data from 384 households.

Results

Results revealed that 66.1% households had partially reverted to non-ODF status. The sanitation-hygiene practices associated with maintenance of ODF includes: use of treated water (OR=3.17; CI=1.20-8.40;p=0.020), use of elevated racks (OR=2.17; CI=1.08-4.37;p=0.030), regularly clean latrines (OR=4.88; CI=1.12-21.37;p=0.035), pouring of ash over the pit of the latrine (OR=4.25; CI=4.20-8.87;p<0.001) and use of dug out pits for waste disposal (OR=4.51; CI=2.09-9.78;p<0.001). On social norms, the study found that laws/penalties (OR=0.31; CI=0.21-0.48;p<0.001), need to improve things in the family (OR=0.50; CI=0.28-0.92;P=0.025), and rewards/incentives (OR=0.21; CI=0.13-0.33;p<0.001) would reduce odds of being ODF. Moreover, odds of being ODF was less likely for households with perception that; construction/maintenance materials were expensive (OR=0.52; CI=0.33-0.80;p=0.003), most people don’t have a latrine (OR=0.40; CI=0.25-0.64; p<0.001) and it is okay to defecate in bushes/rivers/dams (OR=0.31; CI=0.19-0.51; p<0.001).

Conclusion

This study findings provides evidence of ODF status reversion in previously certified villages. However, household with retained ODF status was enhanced by several sanitation hygiene practices. Interestingly, households that displayed social norms were less likely to be ODF. This reveals that the CLTS process failed to instil social norms around proper sanitation to inspire community collective action thus little influence on sustainable behaviour change. The findings of this study therefore highlight the need to enhance good hygiene sanitation practices, while instilling social norms to inspire community collective action.
Characterisation and zoonotic risk of tick viruses in public datasets
Authors: Lin Yuting , Pascall David J
Published: December 2022

Tick-borne viruses remain a substantial zoonotic risk worldwide, so knowledge of the diversity of tick viruses has potential health consequences. Despite their importance, large amounts of sequences in public datasets from tick meta-genomic and –transcriptomic projects remain unannotated, sequence data that could contain undocumented viruses. Through data mining and bioinformatic analyses of more than 37,800 public meta-genomic and -transcriptomic datasets, we found 83 unannotated contigs exhibiting high identity with known tick viruses. These putative viral contigs were classified into three RNA viral families (Alphatetraviridae,Orthomyxoviridae,Chuviridae) and one DNA viral family (Asfaviridae). After manual checking of quality and dissimilarity toward other sequences in the dataset, these 83 contigs were reduced to five putative novel Alphatetra-like viral contigs, four putative novel Orthomyxo-like viral contigs, and one Chu-like viral contig which clustered with known tick-borne viruses, forming a separate clade within the viral families. We further attempted to assess which previously known tick viruses likely represent zoonotic risks and thus deserve further investigation. We ranked the human infection potential of 136 known tick-borne viruses using a genome composition-based machine learning model. We found five high-risk tick-borne viruses (Langat virus, Lonestar tick chuvirus 1, Grotenhout virus, Taggert virus, and Johnston Atoll virus) that have not been known to infect human and two viral families (NairoviridaeandPhenuiviridae) that contain a large proportion of potential zoonotic tick-borne viruses. This adds to the knowledge of tick virus diversity and highlights the importance of surveillance of newly emerging tick-borne diseases.

Importance

Ticks are important hosts of pathogens. Despite this, numerous tick-borne viruses are still unknown or poorly characterised. To overcome this, we re-examined currently known tick-borne viruses and identified putative novel viruses associated with ticks in public datasets. Using genome-based machine learning approach, we predicted five high-risk tick-borne viruses that have not yet been reported to cause human infections. Additionally, we highlighted two viral families,NairoviridaeandPhenuiviridae, which are potential public health threats. Our analysis also revealed 10 putative novel RNA viral contigs clustered with known tick-borne viruses. Our study highlights the importance of monitoring ticks and the viruses they carry in endemic areas to prevent and control zoonotic infectious disease outbreaks. To achieve this, we advocate for a multidisciplinary approach within a One Health and EcoHealth framework that considers the relationship between zoonotic disease outbreaks and their hosts, humans, and the environment.
Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves
Authors: Focosi Daniele , Quiroga Rodrigo , McConnell Scott A. , Johnson Marc C , Casadevall Arturo
Published: December 2022

