bluuebunny/crossref_metadata_2025 huggingface dataset:
A clinical stage LMW-DS drug inhibits cell infection by coronaviruses and modulates reactive cytokine release from microglia
Authors: Logan Ann , Mazzon Michela , Bruce Lars , Barnes Nicholas M.
Published: September 2022

Most coronaviruses infect animals including bats, birds and mammals, which act as hosts and reservoirs for the viruses, but the viruses can sometimes move host species and infect humans. Coronoviruses were first identified as human pathogens in the 1960s and now there are seven types known to infect humans. Whilst four of these types cause mild-to-moderate respiratory disease, the other three may cause more severe and possibly even fatal disease in vulnerable individuals particularly, with the most recent SARS-CoV-2 pandemic being associated with severe acute respiratory syndrome (SARS) in many infected people. The aim of the present study was to evaluate the potential of a unique low molecular weight dextran sulphate (LMW-DS) clinical stage drug, ILB®, to inhibit infection of human cells by the NL63 coronavirus assessed by immunofluorescence of viral particles, and also to see if the drug directly blocked the interaction of the SARS-CoV-2 viral spike protein with the ACE2 receptor. Furthermore, we evaluated if ILB® could modulate the downstream consequences of viral infection including the reactive cytokine release from human microglia induced by various SARS-CoV-2 variant spike proteins. We demonstrated that ILB® blocked ACE2:spike protein interaction and inhibited coronaviral infection. ILB® also attenuated the omicron-induced release of pro-inflammatory cytokines, including TNFα, from human microglia, indicating control of post-viral neuroinflammation. In conclusion, given the safety profile of ILB® established in a number of Phase I and Phase II clinical trials, these results highlight the potential of ILB® to treat patients infected with coronaviruses to both limit infectivity and attenuate the progression to severe disease. There is now an opportunity to translate these findings quickly by the clinical investigation of drug efficacy.
PAMR1 negatively impacts cell proliferation and migration of Human Colon Cancer HT29 Cell Line
Authors: Haymour Layla , Chaunavel Alain , Assaf Mona Diab , Maftah Abderrahman , Legardinier Sébastien
Published: September 2022

Colorectal cancer (CRC) is becoming one of the most prevalent cancers worldwide. Among cancers, it ranks the third place in terms of incidence and the second in terms of mortality. Even though immunological test allows fast and easy diagnostic method, there is no specific and reliable methods for early detection of CRC. Despite different treatments, high risk of re-occurrence is associated with advanced and metastatic CRC stages. An exhaustive knowledge on specific biomarkers or molecular actors involved in CRC could help to eradicate tumors or limit cancer recurrence. In this study, we focused on PAMR1 (Peptidase Domain Containing Associated with Muscle Regeneration 1), which is already considered as a tumor suppressor in breast and cervical cancers.In silicoanalysis of RNASeq data showed that PAMR1 was significantly downregulated in CRC tissues compared to their adjacent normal ones, as well as in cervical cancer. Our analysis showed that this downregulation, probably due to promoter hypermethylation, such as in breast cancer tissues, appeared in the four cancer stages as early as the first stage. In consistency within silicoanalyses, the expression of PAMR1 was found to be lower at the transcript and protein levels in CRC tissue samples compared to normal ones, as well as in different CRC cell lines (HCT116, HT29, and SW620) compared to normal colon cell line (CCD841CoN). To understand the role of PAMR1 in CRC cancer, recombinant purified PAMR1 or concentrated secretome from CHO overexpressing PAMR1 were used to exogenously treat CRC cell lines with a focus on HT-29 cells as well as Hela cervical cancer cell line known to be sensitive to PAMR1. Transient or stable transfections were also performed to determine the impact of PAMR1 overexpression in HT29 and/or HeLa cells. In this study, we finally showed that presence of PAMR1 could reduce both cell proliferation and cell migration with a positive correlation between these biological effects and PAMR1’s quantity. This implies that PAMR1 expresses anti-proliferative and anti-migrative effects in CRC. Further studies to be done in order to confirm the tumor suppressive role of PAMR1 in CRC.
Statistical Learning of Distractor Suppression Down-regulates Pre-Stimulus Neural Excitability in Early Visual Cortex
Authors: Ferrante Oscar , Zhigalov Alexander , Hickey Clayton , Jensen Ole
Published: September 2022

