bluuebunny/crossref_metadata_2025 huggingface dataset:
Corrective feedback guides human perceptual decision-making by informing about the world state rather than rewarding its choice
Authors: Lee Hyang-Jung , Lee Heeseung , Lim Chae Young , Rhim Issac , Lee Sang-Hun
Published: January 2023

Corrective feedback received on perceptual decisions is crucial for adjusting decision-making strategies to improve future choices. However, its complex interaction with other decision components, such as previous stimuli and choices, challenges a principled account of how it shapes subsequent decisions. One popular approach, based on animal behavior and extended to human perceptual decision-making, employs ‘reinforcement learning,’ a principle proven successful in reward-based decision-making. The core idea behind this approach is that decision-makers, although engaged in a perceptual task, treat corrective feedback as rewards from which they learn choice values. Here, we explore an alternative idea, which is that humans consider corrective feedback on perceptual decisions as evidence of the actual state of the world rather than as rewards for their choices. By implementing these ‘feedback-as-reward’ and ‘feedback-as-evidence’ hypotheses on a shared learning platform, we show that the latter outperforms the former in explaining how corrective feedback adjusts the decision-making strategy along with past stimuli and choices. Our work suggests that humans learn about what has happened in their environment rather than the values of their own choices through corrective feedback during perceptual decision-making.
Different rules for binocular combination of luminance flicker in cortical and subcortical pathways
Authors: Segala Federico G. , Bruno Aurelio , Martin Joel T. , Aung Myat T. , Wade Alex R. , Baker Daniel H.
Published: January 2023

1

How does the human brain combine information across the eyes? It has been known for many years that cortical normalisation mechanisms implement ‘ocularity invariance’: equalising neural responses to spatial patterns presented either monocularly or binocularly. Here we used a novel combination of electrophysiology, psychophysics, pupillometry and computational modelling to ask whether this invariance also holds for flickering luminance stimuli with no spatial contrast. We find dramatic violations of ocularity invariance for these stimuli, both in cortex and also in the subcortical pathways that govern pupil diameter. Specifically, we find substantial binocular facilitation in both pathways with the effect being strongest in cortex. Near-linear binocular additivity (instead of ocularity invariance) was also found using a perceptual luminance matching task. Ocularity invariance is therefore not a ubiquitous feature of visual processing, and the brain appears to repurpose a generic normalisation algorithm for different visual functions by adjusting the amount of interocular suppression.
Distinguishing response from stimulus driven history biases
Authors: Sheehan Timothy C. , Serences John T.
Published: January 2023

Perception is shaped by past experience, both cumulative and contextual. Serial dependence reflects a contextual attractive bias to perceive or report the world as more stable than it truly is. As serial dependence has often been examined in continuous report or change detection tasks, it unclear whether attraction is towards the identity of the previous stimulus feature, or rather to theresponsemade to indicate theperceivedstimulus value on the previous trial. The physical and reported identities can be highly correlated depending on properties of the stimulus and task design. However, they are distinct values and dissociating them is important because it can reveal information about the role of sensory and non-sensory contributions to attractive biases. These alternative possibilities can be challenging to disentangle because 1) stimulus values and responses are typically strongly correlated and 2) measuring response biases using standard techniques can be confounded bycontext-independentbiases such ascardinal biasfor orientation (i.e., higher precision, but repelled, responses from vertical and horizontal orientations). Here we explore the issues and confounds related to measuring response biases using simulations. Under a range of conditions, we find that response-induced biases can be reliably distinguished from stimulus-induced biases and from confounds introduced bycontext-independentbiases. We then applied these approaches to a delayed report dataset (N=18) and found evidence for response over a stimulus driven history bias. This work demonstrates that stimulus and response driven history biases can be reliably dissociated and provides code to implement these analysis procedures.
Task history dictates how the dorsolateral striatum controls action strategy and vigor
Authors: Crego Adam C. G. , Amaya Kenneth A. , Palmer Jensen A. , Smith Kyle S.
Published: January 2023

The dorsolateral striatum (DLS) is linked to the learning and honing of action routines. However, the DLS is also important for performing behaviors that have been successful in the past. The learning function can be thought of as prospective, helping to plan ongoing actions to be efficient and often optimal. The performance function is more retrospective, helping the animal continue to behave in a way that had worked previously. How the DLS manages this all is curious. What happens when a learned behavior becomes sub-optimal due to environment changes. In this case, the prospective function of the DLS would cause animals to (adaptively) learn and plan more optimal actions. In contrast, the retrospective function would cause animals to (maladaptively) favor the old behavior. Here we find that, during a change in learned task rules, DLS inhibition causes animals to adjust less rapidly to the new task (and to behave less vigorously) in a ‘maladaptive’ way. Yet, when the task is changed back to the initially learned rules, DLS inhibition instead causes a rapid and vigorous adjustment of behavior in an ‘adaptive’ way. These results show that inhibiting the DLS biases behavior towards initially acquired strategies, implying a more retrospective outlook in action selection when the DLS is offline. Thus, an active DLS could encourage planning and learning action routines more prospectively. Moreover, the DLS control over behavior can appear to be either advantageous/flexible or disadvantageous/inflexible depending on task context, and its control over vigor can change depending on task context.

