bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring emotions in Bach chorales: a multi-modal perceptual and data-driven study
Authors: Parada-Cabaleiro Emilia , Batliner Anton , Zentner Marcel , Schedl Markus
Published: December 2023

The relationship between music and emotion has been addressed within several disciplines, from more historico-philosophical and anthropological ones, such as musicology and ethnomusicology, to others that are traditionally more empirical and technological, such as psychology and computer science. Yet, understanding the link between music and emotion is limited by the scarce interconnections between these disciplines. Trying to narrow this gap, this data-driven exploratory study aims at assessing the relationship between linguistic, symbolic and acoustic features—extracted from lyrics, music notation and audio recordings—and perception of emotion. Employing a listening experiment, statistical analysis and unsupervised machine learning, we investigate how a data-driven multi-modal approach can be used to explore the emotions conveyed by eight Bach chorales. Through a feature selection strategy based on a set of more than 300 Bach chorales and a transdisciplinary methodology integrating approaches from psychology, musicology and computer science, we aim to initiate an efficient dialogue between disciplines, able to promote a more integrative and holistic understanding of emotions in music.
Potential application of bisoprolol derivative compounds as antihypertensive drugs: synthesis and
in silico
study
Authors: Oktaviani Ni Putu Sani , Ivansyah Atthar Luqman , Saputra Muhammad Yogi , Handayani Nurrahmi , Fadylla Nurdiani , Wahyuningrum Deana
Published: December 2023

Two bisoprolol derivatives,
N
-acetyl bisoprolol and
N
-formyl bisoprolol, belonging to the beta-blocker class of antihypertensive drugs, were synthesized using acetylation and formylation reactions. The yields of the reactions were determined to be 32.40% for
N
-acetyl bisoprolol and 20.20% for
N
-formyl bisoprolol.
In silico
methods such as molecular docking, molecular dynamics simulation and SwissADME prediction were employed to evaluate the potential of these bisoprolol derivatives as antihypertensive drugs. These methods were used to assess the interaction between the bisoprolol derivatives and various receptors associated with hypertension, including human angiotensin I-converting enzyme (PDB ID: 1O8A), renin (PDB ID: 2V0Z), beta-1 adrenergic receptors (PDB ID: 4BVN, 7BVQ), voltage-dependent L-type calcium channel subunit alpha-1S (PDB ID: 6JP5) and mineralocorticoid receptor (PDB ID: 6L88). Our results demonstrated the highest binding energy when bisoprolol and its derivatives bound to 4BVN, with binding energy values of 6.74 kcal mol
−1
, 7.03 kcal mol
−1
and 7.63 kcal mol
−1
for bisoprolol,
N
-acetyl bisoprolol and
N
-formyl bisoprolol, respectively. The stability of these complexes was confirmed by molecular dynamics simulations, with a root-mean-square deviation value of approximately 2. Furthermore, the SwissADME results indicated that both derivatives exhibited similar properties to the reference drug bisoprolol.
Heterologously expressed SacP23, a novel bacteriocin from
Paenibacillus polymyxa
#23, is active against methicillin resistant
Staphylococcus aureus
Authors: Khánh Châu Minh , Van Quyen Dong , Van Thi Thu Hao , Moore Robert J.
Published: December 2023

Antimicrobial peptides have the potential to be used in a range of applications, including as an alternative to conventional antibiotics for the treatment of bacterial infections of humans and animals. Therefore, there is interest in identifying novel bacteriocins which have desirable physico-chemical properties or antimicrobial activities.
Paenibacillus polymyxa
#23, isolated from a marine sponge, has wide spectrum antimicrobial activity against Gram-negative and Gram-positive bacteria. To explore the basis of this antimicrobial activity, the complete genome sequence of the strain was examined. Multiple genes predicted to encode antimicrobial peptides were identified. One gene was predicted to encode a novel sactipeptide bacteriocin, named SacP23. To confirm that SacP23 does have antimicrobial activity and to explore the antimicrobial spectrum of the peptide it was heterologously expressed in
Bacillus subtilis
. A cluster of eight genes, encoding a full complement of accessory genes as well as the structural gene expressed from the native promoter, was cloned into
B. subtilis
BS54A. The recombinant strain displayed antimicrobial activity against several Gram-positive bacteria, including multi-drug resistant
Staphylococcus aureus
. Heterologous expression of a whole gene cluster offers a powerful way to interrogate and resolve the various antimicrobial activities expressed by native strains that encode multiple compounds of interest.
Metagenome-assembled genomes from mineral tundra soils in Rásttigáisá, northern Norway
Authors: Pessi Igor S , Rutanen Aino , Hultman Jenni
Published: December 2023