Visual attention is highly influenced by past experiences. Recent behavioral research has shown that expectations about the spatial location of distractors within a search array are implicitly learned, with expected distractors becoming less interfering. Little is known about the neural mechanism supporting this form of statistical learning. Here we used magnetoencephalography (MEG) to measure human brain activity to test whether proactive mechanisms are involved in the statistical learning of distractor locations. Specifically, we used a new technique called rapid invisible frequency tagging (RIFT) to assess neural excitability in early visual cortex during statistical learning of distractor suppression, while concurrently investigating the modulation of posterior alpha-band activity (8-12 Hz). Male and female human participants performed a visual search task in which a target was occasionally presented alongside a color-singleton distractor. Unbeknown to the participants, the distracting stimuli were presented with different probabilities across the two hemifields. RIFT analysis showed that early visual cortex exhibited reduced neural excitability in the pre-stimulus interval at retinotopic locations associated with higher distractor probabilities. In contrast, we did not find any evidence of expectation-driven distractor suppression in alpha-band activity. These findings indicate that proactive mechanisms of attention are involved in predictive distractor suppression and that these mechanisms are associated with altered neural excitability in early visual cortex. Moreover, our findings indicate that RIFT and alpha-band activity might subtend different and possibly independent attentional mechanisms.
DELLA proteins regulate spore germination and reproductive development inPhyscomitrium patens
Authors: Phokas Alexandros , Meyberg Rabea , Briones-Moreno Asier , Hernandez-Garcia Jorge , Wadsworth Panida T. , Vesty Eleanor F. , Blazquez Miguel A. , Rensing Stefan A. , Coates Juliet C.
Published: September 2022

Proteins of the DELLA family integrate environmental signals to regulate growth and development throughout the plant kingdom. Plants expressing non-degradable DELLA proteins underpinned the development of high-yielding ‘Green Revolution’ dwarf crop varieties in the 1960s. In vascular plants, DELLAs are regulated by gibberellins, diterpenoid plant hormones. How DELLA protein function has changed during land plant evolution is not fully understood.

We have examined the function and interactions of DELLA proteins in the mossPhyscomitrium(Physcomitrella)patens, in the sister group of vascular plants (Bryophytes).

PpDELLAs do not undergo the same regulation as flowering plant DELLAs.PpDELLAs are not degraded by diterpenes, do not interact with GID1 gibberellin receptor proteins and do not participate in responses to abiotic stress.PpDELLAs do share a function with vascular plant DELLAs during reproductive development.PpDELLAs also regulate spore germination.PpDELLAs interact with moss-specific photoreceptors although a function forPpDELLAs in light responses was not detected.PpDELLAs likely act as ‘hubs’ for transcriptional regulation similarly to their homologues across the plant kingdom.

Taken together, these data demonstrate thatPpDELLA proteins share some biological functions with DELLAs in flowering plants, but other DELLA functions and regulation evolved independently in both plant lineages.
Shifts in isoform usage underlie transcriptional differences in regulatory T cells in type 1 diabetes
Authors: Newman Jeremy R. B. , Long S. Alice , Speake Cate , Greenbaum Carla J. , Cerosaletti Karen , Rich Stephen S. , Onengut-Gumuscu Suna , McIntyre Lauren M. , Buckner Jane H. , Concannon Patrick
Published: September 2022

Genome-wide association studies have identified numerous loci with allelic associations to Type 1 Diabetes (T1D) risk. Most disease-associated variants are enriched in regulatory sequences active in lymphoid cell types, suggesting that lymphocyte gene expression is altered in T1D. We assayed gene expression between T1D cases and healthy controls in two autoimmunity-relevant lymphocyte cell types, memory CD4+/CD25+ T-regulatory cells (Treg) and memory CD4+/CD25- T-cells, using a splicing event-based approach to characterize tissue-specific transcriptomes. Limited differences in isoform usage between T1D cases and controls were observed in memory CD4+/CD25- T-cells. In Tregs, 553 genes demonstrated differences in isoform usage between cases and controls, particularly RNA recognition and splicing factor genes. Many of these genes are regulated by the variable inclusion of exons that can trigger nonsense mediated decay. Our results suggest that dysregulation of gene expression, through shifts in alternative splicing in Tregs, contributes to T1D etiology.
Spectrin forms a periodic cytoskeleton within the epidermis to preserve axonal integrity
Authors: Coakley Sean , Bonacossa-Pereira Igor , Hilliard Massimo A.
Published: September 2022