The first 2 years of the COVID-19 pandemic were mainly characterized by convergent evolution of mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 across different variants of concern (Alpha, Beta, Gamma, and Delta). Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and refocus antibody-mediated therapeutic efforts on polyclonal preparations that are less likely to allow for viral immune escape.
Superiority of intranasal over systemic administration of bioengineered soluble ACE2 for survival and brain protection against SARS-CoV-2 infection
Authors: Hassler Luise , Wysocki Jan , Ahrendsen Jared T. , Ye Minghao , Gelarden Ian , Nicolaescu Vlad , Tomatsidou Anastasia , Gula Haley , Cianfarini Cosimo , Khurram Nigar , Kanwar Yashpal , Singer Benjamin D. , Randall Glenn , Missiakas Dominique , Henkin Jack , Batlle Daniel
Published: December 2022

The present study was designed to investigate the effects of a soluble ACE2 protein termed ACE2 618-DDC-ABD, bioengineered to have long duration of action and high binding affinity to SARS-CoV-2, when administered either intranasally (IN) or intraperitoneally (IP) and before or after SARS-CoV-2 inoculation.

K18hACE2 mice permissive for SARS-CoV-2 infection were inoculated with 2×104PFU wildtype SARS-CoV-2. In one protocol, ACE2 618-DDC-ABD was given either IN or IP, pre- and post-viral inoculation. In a second protocol, ACE2 618-DDC-ABD was given either IN, IP or IN+IP but only post-viral inoculation. In addition, A549 and Vero E6 cells were used to test neutralization of SARS-CoV-2 variants by ACE2 618-DDC-ABD at different concentrations.

Survival by day 5 was 0% in infected untreated mice, and 40% in mice from the ACE2 618-DDC-ABD IP-pre treated group. By contrast, in the IN-pre group survival was 90%, histopathology of brain and kidney was essentially normal and markedly improved in the lungs. When ACE2 618-DDC-ABD was administered only post viral inoculation, survival was 30% in the IN+IP group, 20% in the IN and 0% in the IP group. Brain SARS-CoV-2 titers were high in all groups except for the IN-pre group where titers were undetectable in all mice. In cells permissive for SARS-CoV-2 infection, ACE2 618-DDC-ABD neutralized wildtype SARS-CoV-2 at high concentrations, whereas much lower concentrations neutralized omicron BA. 1.

We conclude that ACE2 618-DDC-ABD provides much better survival and organ protection when administered intranasally than when given systemically or after viral inoculation and that lowering brain titers is a critical determinant of survival and organ protection.
Structural basis for CaVα2δ:gabapentin binding
Authors: Chen Zhou , Mondal Abhisek , Minor Daniel L.
Published: December 2022

Gabapentinoid drugs for pain and anxiety act on the CaVα2δ-1 and CaVα2δ-2 subunits of high-voltage activated calcium channels (CaV1s and CaV2s). Here, we present the cryo-EM structure of the gabapentin-bound brain and cardiac CaV1.2/CaVβ3/CaVα2δ-1 channel. The data reveal a binding pocket in the CaVα2δ-1 dCache1 domain that completely encapsulates gabapentin and define CaVα2δ isoform sequence variations that explain gabapentin binding selectivity of CaVα2δ-1 and CaVα2δ-2.
Characterization of adult human skeletal cells in different tissues reveals a CD90+CD34+ periosteal stem cell population
Authors: Cao Ye , Bolam Scott M. , Boss Anna L. , Murray Helen C. , Dalbeth Nicola , Brooks Anna E.S. , Matthews Brya G.
Published: December 2022