Microbial communities in tundra soils remain largely unknown despite their important roles in the cycling of greenhouse gases. Here, we report 59 non-redundant metagenome-assembled genomes (MAGs) recovered from mineral tundra soils in Rásttigáisá, northern Norway. The MAGs were obtained by clustering contigs according to tetranucleotide frequency and differential coverage and were manually curated to remove contigs with outlying GC content and/or mean coverage. Most MAGs were assigned to the bacterial phyla Candidatus Dormibacterota (n=12), Verrucomicrobiota (n=10), and Acidobacteriota (n=9). All archaeal MAGs (n=4) belong to the genus Candidatus Nitrosopolaris (phylum Thermoproteota). The 59 Rásttigáisá MAGs expand our knowledge of the diversity and ecological roles of tundra microbiomes.
Turtle species and ecology drive carapace microbiome diversity in three seasonally interconnected wetland habitats
Authors: Parks Matthew , Lee Jun Sheng , Camua Kassandra , Hollender Ethan
Published: December 2023

Different species of freshwater turtles exhibit primary behaviors ranging from aerial basking to benthic bottom-walking, cycle between wet and dry conditions at different time intervals, and undertake short-distance overland movements between aquatic habitats. These behaviors in turn may impact the accumulation of microbes on external shell surfaces of turtles and provide novel niches for differentiation of microbial communities. We assessed microbial diversity using 16S and 18S rRNA metabarcoding on carapace surfaces of six species of freshwater turtles residing in three adjacent and seasonally interconnected wetland habitats in southeast Oklahoma (United States). Communities were highly diverse, with nearly 4,200 prokaryotic and 500 micro-eukaryotic amplicon sequence variants recovered, and included taxa previously reported as common or differentially abundant on turtle shells. 16S rRNA alpha diversity tended to be highest for two species of benthic turtles, while 18S rRNA alpha diversity was highest for two basking and one shallow-water benthic species. Beta diversity of communities was more strongly differentiated by turtle species than by collection site, and ordination patterns were largely reflective of turtle species’ primary habits (i.e., benthic, basking, or benthic-basking). Our data support that freshwater turtles could play a role in microbial ecology and evolution in freshwater habitats and warrant additional exploration including in areas with high native turtle diversity and inter-habitat turtle movements
ICTV Virus Taxonomy Profile: Cruliviridae 2023
Authors: Kuhn Jens H. , Adkins Scott , Brown Katherine , de la Torre Juan Carlos , Digiaro Michele , Hughes Holly R. , Junglen Sandra , Lambert Amy J. , Maes Piet , Marklewitz Marco , Palacios Gustavo , Sasaya Takahide , Turina Massimo , Zhang Yong-Zhen
Published: December 2023

Cruliviridae is a family of negative-sense RNA viruses with genomes of 10.8–11.5 kb that have been found in crustaceans. The crulivirid genome consists of three RNA segments with ORFs that encode a nucleoprotein (NP), a glycoprotein (GP), a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain, and in some family members, a zinc-finger (Z) protein of unknown function. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Cruliviridae, which is available at ictv.global/report/cruliviridae.
Equine dermatitis outbreak associated with parapoxvirus
Authors: Virtanen Jenni , Hautala Katja , Utriainen Mira , Dutra Lara , Eskola Katarina , Airas Niina , Uusitalo Ruut , Ahvenainen Ella , Smura Teemu , Sironen Tarja , Vapalahti Olli , Kant Ravi , Virtala Anna-Maija K. , Kinnunen Paula M.
Published: December 2023

Parapoxviruses (PPV) cause skin and mucous membrane lesions in several animal species, and of the five recognized PPVs, at least three are zoonotic. Equine PPV (EqPPV) is the sixth one initially described in humans in the United States and later in a severely sick horse in Finland in 2013–2015. In 2021–2022, a large-scale pustulo-vesicular pastern dermatitis outbreak occurred in horses all over Finland. This study aimed at analysing the outbreak, identifying and describing the causative agent, describing clinical signs, and searching for risk factors. EqPPV was identified as a probable causative agent and co-infections with several potentially pathogenic and zoonotic bacteria were observed. Histopathologically, suppurative and ulcerative dermatitis was diagnosed. Due to the lack of specific tests for this virus, we developed a novel diagnostic EqPPV-PCR with sensitivity of 10 copies/reaction. Based on a large proportion of the genome sequenced directly from clinical samples, very little variation was detected between the sequences of the case from 2013 and the cases from 2021 to 2022. Based on an epidemiological survey, the main risk factor for pastern dermatitis was having racehorses. Approximately one third of the horses at each affected stable got clinical dermatitis, manifesting as severe skin lesions. Skin lesions were also occasionally reported in humans, indicating potential zoonotic transmission. Case stables commonly reported attendance at race events before acquiring the disease. Survey also identified differences in practises between case and control stables. Taken together, these results enable a better preparedness, diagnostics, and guidelines for future outbreaks.
Visualizing and quantifying structural diversity around mobile resistance genes
Authors: Shaw Liam P. , Neher Richard A.
Published: December 2023