Significant Statement

Basal ganglia networks aid behavioral learning (a prospective planning function) but also favor the use of old behaviors (a retrospective performance function), making it unclear what happens when learned behaviors become suboptimal. Here we inhibit the dorsolateral striatum (DLS) as animals encounter a change in task rules, and again when they shift back to those learned task rules. DLS inhibition reduces adjustment to new task rules (and reduces behavioral vigor), but it increases adjustment back to the initially learned task rules later (and increases vigor). Thus, in both cases, DLS inhibition favored the use of the initially learned behavioral strategy, which could appear either maladaptive or adaptive. We suggest that the DLS might promote a prospective orientation of action control.
Sampling strategies and integrated reconstruction for reducing distortion and boundary slice aliasing in high-resolution 3D diffusion MRI
Authors: Li Ziyu , Miller Karla L. , Andersson Jesper L.R. , Zhang Jieying , Liu Simin , Guo Hua , Wu Wenchuan
Published: January 2023

Purpose

To develop a new method for high-fidelity, high-resolution 3D multi-slab diffusion MRI with minimal distortion and boundary slice aliasing.

Methods

Our method modifies 3D multi-slab imaging to integrate blip-reversed acquisitions for distortion correction and oversampling in the slice direction (kz) for reducing boundary slice aliasing. Our aim is to achieve robust acceleration to keep the scan time the same as conventional 3D multi-slab acquisitions, in which data are acquired with a single direction of blip traversal and without kz-oversampling. We employ a two-stage reconstruction. In the first stage, the blip-up/down images are respectively reconstructed and analyzed to produce a field map for each diffusion direction. In the second stage, the blip-reversed data and the field map are incorporated into a joint reconstruction to produce images that are corrected for distortion and boundary slice aliasing.

Results

We conducted experiments at 7T in six healthy subjects. Stage 1 reconstruction produces images from highly under-sampled data (R=7.2) with sufficient quality to provide accurate field map estimation. Stage 2 joint reconstruction substantially reduces distortion artifacts with comparable quality to fully-sampled blip-reversed results (2.4× scan time). Whole-brain in-vivo results acquired at 1.05mm isotropic resolution demonstrate improved anatomical fidelity compared to conventional 3D multi-slab imaging. Data demonstrate good reliability and reproducibility of the proposed method over multiple subjects.

Conclusion

The proposed acquisition and reconstruction framework provide major reductions in distortion and boundary slice aliasing for 3D multi-slab diffusion MRI without increasing the scan time. This method has the potential to provide high-quality, high-resolution diffusion MRI.
Distinct Mechanisms Underlie Electrical Coupling Resonance and Its Interaction with Membrane Potential Resonance
Authors: Li Xinping , Itani Omar , Bucher Dirk M. , Rotstein Horacio G. , Nadim Farzan
Published: January 2023

Neurons in oscillatory networks often exhibit membrane potential resonance, a peak impedance at a non-zero input frequency. In electrically coupled oscillatory networks, the coupling coefficient (the ratio of post- and prejunctional voltage responses) could also show resonance. Such coupling resonance may emerge from the interaction between the coupling current and resonance properties of the coupled neurons, but this relationship has not been clearly described. Additionally, it is unknown if the gap-junction mediated electrical coupling conductance may have frequency dependence. We examined these questions by recording a pair of electrically coupled neurons in the oscillatory pyloric network of the crabCancer borealis. We performed dual current- and voltage-clamp recordings and quantified the frequency preference of the coupled neurons, the coupling coefficient, the electrical conductance, and the postjunctional neuronal response. We found that all components exhibit frequency selectivity, but with distinct preferred frequencies. Mathematical and computational analysis showed that membrane potential resonance of the postjunctional neuron was sufficient to give rise to resonance properties of the coupling coefficient, but not the coupling conductance. A distinct coupling conductance resonance frequency therefore emerges either from other circuit components or from the gating properties of the gap junctions. Finally, to explore the functional effect of the resonance of the coupling conductance, we examined its role in synchronizing neuronal the activities of electrically coupled bursting model neurons. Together, our findings elucidate factors that produce electrical coupling resonance and the function of this resonance in oscillatory networks.
Evidence for adaptive myelination of subcortical shortcuts for visual motion perception in healthy adults
Authors: Rowe Elise G. , Zhang Yubing , Garrido Marta I.
Published: January 2023

Conscious visual motion information follows a cortical pathway from the retina to the lateral geniculate nucleus (LGN) and on to the primary visual cortex (V1) before arriving at the middle temporal visual area (MT/V5). Alternative subcortical pathways that bypass V1 are thought to convey unconscious visual information. One flows from the retina to the pulvinar (PUL) and on to MT; while the other directly connects the LGN to MT. Evidence for these pathways comes from non-human primates and modest-sized studies in humans with brain lesions. Thus, the aim of the current study was to reconstruct these pathways in a large sample of neurotypical individuals and to determine the degree to which these pathways are myelinated, suggesting information flow is rapid. We used the publicly available 7T (N = 98; ‘discovery’) and 3T (N = 381; ‘validation’) diffusion MRI datasets from the Human Connectome Project to reconstruct the PUL-MT and LGN-MT pathways. We found more fibre tracts with greater density in the left hemisphere. Although the left PUL-MT path was denser, the bilateral LGN-MT tracts were more heavily myelinated, suggesting faster signal transduction. We suggest that this apparent discrepancy may be due to ‘adaptive myelination’ caused by more frequent use of the LGN-MT pathway that leads to greater myelination and faster overall signal transmission.
Phenotypic and genotypic adaptation ofE. colito thermal stress is contingent on genetic background
Authors: Batarseh Tiffany N. , Batarseh Sarah N. , Rodríguez-Verdugo Alejandra , Gaut Brandon S.
Published: January 2023

