bluuebunny/crossref_metadata_2025 huggingface dataset:
Applied Improvisation
Authors: Davis Kasey , Kessler David , Lemke Daniel , Doughty Cara
Published: February 2024

Summary Statement

Behavioral skills, sometimes referred to as nontechnical skills or team-based skills, are fundamental to simulation-based team training. These skills should be afforded the same deliberate practice and development as clinical knowledge and procedural skills in health care education. Applied improvisation, the use of theater games designed to improve individual and team performance, is gaining traction in health care education to train behavioral skills. Simulation educators are experts in experiential learning with debriefing and therefore well poised to incorporate applied improvisational exercises into team training activities.
Characterization of Group A streptococci causing invasive diseases in Sri Lanka
Authors: Weerasekara Madumali , Vidanapathirana Gihani , Li Carmen , Tennegedara Asanka , Dissanayake Rasadanie , Ekanayake Asela , Abeykoon Muditha , Kothalawala Mahen , Liyanapathirana Veranja , Ip Margaret
Published: February 2024

Group A, β haemolytic streptococci (GAS) or Streptococcus pyogenes is a human pathogen which can cause an array of infections including pharyngitis, cellulitis, impetigo, scarlet fever, toxic shock syndrome etc. the present study aimed to characterize GAS isolates obtained from patients with invasive diseases from selected sites in Sri Lanka by identifying their resistance profiles, genetic markers of resistance and selected virulence markers. Fifty one GAS isolates causing invasive diseases were used for the study. All isolates were tested for sensitivity to penicillin, erythromycin and tetracycline. Then, the presence of erm(A), erm(B), mef(A) were detected in erythromycin resistant isolates while tet(M) was detected in the tetracycline resistant isolates. SpeA, SpeB, SpeC, SpeF, SpeG, smez and ssa virulence markers were identified through PCRs. Selected GAS isolates were emm typed using the updated CDC protocol.
All 51 isolates were susceptible to penicillin. The number of isolates non-susceptible  to erythromycin was 16 and 11 of them had the erm(B) gene, while three isolates had the mef(A)  gene and one had the ermA gene. Tetracycline non susceptibility was found in 36 (70.6%) isolates and 26 six of them contained the tet(M) gene. Thirteen (25.5%) isolates were resistant to both tetracycline and erythromycin while 12 (23.5%) isolates were sensitive to both antibiotics. Seven isolates (13.7%) harboured both tet(M) and erm(B) genes. The commonest virulence markers detected among the isolates was SpeB (44, 86.3%), SpeG (36, 70.6%), SpeF (35, 68.6%) while SpeJ (15, 29.4%), SpeA (10, 19.6%) and ssa (5,9.8%) were less common.In conclusion, resistant to erythromycin and tetracycline is emerging in GAS isolates in Sri Lanka while the universal susceptibility to penicillin remains unchanged. Further, these isolates are from diverse backgrounds with different patterns of virulence genes and emm types.
Comparative virulome analysis of four Staphylococcus epidermidis strains from human skin and platelet concentrates using whole genome sequencing
Authors: Yousuf Basit , Flint Annika , Weedmark Kelly , Pagotto Franco , Ramirez-Arcos Sandra
Published: February 2024

Staphylococcus epidermidis is one of the predominant bacterial contaminants in platelet concentrates (PCs), a blood component used to treat bleeding disorders. PCs are a unique niche that triggers biofilm formation, the main contributor to S. epidermidis infections. We performed whole genome sequencing of four S. epidermidis strains isolated from the skin of healthy human volunteers (AZ22 and AZ39) and contaminated PCs (ST10002 and ST11003) to unravel phylogenetic relationships and decipher virulence mechanisms compared to 25 complete S. epidermidis genomes in GenBank. AZ39 and ST11003 formed a separate unique lineage with 14.1.R1 and SE95 strains, while AZ22 formed a cluster with 1457 and ST10002 closely grouped with FDAAGOS_161. The four isolates were assigned to sequence types ST1175, ST1174, ST73, and ST16, respectively. All four genomes exhibited biofilm-associated genes ebh, ebp, sdrG, sdrH, and atl. Additionally, AZ22 had sdrF and aap, whereas ST10002 had aap and icaABCDR. Notably, AZ39 possesses truncated ebh and sdrG and harbors a toxin encoding gene. All isolates carry multiple antibiotic resistance genes conferring resistance to fosfomycin (fosB), β-lactams (blaZ) and fluoroquinolones (norA). This study revealed a unique lineage for S. epidermidis and provided insight into the genetic basis of virulence and antibiotic resistance in transfusion-associated S. epidermidis strains.
Immunogenicity, safety and duration of protection afforded by chikungunya virus vaccines undergoing human clinical trials
Authors: Rao Shambhavi , Erku Daniel , Mahalingam Suresh , Taylor Adam
Published: February 2024

Background. Chikungunya virus (CHIKV) causes chikungunya fever and has been responsible for major global epidemics of arthritic disease over the past two decades. Multiple CHIKV vaccine candidates are currently undergoing or have undergone human clinical trials, with one vaccine candidate receiving FDA approval. This scoping review was performed to evaluate the ‘efficacy’, ‘safety’ and ‘duration of protection’ provided by CHIKV vaccine candidates in human clinical trials.