Spectrins are highly conserved molecules that form a distinct membrane associated periodic scaffold within axons thought to provide mechanical resilience. In C. elegans, UNC-70/ß-Spectrin also functions outside the nervous system, within the epidermis, to maintain the integrity of sensory neurons. The precise molecular organization and cellular mechanisms that mediate this protection are unknown. Here, using 3D-structured illumination microscopy, we show that within the epidermis spectrins form a crescent-shaped scaffold with a periodicity of ∼ 200 nm that embraces adjacent axons. This epidermal spectrin scaffold is induced by developing axons and reformed during axonal regeneration, and creates a “molecular imprint” of the adjacent nervous system. Disruption of this epidermal scaffold causes widespread axonal damage in sensory and motor neurons. These findings reveal the existence of a distinct and periodic spectrin framework within the epidermis that is molded by the developing nervous system and is necessary to protect it from mechanical damage.

Teaser

Spectrin forms a periodic scaffold in the epidermis that protects axons from damage.
Optimal Stimulation Sites and Networks for Deep Brain Stimulation of the Fornix in Alzheimer’s Disease
Authors: Ríos Ana Sofía , Oxenford Simón , Neudorfer Clemens , Butenko Konstantin , Li Ningfei , Rajamani Nanditha , Boutet Alexandre , Elias Gavin J.B. , Germann Jurgen , Loh Aaron , Deeb Wissam , Wang Fuyixue , Setsompop Kawin , Salvato Bryan , Almeida Leonardo , Foote Kelly D. , Amaral Robert , Rosenberg Paul B. , Tang-Wai David F. , Wolk David A. , Burke Anna D. , Salloway Stephen , Sabbagh Marwan N. , Chakravarty M. Mallar , Smith Gwenn S. , Lyketsos Constantine G. , Okun Michael S. , Anderson William S. , Mari Zoltan , Ponce Francisco A. , Lozano Andres M. , Horn Andreas
Published: September 2022

Deep brain stimulation (DBS) to the fornix is an investigational treatment option for patients with mild Alzheimer’s Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. One reason could be variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we analyzed a multi-center cohort of 46 patients with DBS to the fornix. Using normative structural and functional connectivity data, we demonstrate that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.45, p = 0.031). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.33, p = 0.016). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.38, p = 0.006). Findings were robust to multiple cross-validation designs and may now define an optimal network target which could subsequently guide refinement of DBS surgery and programming.
The risk of myocardial ischemia in patients with Kawasaki Disease: Insights from patient-specific simulations of coronary hemodynamics
Authors: Menon Karthik , Seo Jongmin , Kahn Andrew M. , Burns Jane C. , Marsden Alison L.
Published: September 2022

Background

Pediatric patients with aneurysms due to Kawasaki disease require life-long and uninterrupted cardiology follow-up. Current AHA guidelines for risk stratification and long-term management are based primarily on maximal coronary artery luminal dimensions, normalized as Z-scores. Hemodynamic and functional significance of coronary arteries aneurysms on myocardial ischemic risk is not well studied.

Methods

We retrospectively studied a cohort of 15 patients who underwent coronary CT angiography imaging. We constructed patient-specific anatomic models from CT images and performed computational hemodynamic simulations incorporating pulsatile flow and deformable arterial walls. Simulation parameters were tuned to match patient-specific arterial pressure, ejection fraction, and cardiac output. From simulation results, we evaluated hemodynamic iscmemic risk metrics, including fractional flow reserve, wall shear stress, and residence time, in 153 coronary arteries.

Results

Fractional flow reserve (FFR) showed a weak correlation with aneurysm Z-scores. The slope of FFR significantly increased distal to the lumen narrowing at the end of aneurysms. Ischemic risk does not correlate well with aneurysm diameter measured by Z-score, but correlates much better with the ratio of maximum lumen diameter within aneurysms to minimum lumen diameter distal to aneurysms. Wall shear stress also correlates better with this diameter ratio, while residence can be stratified via Z-score.