Evolution can be contingent on history, but we do not yet have a clear understanding of the processes and dynamics that govern contingency. Here we performed the second phase of a two-phase evolution experiment to investigate features of contingency. The first phase of the experiment was based onEscherichia coliclones that had evolved population at the stressful temperature of 42.2°C. The Phase 1 lines generally evolved through two adaptive pathways: mutations ofrpoB, which encodes the beta subunit of RNA polymerase, or throughrho, a transcriptional terminator. We hypothesized that epistatic interactions within the two pathways constrained their future adaptative potential, thus affecting patterns of historical contingency. Using 10 differentE. coliFounders representing both adaptive pathways, we performed a second phase of evolution at 19.0°C to investigate how prior genetic divergence or adaptive history (rpoBvs.rho) may affect the likelihood of parallel responses and evolutionary outcomes. We found that phenotype, as measured by relative fitness, was contingent on founder genotypes and pathways. This finding extended to genotypes, becauseE. colifrom different Phase 1 histories evolved by adaptive mutations in distinct sets of genes. Our results suggest that evolution depends critically on genetic history, likely due to idiosyncratic epistatic interactions within and between evolutionary modules.
Millisecond-scale behaviours of plankton quantifiedin situandin vitrousing the Event-based Vision Sensor (EVS)
Authors: Takatsuka Susumu , Miyamoto Norio , Sato Hidehito , Morino Yoshiaki , Kurita Yoshihisa , Yabuki Akinori , Chen Chong , Kawagucci Shinsuke
Published: January 2023

The Event-based Vision Sensor (EVS) is a bio-inspired sensor that captures detailed motions of objects, developed with the applicability to become the ‘eyes’ of machines and especially self-driving cars. Compared to conventional frame-based image sensors as employed in video cameras, EVS has an extremely fast motion capture equivalent to 10,000-fps even with standard optical settings and additionally has high dynamic ranges for brightness and also lower consumption of memory and energy. These features make the EVS an ideal method to tackle questions in biology, such as the fine-scale behavioural ecology. Here, we developed 22 characteristic features for analysing the motions of aquatic particles from the raw data of the EVS, and deployed the EVS system in both natural environments and laboratory aquariums to test its applicability to filming and analysing plankton behaviour. Our EVS monitoring in turbid water at the bottom of Lake Biwa, Japan identified several particles exhibiting distinct cumulative trajectory with periodicities in their motion (up to 16 Hz), suggesting that they were living organisms with rhythmic behaviour. We also carried out EVS monitoring in the deep sea aided by infrared lighting to minimise influence on behaviour, and observed particles with active motion and periodicities over 40 Hz. Furthermore, we used the EVS to observe laboratory cultures of six species of zooplankton and phytoplankton, confirming that they have species-specific motion periodicities of up to 41 Hz. We applied machine learning to automatically classify particles into five categories (four categories of zooplankton plus passive particles), which achieved an accuracy up to 86%. Our attempts to use the EVS for biological observations, especially focusing on its millisecond-scale temporal resolution and wide dynamic range provide a new avenue to investigate rapid and periodical motion and behaviour in small organisms. Given its compact size with low consumption of battery and memory, the EVS will likely be applicable in the near future for the automated monitoring of the behaviour of plankton by edge computing on autonomous floats, as well as quantifying rapid cellular-level activities under microscopy.
The detection of brood parasitism and quasi-parasitism in the burying beetleNicrophorus quadripunctatusunder natural conditions
Authors: Niida Takuma , Yao Izumi , Nisimura Tomoyosi , Suzuki Seizi
Published: January 2023

Intraspecific brood parasitism (IBP), where a parasitic female lays eggs in the nest of another female of the same species, occurs in insects and birds. Also, quasi-parasitism (QP), where a parasitic female copulates with a host male at his nest and lays eggs that are fertilized by the male, has been documented in a few monogamous birds, but QP has not been observed in any insects.

Burying beetles, genusNicrophorus, use small vertebrate carcasses for reproducing and providing biparental care for their offspring. IBP has been observed in one burying beetle by laboratory experiments, but has not been well reported under natural conditions. IBP and QP may occur under natural conditions in burying beetles.

Here we focused on a burying beetle,Nicrophorus quadripunctatus. Ten broods, consisting of larvae and their parental female and male, were collected from a deciduous forest. To investigate the kin relationship between parents and larvae, eight microsatellite DNA loci were used.