Methods. This scoping literature review addresses studies involving CHIKV vaccine clinical trials using available literature on the PubMed, Medline Embase, Cochrane Library and Clinicaltrial.gov databases published up to 25 August 2023. Covidence software was used to structure information and review the studies included in this article.

Results. A total of 1138 studies were screened and, after removal of duplicate studies, 12 relevant studies were thoroughly reviewed to gather information. This review summarizs that all seven CHIKV vaccine candidates achieved over 90 % seroprotection against CHIKV after one or two doses. All vaccines were able to provide neutralizing antibody protection for at least 28 days.

Conclusions. A variety of vaccine technologies have been used to develop CHIKV vaccine candidates. With one vaccine candidate having recently received FDA approval, it is likely that further CHIKV vaccines will be available commercially in the near future.
Assessment of Technical Efficiency in the Moroccan Public Hospital Network: Using the DEA Method
Authors: Youssef Er-Rays , Meriem M’dioud
Published: February 2024

Background

The public hospital network in Morocco plays a crucial role in providing healthcare services. However, this network faces challenges in terms of technical efficiency in healthcare management.

Objectives

This study aimed to assess the technical efficiency of the public hospital network in Morocco.

Methods

This article compares the efficiency of 77 public hospital networks from 2017 to 2020. Data were collected from the Directorate of Planning and Financial Resources (DPFR) of the Health Ministry Marocco. The Data Envelopment Analysis (DEA) method was employed, using three inputs (Hospital, Physician and Paramedical) and four outputs (Functional capacity, Hospitalization days and Admission). Additionally, the Malmquist index (MI) is utilized to analyse the factors of production, and peer modelling is incorporated to address hospital inefficiency.

Results

The average technical efficiency of public hospital networks under the CRS hypothesis from 2017 to 2020 is 0.697 (71% of DMUs have a score lower than 1), indicating that these networks need to minimize their inputs by approximately 30.3%. The Malmquist index reveals a decline in productivity gain from 2017/2018 (score of 0.980) followed by improvement in 2018/2019 (score of 1.163). In terms of peer modelling, 72.7% of the DMUs should emulate the most effective DMUs beginning in 2020, whereas the lowest score was observed in 2019.

Conclusion

These findings highlight the need for the public hospital network in Morocco to enhance the effective and efficient utilization of inputs, such as the number of hospitals and medical and paramedical staff, to produce the same outputs, including the number of surgical procedures, hospitalization days, admissions, and functional capacity.
Hippocampal DNA methylation promotes memory persistence by facilitating systems consolidation and cortical engram stabilisation
Authors: Kupke Janina , Loizou Stefanos , Bengtson C. Peter , Sticht Carsten , Oliveira Ana M.M.
Published: February 2024

The long-term stabilization of memory traces or engram involves the rapid formation of cortical engrams during encoding that mature functionally over time guided by the activity of the hippocampus. The molecular mechanisms that regulate this process remain largely unknown. Here, we found that hippocampal DNA methylation converts short-lasting into long-lasting memories by promoting systems consolidation and the stabilization of cortical engrams.
Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control
Authors: Detrés Román Carlos R. , Rudloff Michael W. , Revetta Frank , Favret Natalie R. , Murray Kristen A. , Roetman Jessica J. , Erwin Megan M. , Washington Mary K. , Philip Mary
Published: February 2024

Background

Immune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however only a subset of patients with certain types of cancer achieves durable remissions. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term tumor immune reprogramming and arrest cancer progression. We developed a clinically-relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumor-specific CD8 T cells (TST) differentiate in mice with early sporadic lesions as compared to late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, reprogram TST and impact liver cancer progression.

Methods

Mice with a germline floxed allele of the SV40 large T antigen (TAG) undergo spontaneous recombination and activation of the TAG oncogene, leading to rare early pre-cancerous lesions that inevitably progress to established liver cancer. We assessed the immunophenotype and function of TAG-specific CD8 T cells in mice with early and late liver lesions. We vaccinated mice, either alone or in combination with ICB, to test whether these immunotherapeutic interventions could stop liver cancer progression.

Results

In mice with early lesions, a subset of TST were PD1+TCF1+TOX-and could produce IFNγ, while TST present in mice with late liver cancers were PD1+TCF1lo/-TOX+and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitope-expressingListeria monocytogenes(LMTAG) blocked liver cancer development and led to a population of TST that were TCF1+TOX-TST and polyfunctional cytokine producers. In contrast, ICB administration did not slow cancer progression or improve LMTAGvaccine efficacy.

Conclusion

Vaccination, but not ICB, generated a population of progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. In patients with early cancers or at high-risk of cancer recurrence, immunization may be the most effective strategy.

What is already known on this topic

Immunotherapy, including immune checkpoint blockade and cancer vaccines, fails to induce long-term remissions in most patients with cancer.

What this study adds

Hosts with early lesions but not hosts with advanced cancer retain a progenitor TCF1+ TST population. This population can be reprogrammed and therapeutically exploited by vaccination, but not ICB, to block tumor progression.