Conclusions

Z-score alone is not a good indicator of abnormal FFR. Although FFR immediately distal to aneurysms is not critical, it starts to drop more rapidly distal to aneurysms and can therefore present an elevated risk of myocardial ischemia. Maximum-to-minimum lumen diameter is a good proxy for ischemic risk.
Comparison of Peripheral Blood Oxygen Saturation Measurements Using Pulse Oximetry at Three Anatomical Sites on Sleep Patients
Authors: Strickland Kellie R. , Brown Chris J. , Wilks Leigh , Dunn Peter K. , Holmes Mark A.
Published: September 2022

Background and Objective

Accurate measurements of peripheral blood oxygen saturation (SpO2) are important in evaluating sleep patients with frequent desaturations due to pathological breathing events. This project compared synchronised SpO2measurements at the finger, forehead and toe of patients undergoing Type 1 polysomnography (PSG) to evaluate potential SpO2variability across the sites.

Methods

Pulse oximetry SpO2measurements were simultaneously and continuously recorded for 41 sleep patients at the finger, forehead and toe, and synchronised with PSG data. Recordings were scored for desaturations of ≤ 3% (peak to trough, lasting ≤10 seconds), signal dropouts, and artefact occurrences. Forehead and toe SpO2measurements were compared against the finger as the standard PSG oximetry site.

Results

Differences between anatomical sites for mean SpO2, mean number of SpO2desaturations per hour, and time spent below an SpO2level of 95% during total sleep time were significant (P< 0.01). The forehead pulse oximeter had the highest mean SpO2, least number of SpO2desaturations per hour, and experienced the least number of artefact occurrences. Dropouts were lowest for the forehead and toe pulse oximeters.

Conclusion

Differences between SpO2measurements, dropouts and artefact occurrences at the finger, forehead and toe may have diagnostic and prognostic implications for sleep patients. The differences in SpO2 measurements may be attributed to variability in perfusion of the extremities and core during sudden oscillating blood pressure changes associated with breathing events. Further research is required to determine which anatomical site correlates closest to arterial oxygenation for pulse oximetry in sleep patients.

BRIEF SUMMARY

Study rationale

An absence of research investigating anatomical site location for pulse oximetry during overnight polysomnography exists. Our study was performed to fill this gap, as accurate pulse oximetry measurements are key for the diagnosis, treatment and monitoring of sleep patients; a patient cohort where SpO2desaturations are recurrent.

Study impact

Our findings demonstrate there are significant differences between finger, forehead and toe pulse oximetry measurements, particularly SpO2desaturations per hour, which may have diagnostic and clinical implications. This research is applicable and important to not only sleep physicians and scientists, but also other disciplines where continuous SpO2monitoring is required.
Annotating off-label drug usage from unconventional sources
Authors: Avram Sorin , Halip Liliana , Curpan Ramona , Borota Ana , Bora Alina , Oprea Tudor I
Published: September 2022

Physicians have the freedom to prescribe medicines outside the list of approved indications, to treat mild to life-threatening clinical conditions and diseases, particularly when conventional treatments fail or are lacking. Off-label drug usage is more frequently observed in specific populations not often represented in clinical trials, e.g., pediatric, geriatric, or pregnant patients. Despite conflicting reports on patient safety, exploring alternative treatment options in medical practice promotes innovation and extends the applicability of current medicines. This process can be significantly improved by properly documenting and discussing off-label usage. This paper aims to document off-label uses discussed in less conventional sources, such as the r/medicine Reddit subforum. We identified 66 “Reddit off-label uses” (ROLUs) not captured in our reference database, DrugCentral (https://drugcentral.org/), for a set of 40 drugs. These drugs are associated with 209 on-label drug indications (INDs) and 58 “non-Reddit” off-label uses (NROLUs). Most of these drugs are relatively ‘old’ (approved before 2000) and act on the nervous system, many with psychiatric applications. However, ROLUs are distinct from INDs and NROLUs. An automated scientific literature query showed that 90% of the ROLUs are linked to 4 scientific publications or more, with 80% linked to at least 10. A further search in the clinical trials database revealed 46 ROLUs mentioned; 39 are in phase 3 trials. These results indicate that most off-label uses discussed on the Reddit forum are supported by scientific evidence. We conclude that medical social media channels can provide a valuable source of alternative drug applications and should be scientifically explored and evaluated in the future.
Effects of a mindfulness-based intervention and a health self-management programme on psychological well-being in older adults with subjective cognitive decline: Secondary analyses from the SCD-Well randomised clinical trial
Authors: Schlosser Marco , Demnitz-King Harriet , Barnhofer Thorsten , Collette Fabienne , Gonneaud Julie , Chételat Gaël , Jessen Frank , Kliegel Matthias , Klimecki Olga M. , Lutz Antoine , Marchant Natalie L. ,   The Medit-Ageing Research Group
Published: September 2022