Understanding the evolution of mobile genes is important for understanding the spread of antimicrobial resistance (AMR). Many clinically important AMR genes have been mobilized by mobile genetic elements (MGEs) on the kilobase scale, such as integrons and transposons, which can integrate into both chromosomes and plasmids and lead to rapid spread of the gene through bacterial populations. Looking at the flanking regions of these mobile genes in diverse genomes can highlight common structures and reveal patterns of MGE spread. However, historically this has been a largely descriptive process, relying on gene annotation and expert knowledge. Here we describe a general method to visualize and quantify the structural diversity around genes using pangraph to find blocks of homologous sequence. We apply this method to a set of 12 clinically important beta-lactamase genes and provide interactive visualizations of their flanking regions at https://liampshaw.github.io/flanking-regions. We show that nucleotide-level variation in the mobile gene itself generally correlates with increased structural diversity in its flanking regions, demonstrating a relationship between rates of mutational evolution and rates of structural evolution, and find a bias for greater structural diversity upstream. Our framework is a starting point to investigate general rules that apply to the horizontal spread of new genes through bacterial populations.
Atomistic modelling and NMR studies reveal that gallium can target the ferric PQS uptake system in P. aeruginosa biofilms
Authors: Hills Oliver J. , Noble Isaac O.K. , Heyam Alex , Scott Andrew J. , Smith James , Chappell Helen F.
Published: December 2023

Intravenous gallium nitrate therapy is a novel therapeutic strategy deployed to combat chronic

Pseudomonas aeruginosa

biofilm infections in the lungs of cystic fibrosis (CF) patients by interfering with iron (Fe3+) uptake. The therapy is a source of Ga3+, which competes with Fe3+ for siderophore binding, subsequently disrupting iron metabolism and inhibiting biofilm proliferation in vivo. It was recently demonstrated that the

Pseudomonas

quinolone signal (PQS) can chelate Fe3+ to assist in bacterial iron uptake. However, it is unknown whether exogenous gallium also targets [Fe(PQS)3] uptake, which, in turn, would extend the mechanism of gallium therapy beyond siderophore competition, potentially supporting use of the therapy against

P. aeruginosa

mutants deficient in siderophore uptake proteins. To that end, the thermodynamic feasibility of iron-for-gallium cation exchange into [Fe(PQS)3] was evaluated using quantum chemical density functional theory (DFT) modelling and verified experimentally using 1H nuclear magnetic resonance (NMR). We demonstrate here that Ga3+ can strongly bind to three PQS molecules and, furthermore, displace and substitute Fe3+ from the native chelate pocket within PQS complexes, through a Trojan horse mechanism, retaining the key structural features present within the native ferric complex. As such, [Fe(PQS)3] complexes, in addition to ferric–siderophore complexes, represent another target for gallium therapy.
Neural Interoceptive Processing is Modulated by Deep Brain Stimulation for Treatment Resistant Depression
Authors: Xu Elisa , Pitts Samantha , Dahill-Fuchel Jacob , Scherrer Sara , Nauvel Tanya , Overton Jacqueline Guerra , Riva-Posse Patricio , Crowell Andrea , Figee Martijn , Alagapan Sankaraleengam , Rozell Christopher , Choi Ki Sueng , Mayberg Helen S. , Waters Allison C.
Published: December 2023

Background

A critical advance in depression research is to clarify the hypothesized role of interoceptive processing in neural mechanisms of treatment efficacy. This study tests whether cortical interoceptive processing, as indexed by the heartbeat-evoked potential (HEP), is modulated by deep brain stimulation (DBS) to the subcallosal cingulate (SCC) for treatment resistant depression (TRD).

Methods

Eight patients with TRD were enrolled in a study of SCC DBS safety and efficacy. Electroencephalography (EEG) and symptom severity measures were sampled in a laboratory setting over the course of a six-month treatment protocol. The primary outcome measure was an EEG-derived HEP, which reflects cortical processing of heartbeat sensation. Cluster-based permutation analyses were used to test the effect of stimulation and time in treatment on the HEP. The change in signal magnitude after treatment was correlated with change in depression severity as measured by the 17-item Hamilton Depression Rating Scale.

Results

HEP amplitude was greater after 24 weeks of treatment (t(7)=-4.40,p=.003,g=-1.38, 95% Cl [-2.3, -0.42]), and this change was inversely correlated with latency of treatment response (rho = -0.75, 95% Cl [-0.95, -0.11],p=.03). An acute effect of DBS was also observed, but as a decrease in HEP amplitude (t(6) =6.66,p<.001,g=2.19, 95% Cl [0.81, 3.54]). HEP differences were most pronounced over left posterior sensors from 405-425 ms post-stimulus.

Conclusion

Brain-based evidence substantiates a theorized link between interoception and depression, and suggests an interoceptive contribution to the mechanism of treatment efficacy with deep brain stimulation for severe depression.
Prospective validation of clinical deterioration predictive models prior to intensive care unit transfer among patients admitted to acute care cardiology wards
Authors: Keim-Malpass Jessica , Moorman Liza P , Moorman J. Randall , Hamil Susan , Yousevfand Gholamreza , Monfredi Oliver J , Ratcliffe Sarah J , Krahn Katy N , Jones Marieke K , Clark Matthew T , Bourque Jamieson M
Published: December 2023