Skeletal stem and progenitor cells are critical for bone homeostasis and healing, but their identity and diversity in humans are not well understood. In this study, we compared stromal populations in matched tissues from the femoral head and neck of 21 human participants using spectral flow cytometry of freshly isolated cells. High-level analysis indicated significant differences in marker distribution between periosteum, articular cartilage, endosteum and bone marrow stromal populations, and identified populations that were highly enriched or unique to specific tissues. Periosteum-enriched markers included CD90 and CD34. Articular cartilage, which has very poor regenerative potential, showed enrichment of multiple markers, including the PDPN+CD73+CD164+ population previously reported to represent human skeletal stem cells. We further characterized periosteal populations by combining CD90 with other strongly expressed markers. CD90+CD34+ cells sorted directly from periosteum showed significant colony-forming unit fibroblasts (CFU-F) enrichment, rapid expansion, and consistent multi-lineage differentiation of clonal populations. In situ, CD90+CD34+ cells include a perivascular population in the outer layer of the periosteum and non-perivascular cells closer to the bone surface. In conclusion, our study indicates considerable diversity in the stromal cell populations in different tissue compartments within the adult human skeleton, and suggests that periosteal stem cells reside within the CD90+CD34+ population.
Spontaneous and multifaceted ATP release from astrocytes at the scale of hundreds of synapses
Authors: Hatashita Yoshiki , Wu Zhaofa , Fujita Hirotaka , Kumamoto Takuma , Livet Jean , Li Yulong , Tanifuji Manabu , Inoue Takafumi
Published: December 2022

Astrocytes participate in information processing by releasing neuroactive substances termed gliotransmitters, including ATP. Individual astrocytes come into contact with thousands of synapses with their ramified structure, but the spatiotemporal dynamics of ATP gliotransmission remain unclear, especially in physiological brain tissue. Using a genetically encoded fluorescent sensor, GRABATP1.0, we discovered that extracellular ATP increased locally and transiently in absence of stimuli in neuron-glia co-cultures, cortical slices, and the anesthetized mouse brain. Spontaneous ATP release events were tetrodotoxin-insensitive but suppressed by gliotoxin, fluorocitrate, and typically spread over 50–250 μm2area at concentrations capable of activating purinergic receptors. Besides, most ATP events did not coincide with Ca2+transients. Clustering analysis revealed that these events followed multiple distinct kinetics, and blockade of exocytosis only decreased a minor group of slow events. Overall, astrocytes spontaneously release ATP through multiple mechanisms, mainly in non-vesicular and Ca2+-independent manners, thus potentially regulating hundreds of synapses all together.
Convergent evolution of the SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant
Authors: Ito Jumpei , Suzuki Rigel , Uriu Keiya , Itakura Yukari , Zahradnik Jiri , Deguchi Sayaka , Wang Lei , Lytras Spyros , Tamura Tomokazu , Kida Izumi , Nasser Hesham , Shofa Maya , Begum MST Monira , Tsuda Masumi , Oda Yoshitaka , Fujita Shigeru , Yoshimatsu Kumiko , Ito Hayato , Nao Naganori , Asakura Hiroyuki , Nagashima Mami , Sadamasu Kenji , Yoshimura Kazuhisa , Yamamoto Yuki , Nagamoto Tetsuharu , Schreiber Gideon ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Saito Akatsuki , Matsuno Keita , Takayama Kazuo , Tanaka Shinya , Fukuhara Takasuke , Ikeda Terumasa , Sato Kei
Published: December 2022

In late 2022, although the SARS-CoV-2 Omicron subvariants have highly diversified, some lineages have convergently acquired amino acid substitutions at five critical residues in the spike protein. Here, we illuminated the evolutionary rules underlying the convergent evolution of Omicron subvariants and the properties of one of the latest lineages of concern, BQ.1.1. Our phylogenetic and epidemic dynamics analyses suggest that Omicron subvariants independently increased their viral fitness by acquiring the convergent substitutions. Particularly, BQ.1.1, which harbors all five convergent substitutions, shows the highest fitness among the viruses investigated. Neutralization assays show that BQ.1.1 is more resistant to breakthrough BA.2/5 infection sera than BA.5. The BQ.1.1 spike exhibits enhanced binding affinity to human ACE2 receptor and greater fusogenicity than the BA.5 spike. However, the pathogenicity of BQ.1.1 in hamsters is comparable to or even lower than that of BA.5. Our multiscale investigations provide insights into the evolutionary trajectory of Omicron subvariants.
Illuminating the mechanism and allosteric behavior of NanoLuc luciferase
Authors: Nemergut Michal , Pluskal Daniel , Horackova Jana , Sustrova Tereza , Tulis Jan , Barta Tomas , Baatallah Racha , Gagnot Glwadys , Novakova Veronika , Majerova Marika , Sedlackova Karolina , Marques Sérgio M. , Toul Martin , Damborsky Jiri , Prokop Zbynek , Bednar David , Janin Yves L. , Marek Martin
Published: December 2022