How this study might affect research, practice, or policy

For people at high-risk of cancer progression, vaccination administered when a responsive progenitor TST population is present may be the optimal immunotherapy to induce long-lasting progression-free survival.
Deciphering rapid cell signaling and control of cell motility by reverse opto-chemical engineering
Authors: Hamzeh Hussein , Gong An , Balbach Melanie , Fridman Dmitry , Koerschen Heinz Gerd , Pascal Rene , Lavryk Fedir , Rennhack Andreas , Seifert Reinhard , Hernandez-Clavijo Andres , Pifferi Simone , Dusend Vanessa , Fleischmann Bernd , Sasse Philipp , Menini Anna , Friedrich Benjamin M. , Alvarez Luis , Kaupp Ulrich Benjamin
Published: February 2024

Cells transform complex environmental stimuli into physiological responses. For time-varying stimuli or motile cells, the perception of the environment depends on the temporal stimulus pattern and cell motion, respectively. Here we report a concept, reverse optochemical engineering (ROCE), that uses temporal light patterns and photo-triggers to expose cells to virtual sensory landscapes while recording in real time their physiological responses and motor behavior. We studied cyclic-nucleotide signaling in cell lines, sperm, olfactory neurons, and cardiomyocytes. The technique can be employed for remote control of motility by light. We reprogrammed sperm from a chemotactic to a phototactic cell that is attracted towards light. The method provides new opportunities to decipher the mechanisms and signaling molecules underlying rapid cellular computations, and thus reveal the wire diagram of cellular networks.
Detecting Somatic Mutations Without Matched Normal Samples Using Long Reads
Authors: Simpson Jared T.
Published: February 2024

DNA sequencing of tumours to identify somatic mutations has become a critical tool to guide the type of treatment given to cancer patients. The gold standard for mutation calling is comparing sequencing data from the tumour to a matched normal sample to avoid mis-classifying inherited SNPs as mutations. This procedure works extremely well, but in certain situations only a tumour sample is available. While approaches have been developed to find mutations without a matched normal, they have limited accuracy or require specific types of input data (e.g. ultra-deep sequencing). Here we explore the application of single molecule long read sequencing to calling somatic mutations without matched normal samples. We develop a simple theoretical framework to show how haplotype phasing is an important source of information for determining whether a variant is a somatic mutation. We then use simulations to assess the range of experimental parameters (tumour purity, sequencing depth) where this approach is effective. These ideas are developed into a prototype somatic mutation caller, smrest, and its use is demonstrated on two highly mutated cancer cell lines. Finally, we argue that this approach has potential to measure clinically important biomarkers that are based on the genome-wide distribution of mutations: tumour mutation burden and mutation signatures.
Trajectorygeometry suggests cell fate decisions involve branches rather than bifurcations
Authors: Laddach Anna , Shapiro Michael
Published: February 2024

Abstract

Differentiation of multipotential progenitor cells is a key process in the development of any multi-cellular organism and often continues throughout its life. It is often assumed that a bi-potential progenitor develops along a (relatively) straight trajectory until it reaches a decision point where the trajectory bifurcates. At this point one of two directions is chosen, each direction representing the unfolding of a new transcriptomic programme. However, we have lacked quantitative means for testing this model. Accordingly, we have developed the R package TrajectoryGeometry. Applying this to published data we find several examples where, rather than bifurcate, developmental pathwaysbranch. That is, the bipotential progenitor develops along a relatively straight trajectory leading to one of its potential fates. A second relatively straight trajectory branches off from this towards the other potential fate. In this sense only cells that branch off to follow the second trajectory make a “decision”. Our methods give precise descriptions of the genes and cellular pathways involved in these trajectories. We speculate that branching may be the more common behaviour and may have advantages from a control-theoretic viewpoint.
Secondary structure of the SARS-CoV-2 genome is predictive of nucleotide substitution frequency
Authors: Hensel Zach
Published: February 2024

Accurate estimation of the effects of mutations on SARS-CoV-2 viral fitness can inform public-health responses such as vaccine development and predicting the impact of a new variant; it can also illuminate biological mechanisms including those underlying the emergence of variants of concern (Carabelliet al., 2023). Recently, Lanet al. reported a model of SARS-CoV-2 secondary structure and its underlying dimethyl sulfate (DMS) reactivity data (Lanet al., 2022). I investigated whether base reactivities and secondary structure models derived from them can explain some variability in the frequency of observing different nucleotide substitutions across millions of patient sequences in the SARS-CoV-2 phylogenetic tree. Nucleotide basepairing was compared to the estimated “mutational fitness” of substitutions, a measurement of the difference between a substitution’s observed and expected frequency that is correlated with other estimates of viral fitness (Bloom and Neher, 2023). This comparison revealed that secondary structure is often predictive of substitution frequency, with significant decreases in substitution frequencies at basepaired positions. Focusing on the mutational fitness of C→U, the most common type of substitution, I describe C→U substitutions at basepaired positions that characterize major SARS-CoV-2 variants; such mutations may have a greater impact on fitness than appreciated when considering substitution frequency alone.
The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19
Authors: Penrice-Randal Rebekah , Bentley Eleanor G. , Sharma Parul , Kirby Adam , Donovan-Banfield I’ah , Kipar Anja , Mega Daniele F. , Bramwell Chloe , Sharp Joanne , Owen Andrew , Hiscox Julian A. , Stewart James P.
Published: February 2024

Synopsis

Objectives

Immunocompromised individuals are susceptible to severe COVID-19 and potentially contribute to the emergence of variants with altered pathogenicity due to persistent infection. This study investigated the impact of immunosuppression on SARS-CoV-2 infection in k18-hACE2 mice and the effectiveness of antiviral treatments in this context during the first 7 days of infection.