Very few predictive models have been externally validated in a prospective cohort following the implementation of an artificial intelligence analytic system. This type of real-world validation is critically important due to the risk of data drift, or changes in data definitions or clinical practices over time, that could impact model performance in contemporaneous real-world cohorts. In this work, we report the model performance of a predictive analytics tool that was developed prior to COVID-19 and demonstrates model performance during the COVID-19 pandemic. The analytic system (CoMET®, Nihon Kohden Digital Health Solutions LLC, Irvine, CA) was implemented in a randomized controlled trial that enrolled 10,422 patient visits in a 1:1 display-on display-off design. The CoMET scores were calculated for all patients but only displayed in the display-on arm. Only the control/display-off group is reported here because the scores could not alter care patterns. Of the 5184 visits in the display-off arm, 311 experienced clinical deterioration and care escalation, resulting in transfer to the intensive care unit (ICU), primarily due to respiratory distress. The model performance of CoMET was assessed based on areas under the receiver operating characteristic curve, which ranged from 0.732 to 0.745. The models were well-calibrated, and there were dynamic increases in the model scores in the hours preceding the clinical deterioration events. A hypothetical alerting strategy based on a rise in score and duration of the rise would have had good performance, with a positive predictive value more than 10-fold the event rate. We conclude that predictive statistical models developed five years before study initiation had good model performance despite the passage of time and the impact of the COVID-19 pandemic. We speculate that some of the model performance’s stability is due to continuous cardiorespiratory monitoring, which should not drift as practices, policies, and patient populations change.

Clinical Trial registration

ClinicalTrials.govNCT04359641;

https://clinicaltrials.gov/ct2/show/NCT04359641.
Human movement and transmission dynamics early in Ebola outbreaks
Authors: Gonzalez Alexandria , Nikparvar Behnam , Matson M. Jeremiah , Seifert Stephanie N. , Ross Heather D. , Munster Vincent , Bharti Nita
Published: December 2023

Human movement drives the transmission and spread of communicable pathogens. It is especially influential for emerging pathogens when population immunity is low and spillover events are rare. We digitized serial printed maps to measure transportation networks (roads and rivers) in Central and West Africa as proxies for population mobility to assess relationships between movement and Ebola transmission. We find that the lengths of roads and rivers in close proximity to spillover sites at or near the time of spillover events are significantly correlated with the number of EVD cases, particularly in the first 100 days of each outbreak. Early management and containment efforts along transportation networks may be beneficial in mitigation during the early days of transmission and spatial spread for Ebola outbreaks.

Significance Statement

This study links human movement and pathogen transmission across fifty years. While this relationship is well understood for modern outbreaks, it has not been characterized at local scales for historical outbreaks. We compared the number of cases and the spatial spread of each documented outbreak of Ebola (Orthoebolavirus zairense, EBOV) to the road and river networks surrounding each spillover location at the time of each spillover event. We measured the road and river networks by digitizing a series of paper maps that were printed during or near the year of each spillover. We show that the connectivity of spillover locations is consistently correlated to the severity of the outbreak over time and across all locations of EBOV spillover events.
Differences in coagulation responses to vascular injury between uninterrupted dabigatran and apixaban - a clinical prospective randomized study
Authors: Ikami Yasuhiro , Izumi Daisuke , Fujiki Shinya , Sugiura Hirotaka , Otsuki Sou , Suzuki Naomasa , Sakaguchi Yuta , Hakamata Takahiro , Hasegawa Yuki , Yagihara Nobue , Iijima Kenichi , Tanaka Takahiro , Ishizawa Masahiro , Chinushi Masaomi , Minamino Tohru , Inomata Takayuki
Published: December 2023

Background

The coagulation response during vascular injury with uninterrupted administration of direct oral anticoagulants (DOACs) has not been elucidated. Our aim was to evaluate differences in coagulation responses after vascular injury between uninterrupted direct thrombin inhibitor and direct factor Xa inhibitor recipients.

Methods

Patients scheduled for catheter ablation for atrial fibrillation were randomly assigned to receive dabigatran or apixaban in this prospective, randomized, comparative, parallel-group study. Venous blood was collected three times: 180 minutes after taking the anticoagulant on the day before the procedure, before vascular punctures of the ablation procedure, and 10–15 minutes after the start of vascular punctures.

Results

Forty-two patients were enrolled. The prothrombin fragment 1+2 (F1+2) level, the primary endpoint, was much larger after vascular puncture in the uninterrupted dabigatran recipients (median: 83 pmol/L; interquartile range: 56–133 pmol/L) than in the uninterrupted apixaban recipients (median: 1 pmol/L; interquartile range: −3–19 pmol/L; P < 0.001). Antithrombin levels decreased after vascular puncture in dabigatran recipients, and both protein C and antithrombin levels decreased after vascular puncture in apixaban recipients.

Conclusions

Unlike uninterrupted apixaban, uninterrupted dabigatran does not inhibit thrombin generation in response to vascular injury.

Clinical perspective

What is new?

To the best of our knowledge, this is the first randomized clinical comparison of the effects of direct thrombin and factor Xa inhibitors on the physiological coagulation and anticoagulation system after vascular injury while direct oral anticoagulants (DOACs) serum levels were at the peak phase.

Unlike uninterrupted apixaban, uninterrupted dabigatran does not inhibit thrombin generation in response to vascular injury.