We detected three types of parasitic larvae: 1) larva not related to either its parental female or male, 2) larva not related to its parental female, but unknown regarding its parental male, and 3) larva not related to its parental female, but related to its parental male. These results suggested that IBP and QP can occur with certain frequencies in the reproduction ofN. quadripunctatusunder natural conditions. QP is thought to have a benefit for a parental male to enhance his paternity within one brood in this species.
Human papillomavirus 16 E2 interaction with TopBP1 is required for E2 and viral genome stability during the viral life cycle
Authors: Prabhakar Apurva T. , James Claire D. , Fontan Christian T. , Otoa Raymonde , Wang Xu , Bristol Molly L. , Hill Ronald D. , Dubey Aanchal , Morgan Iain M.
Published: January 2023

CK2 phosphorylation of HPV16 E2 at serine 23 promotes interaction with TopBP1, and this interaction is important for E2 plasmid segregation function. Here we demonstrate that the E2-TopBP1 interaction is critical for E2 and viral genome stability during the viral life cycle. Introduction of the S23A mutation into the HPV16 genome results in a loss of E2 expression and viral genome integration during organotypic rafting. Co-culture of N/Tert-1+E2-S23A cells with J2 fibroblasts results in E2-S23A degradation via the proteasome, wild-type E2 is not degraded. TopBP1 siRNA treatment of N/Tert-1+E2-WT cells results in E2 degradation only in the presence of J2 cells demonstrating the critical role for TopBP1 in maintaining E2 stability. The CK2 inhibitor CX4945 promotes E2-WT degradation in the presence of fibroblasts as it disrupts E2-TopBP1 interaction. siRNA targeting SIRT1 rescues E2-S23A stability in N/Tert-1 cells treated with J2 fibroblasts, with an increased E2-S23A acetylation. The results demonstrate that the E2-TopBP1 interaction is critical during the viral life cycle as it prevents fibroblast stimulated SIRT1 mediated deacetylation of E2 that promotes protein degradation. This means that the E2-TopBP1 complex maintains E2 and viral genome stability and that disruption of this complex can promote viral genome integration. Finally, we demonstrate that HPV11 E2 also interacts with TopBP1 and that this interaction is critical for HPV11 E2 stability in the presence of J2 cells. Treatment of N/Tert-1+11E2-WT cells with CX4945 results in 11E2 degradation. Therefore, CK2 inhibition is a therapeutic strategy for alleviating HPV11 diseases, including juvenile respiratory papillomatosis.

Importance

Human papillomaviruses are pathogens that cause a host of diseases ranging from benign warts to cancers. There are no therapeutics available for combating these diseases that directly target viral proteins or processes, therefore we must enhance our understanding of HPV life cycles to assist with identifying novel treatments. In this report, we demonstrate that HPV16 and HPV11 E2 protein expression is dependent upon TopBP1 interaction in keratinocytes interacting with fibroblasts, which recapitulate stromal interactions in culture. The degradation of 16E2 promotes HPV16 genome integration, therefore the E2-TopBP1 interaction is critical during the viral life cycle. We demonstrate that the CK2 inhibitor CX4945 disrupts HPV11 interaction with TopBP1 and destabilizes HPV11 E2 protein in the presence of J2 fibroblasts; we propose that CX4945 could alleviate HPV11 disease burden.
Post-discharge mortality among children under 5 years admitted with suspected sepsis in Uganda: a prospective multi-site study
Authors: Wiens Matthew O , Bone Jeffrey N , Kumbakumba Elias , Businge Stephen , Tagoola Abner , Sherine Sheila Oyella , Byaruhanga Emmanuel , Ssemwanga Edward , Barigye Celestine , Nsungwa Jesca , Olaro Charles , Ansermino J Mark , Kissoon Niranjan , Singer Joel , Larson Charles P , Lavoie Pascal M , Dunsmuir Dustin , Moschovis Peter P , Novakowski Stefanie , Komugisha Clare , Tayebwa Mellon , Mwesigwa Douglas , Zhang Cherri , Knappett Martina , West Nicholas , Nguyen Vuong , Mugisha Nathan Kenya , Kabakyenga Jerome
Published: January 2023

Background

Substantial mortality occurs after hospital discharge in children under 5 years old with suspected sepsis. A better understanding of its epidemiology is needed for effective interventions aimed at reducing child mortality in resource limited settings.

Methods

In this prospective observational cohort study, we recruited 0-60-month-old children admitted with suspected sepsis from the community to the paediatric wards of six Ugandan hospitals. The primary outcome was six-month post-discharge mortality among those discharged alive. We evaluated the interactive impact of age, time of death, and location of death on risk factors for mortality.

Findings

6,545 children were enrolled, with 6,191 discharged alive. The median (interquartile range) time from discharge to death was 32 (10–92) days, with a six-month post-discharge mortality rate of 5·5%, constituting 51% of total mortality. Deaths occurred at home (45%), intransit to care (18%), or in hospital (37%) during a subsequent readmission. Post-discharge death was strongly associated with weight-for-age z-scores < -3 (adjusted hazard ratio [aHR] 5·04; 95%CI: 3·97–6·37), referral for further care (aHR 9·08; 95%CI 6·68–12·34), and unplanned discharge (aHR 3·36; 95%CI 2·64–4·28). The hazard ratio of those with severe anaemia increased with time since discharge, while the hazard ratios of discharge vulnerabilities (unplanned, poor feeding) decreased with time. Children with severe anaemia (<7 g/dL) died 35 days (95%CI 19·4–51·9) later than those without anaemia. Age influenced the effect of several variables, including anthropometric indices (less impact with increasing age), anaemia (greater impact), and admission temperature (greater impact).