Methods

Mice were immunosuppressed using cyclophosphamide and infected with a B daughter lineage of SARS-CoV-2. Molnupiravir and nirmatrelvir, alone and in combination, were administered and viral load and viral sequence diversity was assessed.

Results

Treatment of infected but immune compromised mice with both compounds either singly or in combination resulted in decreased viral loads and pathological changes compared to untreated animals. Treatment also abrogated infection of neuronal tissue. However, no consistent changes in the viral consensus sequence were observed, except for the emergence of the S:H655Y mutation. Molnupiravir, but not nirmatrelvir or immunosuppression alone, increased the transition/transversion (Ts/Tv) ratio, representative of G>A and C>U mutations and this increase was not altered by the co-administration of nirmatrelvir with molnupiravir.

Notably, immunosuppression itself did not appear to promote the emergence of mutational characteristic of variants of concern (VOCs).

Conclusions

Further investigations are warranted to fully understand the role of immunocompromised individuals in VOC development, especially by taking persistence into consideration, and to inform optimised public health strategies. It is more likely that immunodeficiency promotes viral persistence but does not necessarily lead to substantial consensus-level changes in the absence of antiviral selection pressure. Consistent with mechanisms of action, molnupiravir showed a stronger mutagenic effect than nirmatrelvir in this model.
Pre-challenge gut microbial signature predicts RhCMV/SIV vaccine efficacy in rhesus macaques
Authors: Brochu Hayden N. , Smith Elise , Jeong Sangmi , Carlson Michelle , Hansen Scott G. , Tisoncik-Go Jennifer , Law Lynn , Picker Louis J. , Gale Michael , Peng Xinxia
Published: February 2024

Background

RhCMV/SIV vaccines protect ∼59% of vaccinated rhesus macaques against repeated limiting-dose intra-rectal exposure with highly pathogenic SIVmac239M, but the exact mechanism responsible for the vaccine efficacy is not known. It is becoming evident that complex interactions exist between gut microbiota and the host immune system. Here we aimed to investigate if the rhesus gut microbiome impacts RhCMV/SIV vaccine-induced protection.

Methods

Three groups of 15 rhesus macaques naturally pre-exposed to RhCMV were vaccinated with RhCMV/SIV vaccines. Rectal swabs were collected longitudinally both before SIV challenge (after vaccination) and post challenge and were profiled using 16S rRNA based microbiome analysis.

Results

We identified ∼2,400 16S rRNA amplicon sequence variants (ASVs), representing potential bacterial species/strains. Global gut microbial profiles were strongly associated with each of the three vaccination groups, and all animals tended to maintain consistent profiles throughout the pre-challenge phase. Despite vaccination group differences, using newly developed compositional data analysis techniques we identified a common gut microbial signature predictive of vaccine protection outcome across the three vaccination groups. Part of this microbial signature persisted even after SIV challenge. We also observed a strong correlation between this microbial signature and an early signature derived from whole blood transcriptomes in the same animals.

Conclusions

Our findings indicate that changes in gut microbiomes are associated with RhCMV/SIV vaccine-induced protection and early host response to vaccination in rhesus macaques.
Blood metabolomic profiling reveals new targets in the management of psychological symptoms associated with severe alcohol use disorder
Authors: Leclercq Sophie , Ahmed Hany , Amadieu Camille , Petit Géraldine , Koistinen Ville , Leyrolle Quentin , Poncin Marie , Stärkel Peter , Kok Eloise , Karhunen Pekka J. , De Timary Philippe , Layé Sophie , Neyrinck Audrey M. , Kärkkäinen Olli , Hanhineva Kati , Delzenne Nathalie M.
Published: February 2024

Alcohol use disorder (AUD) is a global health problem with limited therapeutic options. The biochemical mechanisms that lead to this disorder are not yet fully understood, and in this respect, metabolomics represents a promising approach to decipher metabolic events related to AUD. The plasma metabolome contains a plethora of bioactive molecules that reflects the functional changes in host metabolism but also the impact of the gut microbiome and nutritional habits. In this study, we investigated the impact of severe AUD (sAUD), and of a three-week period of alcohol abstinence, on the blood metabolome (non-targeted LC-MS metabolomics analysis) in 96 sAUD patients hospitalized for alcohol withdrawal. We found that the plasma levels of different lipids ((lyso)phosphatidylcholines, long-chain fatty acids), short-chain fatty acids (i.e. 3-hydroxyvaleric acid) and bile acids were altered in sAUD patients. In addition, several microbial metabolites, including indole-3-propionic acid, p-cresol sulfate, hippuric acid, pyrocatechol sulfate, and metabolites belonging to xanthine class (paraxanthine, theobromine and theophylline) were sensitive to alcohol exposure and alcohol withdrawal. 3-Hydroxyvaleric acid, caffeine metabolites (theobromine, paraxanthine and theophylline) and microbial metabolites (hippuric acid and pyrocatechol sulfate) were correlated with anxiety, depression and alcohol craving. Metabolomics analysis in post-mortem samples of frontal cortex and cerebrospinal fluid of those consuming a high level of alcohol revealed that those metabolites can be found also in brain tissue. Our data allow to for the identification of neuroactive metabolites, from interactions between food components and microbiota, which may represent new targets in the management of neuropsychiatric diseases such as sAUD.
Virological traits of the SARS-CoV-2 BA.2.87.1 lineage
Authors: Zhang Lu , Dopfer-Jablonka Alexandra , Nehlmeier Inga , Kempf Amy , Graichen Luise , Hampel Noemí Calderón , Cossmann Anne , Stankov Metodi V. , Ramos Gema Morillas , Schulz Sebastian R. , Jäck Hans-Martin , Behrens Georg M. N. , Pöhlmann Stefan , Hoffmann Markus
Published: February 2024