This study shows that physiological anticoagulation factors are consumed during vascular injury in patients receiving DOACs.

What are the clinical implications?

The difference in the thrombin generation response during vascular injury between uninterrupted dabigatran and apixaban may be one of the reasons for different clinical outcomes of thrombotic and hemorrhagic complications.

DOACs may inhibit an excessive coagulation response by retaining physiological anticoagulation factors.
Leveraging informative missing data to learn about acute respiratory distress syndrome and mortality in long-term hospitalized COVID-19 patients throughout the years of the pandemic
Authors: Getzen Emily , Tan Amelia LM , Brat Gabriel , Omenn Gilbert S. , Strasser Zachary ,   The Consortium for Clinical Characterization of COVID-19 by EHR (4CE) (Collaborative Group/Consortium), Long Qi , Holmes John H. , Mowery Danielle
Published: December 2023

Electronic health records (EHRs) contain a wealth of information that can be used to further precision health. One particular data element in EHRs that is not only under-utilized but oftentimes unaccounted for is missing data. However, missingness can provide valuable information about comorbidities and best practices for monitoring patients, which could save lives and reduce burden on the healthcare system. We characterize patterns of missing data in laboratory measurements collected at the University of Pennsylvania Hospital System from long-term COVID-19 patients and focus on the changes in these patterns between 2020 and 2021. We investigate how these patterns are associated with comorbidities such as acute respiratory distress syndrome (ARDS), and 90-day mortality in ARDS patients. This work displays how knowledge and experience can change the way clinicians and hospitals manage a novel disease. It can also provide insight into best practices when it comes to patient monitoring to improve outcomes.
Evolution of resistance to KRASG12Cinhibitor in a non-small cell lung cancer responder
Authors: Xu Jia-Hui , Wang Shi-Jia , Wang Ziming , Huang Jumin , Xie Chun , Cao Yabing , Chen Ming , Leung Elaine Lai-Han
Published: December 2023

Despite initial therapeutic successes, most patients with non-small cell lung cancer (NSCLC) who carry the KRASG12Cmutation ultimately exhibit resistance to targeted treatments. To improve our comprehension of how acquired resistance develops, we present an unprecedented longitudinal case study profiling the transcriptome of peripheral blood mononuclear cells (PBMCs) over 5 months from an NSCLC patient with the KRASG12Cmutation and initial response to sotorasib followed by resistance and death. Single-cell RNA sequencing analysis uncovered notable fluctuations in immune cell populations throughout treatment with sotorasib. Specifically, we observed a decline in circulating CD8+CD161hiT cells correlating with periods of therapeutic response, followed by a resurgence during phases of nonresponse. This study established a high-resolution atlas detailing the evolutionary trajectory of resistance to sotorasib and characterizes a CD8+CD161hiT cells population in KRASG12Cmutation patient.
Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates
Authors: Malewana R. Dilshan , Stalls Victoria , May Aaron , Lu Xiaozhi , Martinez David R. , Schäfer Alexandra , Li Dapeng , Barr Maggie , Sutherland Laura L. , Lee Esther , Parks Robert , Beck Whitney Edwards , Newman Amanda , Bock Kevin W. , Minai Mahnaz , Nagata Bianca M. , DeMarco C. Todd , Denny Thomas N. , Oguin Thomas H. , Rountree Wes , Wang Yunfei , Mansouri Katayoun , Edwards Robert J. , Sempowski Gregory D. , Eaton Amanda , Muramatsu Hiromi , Henderson Rory , Tam Ying , Barbosa Christopher , Tang Juanjie , Cain Derek W. , Santra Sampa , Moore Ian N. , Andersen Hanne , Lewis Mark G. , Golding Hana , Seder Robert , Khurana Surender , Montefiori David C. , Pardi Norbert , Weissman Drew , Baric Ralph S. , Acharya Priyamvada , Haynes Barton F. , Saunders Kevin O.
Published: December 2023

Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs.

One Sentence Summary

Non-stabilized SARS-CoV-2 Spike mRNA vaccination activated B cells that target either conserved epitopes on SARS-CoV-2 Omicron variants of concern, or cross-neutralizing epitopes on pre-emergent Sarbecoviruses.
Multi-site validation of a functional assay to adjudicateSCN5ABrugada Syndrome-associated variants
Authors: Ma Joanne G. , O’Neill Matthew J. , Richardson Ebony , Thomson Kate L. , Ingles Jodie , Muhammad Ayesha , Solus Joseph F. , Davogustto Giovanni , Anderson Katherine C. , Shoemaker M. Benjamin , Stergachis Andrew B. , Floyd Brendan J. , Dunn Kyla , Parikh Victoria N. , Chubb Henry , Perrin Mark J. , Roden Dan M. , Vandenberg Jamie I. , Ng Chai-Ann , Glazer Andrew M.
Published: December 2023