Interpretation

Paediatric post-discharge mortality following suspected sepsis is common, with diminishing, though persistent, risk over the 6 months after discharge. Efforts to improve post-discharge outcomes are critical to achieving Sustainable Development Goal 3.2 (ending preventable childhood deaths under 5 years of age).

Funding

Grand Challenges Canada (#TTS-1809-1939), Thrasher Research Fund (#13878), BC Children’s Hospital Foundation, and Mining4Life.
Evaluation of two red cell inclusion staining methods for assessing spleen function among sickle cell disease patients in North-East Nigeria
Authors: Ladu Adama I , Satumari Ngamariju A , Abba Aisha M , Abulfathi Fatima A , Jeffery Caroline , Adekile Adekunle , Bates Imelda
Published: January 2023

Introduction

The loss of splenic function is associated with an increased risk of infection in sickle cell disease (SCD); however, spleen function is rarely documented among SCD patients in Africa, due partly to the non-availability of sophisticated techniques such as scintigraphy. Methods of assessing splenic function which may be achievable in resource-poor settings include counting red blood cells (RBC) containing Howell Jolly Bodies (HJB) and RBC containing silver-staining (argyrophilic) inclusions (AI) using a light microscope. We evaluated the presence of HJB - and AI - containing RBC as markers of splenic dysfunction among SCD patients in Nigeria.

Methods

We prospectively enrolled children and adults with SCD in steady state attending outpatient clinics at a tertiary hospital in North-East Nigeria. The percentages of HJB- and AI-containing red cells were estimated from peripheral blood smears and compared to normal controls.

Results

There were 182 SCD patients and 102 healthy controls. Both AI- and HJB-containing red cells could be easily identified in the participants blood smears. SCD patients had a significantly higher proportion of red cells containing HJB (1.5%; IQR 0.7% - 3.1%) compared to controls (0.3%; IQR 0.1% - 0.5%) (P= 0.0001). The AI red cell counts were also higher among the SCD patients (47.4%; IQR 34.5% - 66.0%) than the control group (7.1%; IQR 5.1% - 8.7%) (P= 0.0001). The intra-observer reliability for assessment of HJB-(R = 0.92; R2= 0.86) and AI-containing red cells (R = 0.90; R2= 0.82) was high. The estimated intra-observer agreement was better with the HJB count method (95% limits of agreement, −4.5 to 4.3;P= 0.579).

Conclusion

We have demonstrated the utility of light microscopy in the assessment of red cells containing - HJB and AI inclusions as indices of splenic dysfunction in Nigerian SCD patients. These methods can be easily applied in the routine evaluation and care of patients with SCD to identify those at high risk of infection and initiate appropriate preventive measures.
Cross-sectional Ct distributions from qPCR tests can provide an early warning signal for the spread of COVID-19 in communities
Authors: Sharmin Mahfuza , Manivannan Mani , Woo David , Sorel Océane , Auclair Jared , Gandhi Manoj , Mujawar Imran
Published: January 2023

Background

SARS-CoV-2 PCR testing data has been widely used for COVID-19 surveillance. Existing COVID-19 forecasting models mainly rely on case counts, even though the binary PCR results provide a limited picture of the pandemic trajectory. Most forecasting models have failed to accurately predict the COVID-19 waves before they occur. Recently a model utilizing cross-sectional population cycle threshold (Ct) values obtained from PCR tests (Ct-based model) was developed to overcome the limitations of using only binary PCR results. In this study, we aimed to improve on COVID-19 forecasting models using features derived from the Ct-based model, to detect epidemic waves earlier than case-based trajectories.

Methods

PCR data was collected weekly at Northeastern University (NU) between August 2020 and January 2022. The NU campus epidemic trajectories were generated from the campus incidence rates. In addition, epidemic trajectories were generated for Suffolk County, where NU is located, based on publicly available case-counts. A novel forecasting approach was developed by enhancing a recent deep learning model with Ct-based features, along with the model’s default features. For this, cross-sectional Ct values from PCR data were used to generate Ct-based epidemic trajectories, including effective reproductive rate (Rt) and incidence. The improvement in forecasting performance was compared using absolute errors and residual squared errors with respect to actual observed cases at the 7-day and 14-day forecasting horizons. The model was also tested prospectively over the period January 2022 to April 2022.

Results

Rt estimates from the Ct-based model preceded NU campus and Suffolk County cases by 12 and 14 days respectively, with a three-way synched Spearman correlation of 0.57. Enhancing the forecasting models with Ct-based information significantly decreased absolute error and residual squared error compared to the original model without Ct features (p-value <0.001 for both 7 and 14-days forecasting horizons).

Conclusion

Ct-based epidemic trajectories can herald an earlier signal for impending epidemic waves in the community and forecast transmission peaks. Moreover, COVID-19 forecasting models can be enhanced using these Ct features to improve their forecasting accuracy.