The highly mutated SARS-CoV-2 BA.2.87.1 lineage was recently detected in South Africa, but its transmissibility is unknown. Here, we report that BA.2.87.1 efficiently enters human cells but is more sensitive to antibody-mediated neutralization than the currently dominating JN.1 variant. Acquisition of adaptive mutations might thus be needed for high transmissibility.
Influence of feedback transparency on motor imagery neurofeedback performance: the contribution of agency
Authors: Dussard Claire , Pillette Léa , Dumas Cassandra , Pierrieau Emeline , Hugueville Laurent , Lau Brian , Jeunet-Kelway Camille , George Nathalie
Published: February 2024

Objective

Neurofeedback (NF) is a cognitive training procedure based on real-time feedback (FB) of a participant’s brain activity that they must learn to self-regulate. A classical visual FB delivered in a NF task is a filling gauge reflecting a measure of brain activity. This abstract visual FB is not transparently linked—from the subject’s perspective—to the task performed (e.g., motor imagery). This may decrease the sense of agency, that is, the participants’ reported control over FB. Here, we assessed the influence of FB transparency on NF performance and the role of agency in this relationship.

Approach

Participants performed a NF task using motor imagery to regulate brain activity measured using electroencephalography. In separate blocks, participants experienced three different conditions designed to vary transparency: FB was presented as either 1) a swinging pendulum, 2) a clenching virtual hand, 3) a clenching virtual hand combined with a motor illusion induced by tendon vibration. We measured self-reported agency and user experience after each NF block.

Main results

We found that FB transparency influences NF performance. Transparent visual FB provided by the virtual hand resulted in significantly better NF performance than the abstract FB of the pendulum. Surprisingly, adding a motor illusion to the virtual hand significantly decreased performance relative to the virtual hand alone. When introduced in incremental linear mixed effect models, self-reported agency was significantly associated with NF performance and it captured the variance related to the effect of FB transparency on NF performance.

Significance

Our results highlight the relevance of transparent FB in relation to the sense of agency. This is likely an important consideration in designing FB to improve NF performance and learning outcomes.
Syngap1regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex
Authors: Francavilla Ruggiero , Chattopadhyaya Bidisha , Kamda Jorelle Linda Damo , Jadhav Vidya , Kourrich Saïd , Michaud Jacques L. , Di Cristo Graziella
Published: February 2024

SYNGAP1 haploinsufficiency-related intellectual disability (SYNGAP1-ID) is characterized by moderate to severe ID, generalized epilepsy, autism spectrum disorder, sensory processing dysfunction and other behavioral abnormalities. While numerous studies have highlighted a role of Syngap1 in cortical excitatory neurons development; recent studies suggest that Syngap1 plays a role in GABAergic inhibitory neuron development as well. However, the molecular pathways by which Syngap1 acts on GABAergic neurons, and whether they are similar or different from the mechanisms underlying its effects in excitatory neurons, is unknown. Here, we examined whether, and how, embryonic-onsetSyngap1haploinsufficiency restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE) impacts their synaptic and intrinsic properties in adult primary auditory cortex (A1). We found thatSyngap1haploinsufficiency affects the intrinsic properties, overall leading to increased firing threshold, and decreased excitatory synaptic drive of Parvalbumin (PV)+ neurons in adult Layer IV A1, whilst Somatostatin (SST)+ interneurons were mostly resistant toSyngap1haploinsufficiency. Further, the AMPA component of thalamocortical evoked-EPSC was decreased in PV+ cells from mutant mice. Finally, we found that the selective blocking of voltage-gated D-type K+ currents was sufficient to rescue PV+ mutant cell-intrinsic properties to wild-type levels. Together, these data suggest thatSyngap1plays a specific role in the maturation of PV+ cell intrinsic properties and synaptic drive, and its haploinsufficiency may lead to reduced PV cell recruitment in the adult A1, which could in turn contribute to the auditory processing alterations found in SYNGAP1-ID preclinical models and patients.
How distinct sources of nuisance variability in natural images and scenes limit human stereopsis
Authors: White David N. , Burge Johannes
Published: February 2024

2

Stimulus variability—a form of nuisance variability—is a primary source of perceptual uncertainty in every-day natural tasks. How do different properties of natural images and scenes contribute to this uncertainty? Using binocular disparity as a model system, we report a systematic investigation of how various forms of natural stimulus variability impact performance in a stereo-depth discrimination task. With stimuli sampled from a stereo-image database of real-world scenes having pixel-by-pixel ground-truth distance data, three human observers completed two closely related double-pass psychophysical experiments. In the two experiments, each human observer responded twice to ten thousand unique trials, in which twenty thousand unique stimuli were presented. New analytical methods reveal, from this data, the specific and nearly dissociable effects of two distinct sources of natural stimulus variability—variation in luminance-contrast patterns and variation in local-depth structure—on discrimination performance, as well as the relative importance of stimulus-driven-variability and internal-noise in determining performance limits. Between-observer analyses show that both stimulus-driven sources of uncertainty are responsible for a large proportion of total variance, have strikingly similar effects on different people, and—surprisingly—make stimulus-by-stimulus responses more predictable (not less). The consistency across observers raises the intriguing prospect that image-computable models can make reasonably accurate performance predictions in natural viewing. Overall, the findings provide a rich picture of stimulus factors that contribute to human perceptual performance in natural scenes. The approach should have broad application to other animal models and other sensory-perceptual tasks with natural or naturalistic stimuli.