Brugada Syndrome (BrS) is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in the cardiac sodium channel gene,SCN5A. Interpreting the pathogenicity ofSCN5Amissense variants is challenging and ∼79% ofSCN5Amissense variants in ClinVar are currently classified as Variants of Uncertain Significance (VUS). Anin vitro SCN5A-BrS automated patch clamp assay was generated for high-throughput functional studies of NaV1.5. The assay was independently studied at two separate research sites – Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute – revealing strong correlations, including peakINadensity (R2=0.86). The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. The assay accurately distinguished benign controls (24/25) from pathogenic controls (23/24). Odds of Pathogenicity values derived from the experimental results yielded 0.042 for normal function (BS3 criterion) and 24.0 for abnormal function (PS3 criterion), resulting in up to strong evidence for both ACMG criteria. The calibrated assay was then used to studySCN5AVUS observed in four families with BrS and other arrhythmia phenotypes associated withSCN5Aloss-of-function. The assay revealed loss-of-function for three of four variants, enabling reclassification to likely pathogenic. This validated APC assay provides clinical-grade functional evidence for the reclassification of current VUS and will aid futureSCN5A-BrS variant classification.
Persistent Hyposmia as Surrogate for α-Synuclein-Linked Brain Pathology
Authors: Mollenhauer Brit , Li Juan , Schade Sebastian , Weber Sandrina , Trenkwalder Claudia , Concha-Marambio Luis , Tomlinson Julianna J. ,   aSCENT-PD Investigators, Schlossmacher Michael G.
Published: December 2023

Impaired olfaction can be associated with neurodegenerative disorders. We examined odor identification in newly diagnosed patients with parkinsonism and those at increased risk, measured olfactory performances longitudinally, and juxtaposed results to cerebrospinal fluid (CSF) values. Using Sniffin’-Sticks-Identification Tests (SST-ID), we examined 312 age-matched individuals at a German center, including: 126 with Parkinson disease (PD), 109 healthy controls, 25 with other neurodegenerative disorders and 52 with a REM-sleep behavior disorder (RBD). As expected, PD patients had significantly lower SST-ID scores than controls. Scent identification by subjects with other neurodegenerative diseases fell between those with PD and healthy individuals. Those with isolated RBD, who subsequently converted to PD or dementia, had lower baseline scores than non-converters. When monitoring olfaction in participants up to a decade, we saw small group differences in progression rates for hyposmia. However, these variations were insignificant after controlling for age, sex and length of intervals between testing. When analyzing participants’ sense of smell versus several CSF biomarkers linked to neurodegeneration, we found no correlation with SST-ID scores. However, the means for normalized concentrations of α-synuclein, total tau, phosphorylated tau and amyloid-β peptide42were reduced in PD. We also identified significant age- and sex-linked differences in CSF values. Finally, we compared olfaction to the results of a validated α-synuclein ‘Seed Amplification Assay’ (SAA) using CSF. We found that hyposmia strongly correlated with a positive CSF α-synuclein SAA-test. We conclude that chronically impaired olfaction in older adults is strongly associated with a positive α-synuclein SAA-test from CSF but not with the concentrations of several, neuropathologically relevant CSF markers. We posit that simple-to-administer, quantitative smell tests could serve as inexpensive screening tools in future population studies for the identification of α-synuclein-related brain disorders, including Parkinson’s during its premotor phase.
Is increased trunk flexion in standing up related to muscle weakness or pain avoidance in individuals with unilateral knee pain?; a simulation study
Authors: van der Kruk Eline , Geijtenbeek Thomas
Published: December 2023

The ‘Timed Up and Go’ test (TUG) is a widely used clinical tool for assessing gait and balance, relying primarily on timing as a measure. However, there are more observable biomechanical compensation strategies within TUG that are indicative of underlying neuromuscular issues and movement priorities. In individuals with unilateral knee osteoarthritis, an increased trunk flexion during TUG is a common phenomenon, often attributed to muscle weakness and/or pain avoidance. Unfortunately, it is difficult to differentiate between these underlying causes using experimental studies alone. This study aimed to distinguish between muscle weakness and pain avoidance as contributing factors, using predictive neuromuscular simulations of the sit-to-walk movement. Muscle weakness was simulated by reducing the maximum isometric force of the vasti muscles (ranging from 20% to 60%), while pain avoidance was integrated as a movement objective, ensuring that peak knee load did not exceed predefined thresholds (2-4 times body weight). The simulations demonstrate that a decrease in muscular capacity led to greater trunk flexion, while pain avoidance led to slower movement speeds and altered muscle recruitments, but not to greater trunk flexion. Our predictive simulations thus indicate that increased trunk flexion is more likely the result of lack of muscular reserve rather than pain avoidance. These findings align with reported differences in kinematics and muscle activations between moderate and severe knee osteoarthritis patients, emphasizing the impact of severe muscle weakness in those with advanced knee osteoarthritis. The simulations offer valuable insights into the mechanisms behind altered movement strategies, potentially guiding more targeted treatment.
Estimating social contact rates for the COVID-19 pandemic using Google mobility and pre-pandemic contact surveys
Authors: Prestige Em , Coletti Pietro , Backer Jantien A. , Davies Nicholas J. , Edmunds W. John , Jarvis Christopher I.
Published: December 2023