Policy implications

We make the case that public health agencies should publish Ct values along with the binary positive/negative PCR results. Early and accurate forecasting of epidemic waves can inform public health policies and countermeasures which can mitigate spread.
Peri- and Post-natal Risk Factors Associated with Health of Newborns
Authors: Long Yanan , Khan Atif , Rzhetsky Andrey
Published: January 2023

Designing prophylactic strategies for newborns requires understanding of the factors that contribute to immunity and resistance to infection. We analyzed 1,892,035 mother-newborn pairs in which both the mother and newborn were observed continuously for at least one year before and after birth. As part of this study, we considered maternal exposures to infections and immune disorders during pregnancy, exposures to anti-infection medications by both mother and newborn, as well as the newborn’s delivery type and reported complications. According to our analyses, infection rates and immune disorder rates were over-dispersed among newborns. The most consequential factors predicting newborns’ immune health were preterm birth, with 276.3% and 193.9% risk increases for newborn bacterial infections. Newborn anti-infective prescriptions were associated with considerable increases in risk of diseases affecting immune health, while maternal prescriptions were associated with fewer outcomes and with mixed signs. The Cesarean section mode of delivery, the mother’s age, the sex of the newborn, and the mother’s exposure to infections all showed significant but smaller effects on the newborn’s immune health. Female newborn appeared to be better protected against diseases with immune system etiology, except for miscellaneous infections.
Assessing spontaneous sensory neuron activity usingin vivocalcium imaging
Authors: Ingram Sonia L , Chisholm Kim I , Wang Feng , De Koninck Yves , Denk Franziska , Goodwin George L
Published: January 2023

Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whetherin vivocalcium imaging with GCaMP6s can be used as an alternative approach. We show that spontaneously active calcium transients can be visualised in the fourth lumbar dorsal root ganglion (L4 DRG) viain vivoimaging in a mouse model of pain. Application of lidocaine to the nerve, between the inflamed site and the DRG, silenced spontaneous firing and revealed the true baseline level of calcium for spontaneously active neurons. We used this data to train a machine leaning algorithm to predict when a neuron is spontaneously active. We show that our algorithm is accurate in two different models of pain: intraplantar Complete Freund’s Adjuvant and antigen-induced arthritis, with accuracies of 90.0% +/-1.2 and 85.9 % +/-2.1, respectively, assessed against visual inspection by an experienced observer. The algorithm can also detect neuronal activity in imaging experiments generated in a different lab using a different microscope configuration (Accuracy = 94.0 % +/2.2). We provide a Google Colaboratory Notebook to allow anyone easy access to this novel tool, for assessment of peripheral neuron activity in their own calcium imaging setups.
Bovine blood and milk T-cell subsets in distinct states of activation and differentiation during subclinicalStaphylococcus aureusmastitis
Authors: Tucker Nisha , Cunha Patricia , Gilbert Florence B. , Rambault Marion , Santos Kamila Reis , Remot Aude , Germon Pierre , Rainard Pascal , Martins Rodrigo Prado
Published: January 2023

T-lymphocytes are key mediators of adaptive cellular immunity and knowledge about distinct subsets of these cells in healthy and infected mammary gland secretions remains limited. In this study, we used a multiplex cytometry panel to show that staphylococcal mastitis causes the activation of CD4+, CD8+and γδ T-cells found in bovine milk. We also highlight remarkable differences in the proportions of naïve and memory T-cells subsets found in blood and milk. These observations will contribute to a better understanding of cell-mediated immune mechanisms in the udder and to the development of new therapeutic and preventive strategies targeting mastitis.
From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions
Authors: Tiane Assia , Schepers Melissa , Reijnders Rick A. , van Veggel Lieve , Chenine Sarah , Rombaut Ben , Dempster Emma , Verfaillie Catherine , Wasner Kobi , Grünewald Anne , Prickaerts Jos , Pishva Ehsan , Hellings Niels , van den Hove Daniel , Vanmierlo Tim
Published: January 2023

Introduction

In the progressive phase of multiple sclerosis (MS), the hampered differentiation capacity of oligodendrocyte precursor cells (OPCs) eventually results in remyelination failure. We have previously shown that DNA methylation ofId2/Id4is highly involved in OPC differentiation and remyelination. In this study, we took an unbiased approach by determining genome-wide DNA methylation patterns within chronically demyelinated MS lesions and investigated how certain epigenetic signatures relate to OPC differentiation capacity.

Methods

We compared genome-wide DNA methylation and transcriptional profiles between chronically demyelinated MS lesions and matched normal-appearing white matter (NAWM), making use of post-mortem brain tissue (n=9/group). DNA methylation differences that inversely correlated with mRNA expression of their corresponding genes were validated for their cell-type specificity in laser-captured OPCs using pyrosequencing. The CRISPR-dCas9-DNMT3a/TET1 system was used to epigenetically edit human-iPSC-derived oligodendrocytes to assess the effect on cellular differentiation.