1

Significance

Linking properties of the external world, and of sensory stimuli, to how neurons and animals respond has proven an important approach to understanding how the brain works. Much is known about how nervous systems respond to simple stimuli. Less is known about how systems respond during real-world viewing. Using data from two human stereo-depth discrimination experiments, we develop a new approach that reveals how distinct features of natural scenes and images contribute to perceptual performance. Results show that stimulus-by-stimulus variation has highly consistent effects on different people. The approach should have broad application to other animal models and other sensory-perceptual tasks.
Unraveling the Interplay between Phytochemicals and Rhizosphere Bacteria inFicus racemosa
Authors: Balkrishna Acharya , Kaushik Priya , Ghosh Sourav , Arya Vedpriya
Published: February 2024

Plant-microbe interactions in the rhizosphere play crucial roles in plant health and ecosystem functioning. Despite extensive research, gaps persist in understanding the relationship between phytochemicals and rhizosphere bacteria, particularly in species likeFicus racemosa. This study aims to investigate this interplay by characterizing the diversity and abundance of rhizosphere bacteria inFicus racemosaand assessing the influence of phytochemical composition on microbial community structure and function. Through a multidisciplinary approach integrating microbiology and phytochemistry, our findings contribute to a holistic understanding of rhizosphere ecology and inform strategies for optimizing plant-microbe interactions in agricultural and environmental contexts.
A Systematic Review on Malaria and Tuberculosis (TB) Vaccine Challenges in Sub-Saharan African Clinical Trials
Authors: Hamisi Maonezi Abas , Mohd Asri Nur Ain , Mat Yassim Aini Syahida , Suppian Rapeah
Published: February 2024

Abstract Objective: For decades, developing novel and effective vaccines against malaria and tuberculosis (TB) infections has been a challenge. This review sought to investigate the reasons for the slow progress of malaria and TB vaccine candidates in sub-Saharan African clinical trials. Methods: The systematic review protocol was registered on PROSPERO on July 26, 2023 (CRD42023445166).  The research articles related to the immunogenicity, efficacy, or safety of malaria or TB vaccines that were published between January 1, 2012, and August 31, 2023, were searched on three databases: Web of Science (WoS), PubMed, and ClinicalTrials.gov. Results: A total of 2342 articles were obtained, 50 of which met the inclusion criteria. 28 (56%) articles reported on malaria vaccine attributes, while 22 (44%) articles reported on TB vaccines. In both cases, the major challenges in sub-Saharan African clinical trials were immunogenicity and efficacy, rather than safety. Conclusion: Factors such as population characteristics, pathogen genetic diversity, vaccine nature, strategy, and formulation were associated with slow progress of the malaria and TB vaccine candidates in sub-Saharan African clinical trials.
Chronic pulmonary aspergillosis incidence in newly detected pulmonary tuberculosis cases during follow-up
Authors: Jha Dhouli , Kumar Umesh , Meena Ved Prakash , Sethi Prayas , Singh Amandeep , Nischal Neeraj , Jorwal Pankaj , Vyas Surabhi , Singh Gagandeep , Xess Immaculata , Singh Urvashi B , Sinha Sanjeev , Mohan Anant , Wig Naveet , Kabra Sushil Kumar , Ray Animesh
Published: February 2024

Background

Chronic pulmonary aspergillosis (CPA) is known to complicate patients with post-tubercular lung disease. However, some evidence suggests that CPA might co-exist in patients with newly-diagnosed pulmonary tuberculosis (P.TB) at diagnosis and also develop during therapy. The objective of this study was to confirm the presence of CPA in newly diagnosed P.TB at baseline and at end-of-therapy.

Materials & Methods

This prospective longitudinal study included newly diagnosed P.TB patients, followed up at third month and end-of-therapy with symptom assessment, anti-AspergillusIgG antibody and imaging of chest for diagnosing CPA.

Results

We recruited 255 patients at baseline out of which 158 (62%) completed their follow-up. Anti-AspergillusIgG was positive in 11.1% at baseline and 27.8% at end-of-therapy. Overall, proven CPA was diagnosed in 7% at baseline and 14.5% at end-of-therapy. Around 6% patients had evidence of aspergilloma in CT chest at the end-of-therapy.