During the COVID-19 pandemic, aggregated mobility data was frequently used to estimate changing social contact rates. By taking pre-pandemic contact matrices, and transforming these using pandemic-era mobility data, infectious disease modellers attempted to predict the effect of large-scale behavioural changes on contact rates. This study explores the most accurate method for this transformation, using pandemic-era contact surveys as ground truth. We compared four methods for scaling synthetic contact matrices: two using fitted regression models and two using ″naïve″ mobility or mobility squared models. The regression models were fitted using the CoMix contact survey and Google mobility data from the UK over March 2020 - March 2021. The four models were then used to scale synthetic contact matrices-a representation of pre-pandemic behaviour-using mobility data from the UK, Belgium and the Netherlands to predict the number of contacts expected in ″work″ and ″other″settings for a given mobility level. We then compared partial reproduction numbers estimated from the four models with those calculated directly from CoMix contact matrices across the three countries. The accuracy of each model was assessed using root mean squared error. The fitted regression models had substantially more accurate predictions than the naïve models, even when models were applied to out-of-sample data from the UK, Belgium and the Netherlands. Across all countries investigated, the linear fitted regression model was the most accurate and the naïve model using mobility alone was the least accurate. When attempting to estimate social contact rates during a pandemic without the resources available to conduct contact surveys, using a model fitted to data from another pandemic context is likely to be an improvement over using a ″naïve″ model based on mobility data alone. If a naïve model is to be used, mobility squared may be a better predictor of contact rates than mobility per se.
Attitudes of chronic pain patients on long-term opioid therapy toward opioid tapering
Authors: Jabakhanji R. , Tokunaga F. , Rached G. , Vigotsky A.D. , Griffith J. , Schnitzer T.J. , Apkarian A. V.
Published: December 2023

The chronic pain and opioid addiction epidemics interact with each other, potentially exacerbating each respective condition. Despite having modest efficacy, millions of chronic pain patients in the USA continue to use opioids as their primary source of pain management. The Centers for Disease Control recommends opioid tapering to diminish the risk of opioid dependence in chronic pain patients. However, tapering, even with physician oversight, can introduce additional harm. Thus, many pain clinicians remain ambivalent about undertaking opioid tapering. Here, we surveyed attitudes on the topic from the viewpoint of chronic pain patients who have been consuming opioids over long durations. We queried 127 chronic pain patients (pain duration = 13.5 ± 9.6 years) on long-term opioids (10.3 ± 8.2 years), primarily consuming hydrocodone or oxycodone. Sixty-six percent of participants were “very” or “extremely” interested in participating in an opioid tapering study. Patients emphasized the importance of controlling their pain during opioid tapering, and over 50% were also worried about craving symptoms. Both the desire for tapering and the worry of pain control were more pronounced in participants with a higher magnitude of ongoing back pain. The study demonstrates that most chronic pain patients using opioids are interested in decreasing opioid consumption. Yet, they worry about losing control of their chronic pain. These results imply patient-physician strategies that may aid the engagement of both parties in opioid tapering.
Detailed microbiome analysis of sticker-stripped surface materials of acne lesions revealed acne-relatedCutibacterium acnessubtypes: a pilot study
Authors: Shimokawa Yutaka , Funatsu Osamu , Ohata Kazuma , Inoue Fukashi , Tachibana Kota , Dekio Itaru
Published: December 2023

Cutibacterium acnes (C. acnes)is known to play a central role in pathogenesis of acne vulgaris. It has been understood that multiple phylotypes ofC. acnesexist, with certain types being more prevalent in patient with acne vulgaris and others more common in healthy individuals. In this context, we conducted a preliminary study using self-collected samples via an adhesive sticker (MySkin® patch) to analyze the skin microbiome of Japanese women. The study aimed to determine the role ofC. acnesand its specific phylotypes in the development of acne vulgaris.

Participants in this study were Japanese females aged between their 20s and 40s. Dermatologists evaluate the data from web-based questionnaires and smartphone image submissions to classify subjects into either Acne group (n = 219) or Non-acne group (n = 77). Quality assessment of DNA extracted from the sticker was conducted, followed by amplification of the16S rRNAregion using PCR. Subsequent microbial community analysis was performed using next-generation sequencing techniques. Genetic classification ofC. acneswas accomplished through single locus sequence typing.

Results indicated a bacterial community composition on the facial skin surface predominantly consisting ofC. acnesclusters, with over half of these clusters constituted byC. acnes. Notably, the Acne group exhibited a significantly higher proportion ofC. acnesrelative to total bacterial presence compared to the Non-acne group. Analysis ofC. acnesphylotypes revealed a markedly lower presence of type III (subspecieselongatum) in the Acne group (vs. Non-acne group,p< 0.05). No significant differences were observed in the prevalence of Types IA1, IA2, II, and IB between the two groups. The predominantsequence types (ST) ofC. acnesidentified were IA2_2_F0 (23.9%), IA1_4_A0 (20.6%), and II_2_K0 (18.6%). Within the Acne group, an increase in IA2_1_F1 and a decrease in III_1_L0 were observed (vs. Non-acne group,p< 0.05).