Results

Our data show hypermethylation of CpGs within genes that cluster in gene ontologies related to myelination and axon ensheathment. Cell type-specific validation indicates a region-dependent hypermethylation ofMBP, encoding for myelin basic protein, in OPCs obtained from white matter lesions compared to NAWM-derived OPCs. By altering the DNA methylation state of specific CpGs within the promotor region ofMBP, using epigenetic editing, we show that cellular differentiation can be bidirectionally manipulated using the CRISPR-dCas9-DNMT3a/TET1 systemin vitro.

Conclusion

Our data indicate that OPCs within chronically demyelinated MS lesions acquire an inhibitory phenotype, which translates into hypermethylation of crucial myelination related genes. Altering the epigenetic status ofMBPcan restore the differentiation capacity of OPCs and possibly boost (re)myelination.
A human iPSC-basedin vitroneural network formation assay to investigate neurodevelopmental toxicity of pesticides
Authors: Bartmann Kristina , Bendt Farina , Dönmez Arif , Haag Daniel , Keßel Eike , Masjosthusmann Stefan , Noel Christopher , Wu Ji , Zhou Peng , Fritsche Ellen
Published: January 2023

Proper brain development is based on the orchestration of key neurodevelopmental processes, including the formation and function of neural networks. If at least one key neurodevelopmental process is affected by a chemical, an adverse outcome is expected. To allow a higher testing throughput than the guideline animal experiments, a developmental neurotoxicity (DNT)in vitrotesting battery (DNT IVB) has been set up that includes a variety of assays, which model several key neurodevelopmental processes. Gap analyses of the DNT IVB revealed the need of a human-based assay to assess neural network formation and function (NNF). Therefore, here we established the human NNF (hNNF) assay. A co-culture comprised of human-induced pluripotent stem cell (hiPSC)- derived excitatory and inhibitory neurons, as well as primary human astroglia, was differentiated for 35 days on micro-electrode arrays (MEA) and spontaneous electrical activity, together with cytotoxicity, was assessed on a weekly basis after washout of the compounds 24 h prior to measurements. In addition to the characterization of the test system, the assay was challenged with 28 compounds, mainly pesticides, identifying their DNT potential by evaluation of specific spike-, burst- and network parameters. This approach confirmed the suitability of the assay for screening environmental chemicals. Comparison of benchmark concentrations (BMC) with an NNFin vitroassay (rNNF) based on primary rat cortical cells, revealed differences in sensitivity. Together with the successful implementation of hNNF data into a postulated stressor-specific adverse outcome pathway (AOP) network associated with a plausible molecular initiating event for deltamethrin, this study suggests the hNNF assay as a useful complement to the current DNT IVB.
SERS nanowire chip and machine learning enabled instant identification and classification of clinically relevant wild-type and antibiotic resistant bacteria at species and strain level
Authors: Das Sathi , Saxena Kanchan , Tinguely Jean-Claude , Pal Arijit , Wickramasinghe Nima L. , Khezri Abdolrahman , Dubey Vishesh , Ahmed Azeem , Vivekanandan Perumal , Ahmad Rafi , Wadduwage Dushan N. , Ahluwalia Balpreet Singh , Mehta Dalip Singh
Published: January 2023

The world health organization considers antimicrobial resistance (AMR) to be a critical global public health problem. Conventional culture-based methods that are used to detect and identify bacterial infection are slow. Thus, there is a growing need for the development of robust, cost-effective, and fast diagnostic solutions for the identification of pathogens. Surface-enhanced Raman spectroscopy (SERS) can be used to identify target analytes with sensitivity down to the single-molecule level. Here, we developed a SERS chip by optimizing the entire fabrication pipeline of the metal-assisted chemical etching (MACE) method. The MACE approach offers a large-scale, densely packed silver (Ag) nanostructure on top of silicon nanowires (Si-NWs) with a large aspect ratio that significantly enhances the Raman signal due to localised surface plasmonic enhancement. The optimised SERS chips exhibited sensitivity down to 10-12M concentration of R6G molecule and detected reproducible Raman spectra of bacteria down to a concentration of 100 colony forming units (CFU)/ml, which is a thousand times lower than the clinical threshold of bacterial infections like UTI (105CFU/ml). A Siamese neural network model was used to classify SERS Raman spectra from bacteria specimens. The trained model identified 12 different bacterial species, including those which are causative agents for tuberculosis and urinary tract infection (UTI). Next, the SERS chips and another Siamese neural network model were used to differentiate antibiotic-resistant strains from susceptible strains ofE. coli. The enhancement offered by SERS chip enabled acquisitions of Raman spectra of bacteria directly in the synthetic urine by spiking the sample with only 103CFU/mlE. coli. Thus, the present study lays the ground for the identification and quantification of bacteria on SERS chips, thereby offering a potential future use for rapid, reproducible, label-free, and low limit detection of clinical pathogens.
A sensation for inflation: initial swim bladder inflation in larval zebrafish is mediated by the mechanosensory lateral line
Authors: Venuto Alexandra , Thibodeau-Beganny Stacey , Trapani Josef G. , Erickson Timothy
Published: January 2023

Larval zebrafish achieve neutral buoyancy by swimming up to the surface and taking in air through their mouths to inflate their swim bladders. We define this behavior as ‘surfacing’. Little is known about the sensory basis for this underappreciated behavior of larval fish. A strong candidate is the mechanosensory lateral line, a hair cell-based sensory system that detects hydrodynamic information from sources like water currents, predators, prey, and surface waves. However, a role for the lateral line in mediating initial inflation of the swim bladder has not been reported.