Conclusions

CPA can be present in newly diagnosed P.TB patients at diagnosis and also develop during anti-tubercular treatment. Patients with persistent symptoms or developing new symptoms during treatment for P.TB should be evaluated for CPA.
What works to support better access to mental health services (from primary care to inpatients) for minority groups to reduce inequalities? A rapid evidence summary
Authors: Csontos Judit , Edwards Deborah , Gillen Elizabeth , Hounsome Juliet , Kiseleva Meg , Mann Mala , Sha’aban Abubakar , Lewis Ruth , Cooper Alison , Edwards Adrian
Published: February 2024

It is estimated that one in four people will experience poor mental health throughout their lifetimes. However, ethnic minority groups, refugees and asylum seekers experience more barriers accessing mental health services and have poorer mental health outcomes than those from non-ethnic minority groups. Evidence suggests that interventions that improve access and engagement with mental health services may help reduce disparities affecting ethnic minority groups, refugees and asylum seekers. Thus, the aim of this rapid evidence summary was to explore the literature on what works to support better access to mental health services for ethnic minority groups, refugees and asylum seekers to reduce inequalities. The review included interventions that were developed or assessed to improve equity in access, engagement, utilisation, or provision of mental health services.

Research Implications and Evidence Gaps

There is limited review evidence regarding the effectiveness of interventions to improve access to mental healthcare across ethnic minority groups. Review evidence regarding interventions to support refugees and asylum seekers access to primary healthcare or specialised clinics (for example pregnancy and postpartum) is available, but the findings related to mental health care cannot be extracted.
The FDA’s Proposed Rule on Laboratory-Developed Tests: Impacts on Clinical Laboratory Testing and Patient Care
Authors: Smith Leslie , Carricaburu Lisa A. , Genzen Jonathan R.
Published: February 2024

In October 2023, the U.S. Food and Drug Administration (FDA) released a proposed rule to regulate laboratory-developed tests (LDTs) as medical devices. While approximately 6,700 public comments were submitted during the open comment period, there is not a reliable mechanism to quantify how clinical laboratorians as a sector perceive the proposed rule. To solicit quantifiable feedback on the FDA’s proposed rule, a ten-item questionnaire was developed and submitted to clinical laboratory customers of ARUP Laboratories, a national nonprofit clinical laboratory of the University of Utah Department of Pathology.

Of 503 clinical laboratory respondents, only 41 (8.2%) support the FDA’s proposed rule. 66.9% of respondents work in laboratories that perform LDTs and were therefore asked additional questions regarding the proposed rule. 83.9% of these respondents believe that the proposed rule will negatively impact their laboratories, while only 3.0% believe that they have the financial resources to pay for FDA user fees. 60.9% of respondents anticipate removing tests from their laboratory menus if the proposed rule is enacted, while an additional 33.2% indicated that they do not yet know. Only 11.2% of respondents believe that they would pursue FDA submissions for all of their existing LDTs if the final rule is enacted.

The vast majority of respondents (>80%) were either ‘extremely concerned’ or ‘very concerned’ about the impact of the proposed rule on patient access to essential testing, financial and personnel resources to comply, innovation, the FDA’s ability to implement the proposed rule, and send-out costs and test prices. Respondents indicated that they would rely heavily on reference laboratory partners for advocacy against the proposed rule, testing options, education, and consultation if the rule was enacted. Thematic analysis of open comments revealed strong opposition to the proposed rule and significant concern regarding negative impacts to patient care across clinical laboratory settings.
Effect of neonatal BCG vaccination on the evolution of Hashimoto’s Thyroiditis
Authors: Agrawal Kanhaiya , Basak Preetam , Badal Darshan , Dutta Pinaki , Walia Rama , Sachdeva Naresh
Published: February 2024

Background

Hashimoto’s thyroiditis (HT) involves the autoimmune destruction of thyrocytes with the presence of anti-thyroid peroxidase (TPO) and/or anti-thyroglobulin (TG) antibodies. In autoimmune diseases, an immunomodulatory role of Bacillus Calmette-Guerin (BCG) vaccination has been reported with decreased autoantibody production and induction of regulatory T cells. We hypothesize that a decline in the efficacy of BCG might be associated with the appearance of HT during adulthood.

Methods

Adult subjects with subclinical HT (HT-SCH) (n=39) and non-autoimmune subclinical hypothyroidism (NA-SCH) (n=25) were enrolled along with euthyroid healthy controls (HC) (n=20). The BCG-specific immune responses were determined by the Mantoux test and BCG-induced in-vitro proliferation of peripheral blood mononuclear cells (PBMC). Anti-thyroid cellular immune responses were assessed in subjects with human leukocyte antigen (HLA)-A*02 and HLA-A*24 alleles by determining the frequency of CD8+ T cells recognizing major histocompatibility complex (MHC) dextramers (DMR) carrying TPO-derived peptides, by flow cytometry.

Results

The HT-SCH group had a lower rate of Mantoux test reactivity (38.5%) as compared to NA-SCH (64%) and HC subjects (65%) (p=0.047). However, the BCG-induced in-vitro proliferation of PBMC was similar in HT-SCH, NA-SCH, and HC groups. Further, the BCG-vaccinated SCH subjects had lower levels of thyroid stimulating hormone (TSH) (p=0.026). Next, the SCH subjects had higher frequencies of peripheral DMR+ CD8+ T cells as compared to HC subjects (p=0.001). Interestingly, the frequency of peripheral DMR+ CD8+ T cells was significantly higher in HT-SCH than HC subjects (p=0.045). Finally, we observed a positive correlation between the frequency of DMR+CD8+ T cells and TSH levels (r = +0.620, p=0.006).