NanoLuc, a superior β-barrel fold luciferase, was engineered 10 years ago but the nature of its catalysis remains puzzling. Here experimental and computational techniques were combined, revealing that imidazopyrazinone luciferins bind to an intra-barrel catalytic site but also to an allosteric site shaped on the enzyme surface. Structurally, binding to the allosteric site prevents simultaneous binding to the catalytic site, andvice versa, through concerted conformational changes. We demonstrate that restructuration of the allosteric site can boost the luminescent reaction in the remote active site. Mechanistically, an intra-barrel arginine coordinates the imidazopyrazinone component of luciferin, which reacts with O2via a radical charge-transfer mechanism, and then it also protonates the resulting excited amide product to form a light-emitting neutral species. Concomitantly, an aspartate, supported by two tyrosines, fine-tunes the blue color emitter to secure a high emission intensity. This information is critical to engineering the next-generation of ultrasensitive bioluminescent reporters.
Processing of the hepatitis E virus polyprotein can be mediated by a cellular protease
Authors: Pierce Danielle M. , Buchanan Frazer J.T. , Cox Abigail , Abualsaoud Khadijah , Ward Joseph C. , Harris Mark , Stonehouse Nicola J. , Herod Morgan R.
Published: December 2022

The genomes of positive-sense RNA viruses encode polyproteins that are essential for controlling viral replication. These viral polyproteins must undergo proteolysis (also termed polyprotein processing) to generate functional protein units. This proteolysis can be performed by virally-encoded proteases as well as host cellular proteases, and is generally believed to be a key step in regulating viral replication. Hepatitis E virus (HEV), a leading cause of acute viral hepatitis, translates its positive-sense RNA genome to generate a polyprotein, termed pORF1, which is necessary and sufficient for viral genome replication. However, the mechanism of polyprotein processing in HEV remains to be determined. In this study, we aimed to understand processing of this polyprotein and its role in viral replication using a combination ofin vitrotranslation experiments and HEV sub-genomic replicons.

Our data suggest no evidence for a virally-encoded protease or auto-proteolytic activity asin vitrotranslation predominantly generates unprocessed viral polyprotein precursors. However, seven cleavage sites within the polyprotein (suggested by bioinformatic analysis) are susceptible to the host cellular protease, thrombin. Using a sub-genomic replicon system, we demonstrate that mutagenesis of these sites prevents replication, as does pharmacological inhibition of serine proteases. Overall, our data supports a model where HEV uses host proteases to support its replication and could have uniquely evolved not to rely on a virally-encoded protease for replication.

Author summary

Positive-strand RNA viruses produce polyproteins that are cleaved by proteases that control viral replication. The polyproteins of all well studied positive-strand viruses undergo proteolysis in a highly controlled manner to generate functional proteins and regulate the transition from translation to RNA replication. Proteolysis of viral polyproteins is generally performed by virally-encoded proteases, although host cell proteases are used by some viruses. In this report, we provide evidence that suggests that hepatitis E virus, a medically important human pathogen, does not encode a protease and unlike other viral polyproteins cannot undergo auto-catalytic processing. Instead, we provide evidence that the polyprotein is susceptible to proteolysis by host cell proteases and that this is essential for viral replication. Our data contradict the previous dogma of positive-sense viral replication and suggests a model where this virus has evolved to use a host protease to control viral replication and tropism.
Dynamin A as a one-component division machinery for synthetic cells
Authors: De Franceschi Nicola , Barth Roman , Meindlhumer Sabrina , Fragasso Alessio , Dekker Cees
Published: December 2022