This study underscores the feasibility of using self-collected and mailed-in samples for qPCR and microbiome analysis, maintaining diagnostic quality comparable to in-person assessments. Furthermore, the variation in the expression ofC. acnesphylotypes across skin surfaces between acne-afflicted and healthy individuals could suggest that shifts in phylotype expression patterns may be indicative of skin susceptibilities to acne development.
Stage-sensitive potential of isolated rabbit ICM to differentiate into extraembryonic lineages
Authors: Filimonow Katarzyna , Chołoniewska Anna , Chołoniewski Jan , Madeja Zofia E. , Barłowska Katarzyna , Grabarek Joanna , Plusa Berenika , Piliszek Anna
Published: December 2023

In the course of mammalian development initial state of totipotency must be lost to allow acquisition of specific cell fates. The first differentiation event results in the formation of trophectoderm (TE) and the inner cell mass (ICM). In the mouse embryo the cell fate of these two compartments is set quickly after formation of a blastocyst. However, recent reports suggest that plasticity of these two lineages might be extended in species other than the mouse. Here we investigated how the cellular plasticity of early mammalian embryos relates to developmental time scale and changes in gene expression using rabbit isolated ICMs. We studied the dynamics of rabbit blastocyst formation using time-lapse imaging and identified GATA3 as an early marker of rabbit TE and CDX2 as a marker of fully formed TE. We then analysed developmental potential of rabbit ICMs isolated by immunosurgery and subsequently culturedin vitro. ICMs originating from early- to mid-blastocyst stage embryos are able to re-form a blastocyst-like structure, with a functional TE, and an ICM containing both SOX2-positive epiblast cells and SOX17-positive primitive endoderm cells. We further observed that rabbit ICMs isolated from later blastocyst stages lose the ability for TE specification, instead forming a halo-like cavity with an outer layer of SOX17-positive cells. Our data indicate that in mammalian embryos the potential for TE differentiation gives way to formation of a different type of extraembryonic epithelial layer, suggesting potential common mechanism of pluripotency restriction between eutherian mammals.
On the expression of reproductive plasticity inDrosophila melanogasterfemales in spatial and socially varying environments!
Authors: Nwajei Oghenerho , Talagala Sanduni , Hampel Laura , Punj Bhavya , Li Nuek Yin , Long Tristan A.F.
Published: December 2023

Individuals often adjust their behaviour based on their perception and experiences with the social and/or physical environment. In this study, we examined the extent of reproductive plasticity expressed in mating rates, mating latencies, mating durations, and offspring production in female fruit flies,Drosophila melanogaster, that encountered different numbers of males in different sized chambers. We found that mating latency length decreased with more courting males and smaller environments and that matings durations were longer in larger chambers and in the presence of two males. These results illustrate the sensitivity of these behavioural phenotypes to changes in local environmental conditions.
TCRfp: a new fingerprint-based approach for TCR repertoire analysis
Authors: Mayol-Rullan Francesca , Bugnon Marine , Perez Marta A. S. , Zoete Vincent
Published: December 2023

The development of cancer immunotherapy has accelerated in recent years. Understanding the specificity of T cell receptors (TCR) for peptides presented by the major histocompatibility complex (pMHC) is a major step towards improving immunotherapy approaches, such as adoptive cell transfer and peptide vaccination. Despite recent computational advances, the unambiguous pairing of TCR with pMHC, from pools of thousands of candidates, remains out of reach. To tackle this challenge, we have developed a new tool that converts the 3D structure of TCR into individual one-dimensional structural fingerprints (TCRfp). We have modelled over 10’000 3D structures of paired TCR alpha and beta chains with known sequences and pMHC specificity and encoded them into 1D TCRfp. For future clinical needs, we have translated the TCR modelling process into a fast pipeline. Similarity measures between TCR FPs correlate with their ability to recognise similar or identical epitopes in the training set and in the external validation sets. TCRfp constitutes the first rapid approach for high-throughput TCR comparison and repertoire analysis based on molecular 3D structures, which is efficient enough to complement sequence-based approaches.
Cytokinins specify pluripotent stem cell identity in the mossPhyscomitrium patens
Authors: Hata Yuki , Ohtsuka Juri , Hiwatashi Yuji , Naramoto Satoshi , Kyozuka Junko
Published: December 2023

The shoot apical meristem (SAM) contains pluripotent stem cells that produce all the aerial parts of the plant. Stem cells undergo asymmetric cell divisions to self-renew and to produce differentiating cells. Our research focused on unraveling the mechanisms governing the specification of these two distinct cell fates following the stem cell division. For this purpose, we used the model organismPhyscomitrium patens, which features a singular pluripotent stem cell known as the gametophore apical cell. We show that the activity of cytokinins, critical stem cell regulators, is restricted to the gametophore apical cell due to the specific localization of PpLOG, the enzyme responsible of cytokinin activation. In turn, PpTAW, which promotes differentiating cell identity of the merophyte, is excluded from the gametophore apical cell by the action of cytokinins. We propose a cytokinin-based model for the establishment of asymmetry in the pluripotent stem cell division.

One Sentence Summary

Cytokinins are confined to the pluripotent stem cells and exclude the differentiation factor TAW1 to establish the SAM from a single stem cell.