To explore the connection between the lateral line and surfacing, we utilized a genetic mutant (lhfpl5b-/-) that renders the zebrafish lateral line insensitive to mechanical stimuli. We observe that approximately half of these lateral line mutants over-inflate their swim bladders during initial inflation and become positively buoyant. Thus, we hypothesize that larval zebrafish use their lateral line to moderate interactions with the air-water interface during surfacing to regulate swim bladder inflation. To test the hypothesis that lateral line defects are responsible for swim bladder over-inflation, we show exogenous air is required for the hyperinflation phenotype and transgenic rescue of hair cell function restores normal inflation. We also find that chemical ablation of anterior lateral line hair cells in wild type larvae causes hyperinflation. Furthermore, we show that manipulation of lateral line sensory information results in abnormal inflation. Finally, we report spatial and temporal differences in the surfacing behavior between wild type and lateral line mutant larvae. In summary, we propose a novel sensory basis for achieving neutral buoyancy where larval zebrafish use their lateral line to sense the air-water interface and regulate initial swim bladder inflation.
Salmonellacancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity
Authors: Copland Alastair , Mackie Gillian M. , Scarfe Lisa , Lecky David A.J. , Gudgeon Nancy , McQuade Riahne , Ono Masahiro , Barthel Manja , Hardt Wolf-Dietrich , Ohno Hiroshi , Dimeloe Sarah , Bending David , Maslowski Kendle M.
Published: January 2023

Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours.Salmonella entericaTyphimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) reporter mice (Nr4a3-Tocky-Ifng-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic TILs exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced TCMformation. Modelling of T-cell–tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginaseansBreinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.
Myricetin protected against Aβ oligomer-induced synaptic impairment, mitochondrial function and oxidative stress in SH-SY5Y cells via ERK1/2/GSK-3β pathways
Authors: Wang Li , Tang Zhi , Deng Yuxin , Peng Yaqian , Xiao Yan , Xu Jianwei , Ni Ruiqing , Qi Xiaolan
Published: January 2023

Alzheimer’s disease is characterized by abnormal β-amyloid (Aβ) plaque accumulation, tau hyperphosphorylation, reactive oxidative stress, mitochondrial dysfunction and synaptic loss. Myricetin, a dietary flavonoid, has been shown to have neuroprotective effects in vitro and in vivo. Here, we aimed to elucidate the mechanism and pathways involved in myricetin’s protective effect on the toxicity induced by the Aβ42 oligomer. Neuronal SH-SY5Y cells were pretreated with myricetin before incubation with Aβ42 oligomer. The levels of pre- and postsynaptic proteins, mitochondrial division and fusion proteins, glycogen synthase kinase-3 β (GSK-3β) and extracellular regulated kinase (ERK) 1/2 were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well immunofluorescence staining for lipid peroxidation (4-HNE) and DNA oxidation (8-OHdG), were performed. We found that myricetin prevented Aβ42 oligomer-induced tau phosphorylation and the reduction in pre/postsynaptic proteins. In addition, myricetin reduced reactive oxygen species generation, lipid peroxidation, and DNA oxidation induced by the Aβ42 oligomer. Moreover, myricetin prevented the Aβ42 oligomer-induced reduction in mitochondrial fusion proteins (mitofusin-1, mitofusin-2), fission protein (dynamin-related protein 1) phosphorylation, and mitochondrial membrane potential via the associated GSK-3β and ERK 1/2 signaling pathways. In conclusion, this study provides new insight into the neuroprotective mechanism of myricetin against Aβ42 oligomer-induced toxicity.
Reactivation of the progenitor gene Trim71 enhances the mitotic and hair cell-forming potential of cochlear supporting cells
Authors: Li Xiao-Jun , Morgan Charles , Nadar-Ponniah Prathamesh T , Kolanus Waldemar , Doetzlhofer Angelika
Published: January 2023

Cochlear hair cell loss is a leading cause of deafness in humans. Neighboring supporting cells have some capacity to regenerate hair cells. However, their regenerative potential sharply declines as supporting cells undergo maturation (postnatal day 5 in mice). We recently reported that reactivation of the RNA-binding protein LIN28B restores the hair cell-regenerative potential of P5 cochlear supporting cells. Here, we identify the LIN28B targetTrim71as a novel and equally potent enhancer of supporting cell plasticity. TRIM71 is a critical regulator of stem cell behavior and cell reprogramming, however, its role in cell regeneration is poorly understood. Employing an organoid-based assay, we show that TRIM71 reactivation increases the mitotic and hair cell-forming potential of P5 cochlear supporting cells by facilitating their de-differentiation into progenitor-like cells. Our mechanistic work indicates that TRIM71’s RNA-binding activity is essential for such ability, and our transcriptomic analysis identifies gene modules that are linked to TRIM71 and LIN28B-mediated supporting cell reprogramming. Furthermore, our study uncovers that the TRIM71-LIN28B targetHmga2is essential for supporting cell self-renewal and hair cell formation.