Membrane abscission, the final cut of the last connection between emerging daughter cells, is an indispensable event in the last stage of cell division, as well as in other cellular processes such as endocytosis, virus release, or bacterial sporulation. However, its mechanism remains poorly understood, which also impedes its application as a cell-division machinery for synthetic cells. Here, we use fluorescence microscopy and Fluorescence Recovery After Photobleaching (FRAP) to study thein vitroreconstitution of the bacterial protein Dynamin A (DynA) inside liposomes. Upon external reshaping of the liposomes into dumbbells, DynA self-assembles at the membrane neck, resulting in membrane hemi-scission and even full scission. DynA proteins constitute a simple one-component division machinery that is capable of splitting dumbbell-shaped liposomes, marking an important step towards building a synthetic cell.
The canonical E2Fs together with RETINOBLASTOMA-RELATED are required to establish quiescence during plant development
Authors: Gombos Magdolna , Raynaud Cécile , Nomoto Yuji , Molnár Eszter , Brik-Chaouche Rim , Takatsuka Hirotomo , Zaki Ahmad , Bernula Dóri , Latrasse David , Mineta Keito , Nagy Fruzsina , He Xiaoning , Iwakawa Hidekazu , Őszi Erika , An Jing , Suzuki Takamasa , Papdi Csaba , Bergis Clara , Benhamed Moussa , Bögre László , Ito Masaki , Magyar Zoltán
Published: December 2022

Maintaining stable and transient quiescence in differentiated and stem cells, respectively, requires repression of the cell cycle. The plant RETINOBLASTOMA-RELATED (RBR) has been implicated in stem cell maintenance, presumably by forming repressor complexes with E2F transcription factors. Surprisingly we find that mutations in all three canonical E2Fs do not compromise the cell cycle, but similarly toRBRsilencing, result in overproliferation. Contrary to the growth arrest upon RBR silencing, when exit from proliferation to differentiation is inhibited, thee2fabcmutant develops enlarged organs with supernumerary stem and differentiated cells as the quiescence is compromised. While E2F, RBR and the M-phase regulatory MYB3Rs are part of the DREAM repressor complexes, and recruited to overlapping groups of targets, they regulate distinct sets of genes. Only the loss of E2Fs but not the MYB3Rs interferes with quiescence, which might be due to the ability of E2Fs to control both G1-S and some key G2-M targets. We conclude that collectively the three canonical E2Fs in complex with RBR have central roles in establishing cellular quiescence during organ development, leading to enhanced plant growth.
DiffDomain enables identification of structurally reorganized topologically associating domains
Authors: Hua Dunming , Gu Ming , Zhang Xiao , Du Yanyi , Xie Hangcheng , Qi Li , Du Xiangjun , Bai Zhidong , Zhu Xiaopeng , Tian Dechao
Published: December 2022

Topologically associating domains (TADs) are critical structural units in three-dimensional genome organization of mammalian genome. Dynamic reorganizations of TADs between health and disease states are associated with transcription and other essential genome functions. However, computational methods that can identify reorganized TADs are still in the early stages of development. Here, we present DiffDomain, an algorithm leveraging high-dimensional random matrix theory to identify structurally reorganized TADs using chromatin contact maps. Method comparison using multiple real Hi-C datasets reveals that DiffDomain outperforms alternative methods for FPRs, TPRs, and identifying a new subtype of reorganized TADs. The robustness of DiffDomain and its biological applications are demonstrated by applying on Hi-C data from different cell types and disease states. Identified reorganized TADs are associated with structural variations and changes in CTCF binding sites and other epigenomic changes. By applying to a single-cell Hi-C data from mouse neuronal development, DiffDomain can identify reorganized TADs between cell types with reasonable reproducibility using pseudo-bulk Hi-C data from as few as 100 cells per condition. Moreover, DiffDomain reveals that TADs have differential cell-to-population variability and heterogeneous cell-to-cell variability. Therefore, DiffDomain is a statistically sound method for better comparative analysis of TADs using both Hi-C and single-cell Hi-C data.