Conclusions

Collectively, our results highlight a complex relationship of neonatal BCG vaccination with the genesis of HT, via modulation of autoimmune responses directed towards thyroid autoantigens.
Proportion and distribution of neurotransmitter-defined cell types in the ventral tegmental area and substantia nigra pars compacta
Authors: Conrad William S. , Oriol Lucie , Kollman Grace J. , Faget Lauren , Hnasko Thomas S.
Published: February 2024

Most studies on the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) have focused on dopamine neurons and their role in processes such as motivation, learning, movement, and associated disorders such as addiction and Parkinson’s disease. However there has been increasing attention on other VTA and SNc cell types that release GABA, glutamate, or a combination of neurotransmitters. Yet the relative distributions and proportions of neurotransmitter-defined cell types across VTA and SNc has remained unclear. Here, we used fluorescent in situ hybridization in male and female mice to label VTA and SNc neurons that expressed mRNA encoding the canonical vesicular transporters for dopamine, GABA, or glutamate: vesicular monoamine transporter (VMAT2), vesicular GABA transporter (VGAT), and vesicular glutamate transporter (VGLUT2). Within VTA, we found that no one type was particularly more abundant, instead we observed similar numbers of VMAT2+ (44%), VGAT+ (37%) and VGLUT2+ (41%) neurons. In SNc we found that a slight majority of neurons expressed VMAT2 (54%), fewer were VGAT+ (42%), and VGLUT2+ neurons were least abundant (16%). Moreover, 20% of VTA neurons and 10% of SNc neurons expressed more than one vesicular transporter, including 45% of VGLUT2+ neurons. We also assessed within VTA and SNc subregions and found remarkable heterogeneity in cell-type composition. And by quantifying density across both anterior-posterior and medial-lateral axes we generated heatmaps to visualize the distribution of each cell type. Our data complement recent single-cell RNAseq studies and support a more diverse landscape of neurotransmitter-defined cell types in VTA and SNc than is typically appreciated.
Novel misos shape distinct microbial ecologies: opportunities for flavourful sustainable food innovation
Authors: Kothe Caroline Isabel , Carøe Christian , Mazel Florent , Zilber David , Cruz-Morales Pablo , Mohellibi Nacer , Evans Joshua
Published: February 2024

Fermentation is resurgent around the world as people seek healthier, more sustainable, and tasty food options. This study explores the microbial ecology of miso, a traditional Japanese fermented paste, made with novel regional substrates to develop new plant-based foods. Eight novel miso varieties were developed using different protein-rich substrates: yellow peas, Gotland lentils, and fava beans (each with two treatments: standard and nixtamalisation), as well as rye bread and soybeans. The misos were produced at Noma, a restaurant in Copenhagen, Denmark. Samples were analysed with biological and technical triplicates at the beginning and end of fermentation. We also incorporated in this study six samples of novel misos produced following the same recipe at Inua, a former affiliate restaurant of Noma in Tokyo, Japan. To analyse microbial community structure and diversity, metabarcoding (16S and ITS) and shotgun metagenomic analyses were performed. The misos contain a greater range of microbes than is currently described for miso in the literature. The composition of the novel yellow pea misos was notably similar to the traditional soybean ones, suggesting they are a good alternative, which supports our culinary collaborators’ sensory conclusions. For bacteria, we found that overall substrate had the strongest effect, followed by time, treatment (nixtamalisation), and geography. For fungi, there was a slightly stronger effect of geography and a mild effect of substrate, and no significant effects for treatment or time. Based on an analysis of metagenome-assembled genomes (MAGs), strains ofS. epidermidisdifferentiated according to substrate. Carotenoid biosynthesis genes in these MAGs appeared in strains from Japan but not from Denmark, suggesting a possible gene-level geographical effect. The benign and possibly functional presence ofS. epidermidisin these misos, a species typically associated with the human skin microbiome, suggests possible adaptation to the miso niche, and the flow of microbes between bodies and foods in certain fermentation as more common than is currently recognised. This study improves our understanding of miso ecology, highlights the potential for developing novel misos using diverse local ingredients, and suggests how fermentation innovation can contribute to studies of microbial ecology and evolution.
CyanoTag: Discovery of protein function facilitated by high-throughput endogenous tagging in a photosynthetic prokaryote
Authors: Perrin Abigail J. , Dowson Matthew , Dowle Adam A. , Calder Grant , Springthorpe Victoria J. , Zhao Guoyan , Mackinder Luke C. M.
Published: February 2024

Despite their fundamental importance to aquatic ecosystems, global carbon cycling and exciting potential in sustainable bioindustries, the genomes of photosynthetic prokaryotes still contain large numbers of uncharacterised protein-coding genes. Here we present a high-throughput approach for scarless endogenous fluorescent protein tagging in the model cyanobacteriumSynechococcus elongatusPCC7942. From 400 targets we successfully endogenously tag over 330 proteins corresponding to >10% of the proteome. We demonstrate how this resource can be used at scale to determine subcellular localisation, track relative protein abundances and to elucidate protein-protein interaction networks. Our data has provided biological insights into a diverse range of processes - from photosynthesis to cell division. Of particular interest, our ‘CyanoTag’ lines enabled us to visualise in real time the rapid condensation of Calvin Cycle proteins Prk and Gap2 within seconds of withdrawal of light, effectively ‘switching off’ photosynthesis in the dark. These insights, CyanoTag cell lines, associated data and optimised methods are intended to be shared as a resource to facilitate further discoveries relevant to cyanobacteria and more broadly to all photosynthetic life.