Objectives

Older adults with subjective cognitive decline (SCD) recruited from memory clinics have an increased risk of developing dementia and regularly experience reduced psychological well-being related to memory concerns and fear of dementia. Research on improving well-being in SCD is limited and lacks non-pharmacological approaches. We investigated whether mindfulness-based and health education interventions can enhance well-being in SCD.

Methods

The SCD-Well trial (ClinicalTrials.gov: NCT03005652) randomised 147 older adults with SCD to an 8-week caring mindfulness-based approach for seniors (CMBAS) or an active comparator (health self-management programme [HSMP]). Well-being was assessed at baseline, post-intervention, and 6-month post-randomisation using the Psychological Well-being Scale (PWBS), the World Health Organisation’s Quality of Life (QoL) Assessment psychological subscale, and composites capturing meditation-based well-being dimensions of awareness, connection, and insight. Mixed effects models were used to assess between- and within-group differences in change.

Results

CMBAS was superior to HSMP on changes in connection at post-intervention. Within both groups, PWBS total scores, psychological QoL, and composite scores did not increase. Exploratory analyses indicated increases in PWBS autonomy at post-intervention in both groups.

Conclusion

Two non-pharmacological interventions were associated with only limited effects on psychological well-being in SCD. Longer intervention studies with waitlist/retest control groups are needed to assess if our findings reflect intervention brevity and/or minimal base rate changes in well-being.
Deep Brain Stimulation Normalizes Amygdala Responsivity in Treatment-Resistant Depression
Authors: Runia N. , Bergfeld I.O. , de Kwaasteniet B.P. , Luigjes J. , van Laarhoven J. , Notten P. , Beute G. , van den Munckhof P. , Schuurman P.R. , Denys D.A.J.P. , van Wingen G.A.
Published: September 2022

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is a promising intervention for treatment-resistant depression (TRD). However, the working mechanisms of vALIC DBS in TRD remain largely unexplored. As major depressive disorder has been associated with aberrant amygdala functioning, we investigated whether vALIC DBS affects amygdala responsivity and functional connectivity. To investigate the long-term effects of DBS, eleven patients with TRD performed an implicit emotional face viewing paradigm during functional magnetic resonance imaging (fMRI) before DBS surgery and after DBS parameter optimization. Sixteen matched healthy controls performed the fMRI paradigm at two time points to control for test-retest effects. To investigate the short-term effects of DBS de-activation after parameter optimization, thirteen patients additionally performed the fMRI paradigm after double-blind periods of active and sham stimulation. Results showed that TRD patients had decreased right amygdala responsivity compared to healthy controls at baseline. Long-term vALIC DBS normalized right amygdala responsivity, which was associated with faster reaction times. Furthermore, active compared to sham DBS increased amygdala connectivity with sensorimotor and cingulate cortices. These results suggest that vALIC DBS may relieve emotional blunting and depression by restoring amygdala responsivity and behavioral vigilance.
Dynamics of SARS-CoV-2 seroassay sensitivity: a systematic review and modeling study
Authors: Owusu-Boaitey Nana , Russell Timothy W. , Meyerowitz-Katz Gideon , Levin Andrew T. , Herrera-Esposito Daniel
Published: September 2022

Background

Serological surveys have been the gold standard to estimate the numbers of SARS-CoV-2 infections, epidemic dynamics, and disease severity. Serological assays have decaying sensitivity with time that can bias their results, but there is a lack of guidelines to account for this phenomenon for SARS-CoV-2.

Aim

Our goal is to assess the sensitivity decay of seroassays for detecting SARS-CoV-2 infections, the dependence of this decay on assay characteristics, and to provide a simple method to correct for this phenomenon.

Methods

We performed a systematic review and meta-analysis of SARS-CoV-2 serology studies. We included studies testing previously diagnosed individuals, without any SARS-CoV-2 vaccines, and excluded studies of cohorts highly unrepresentative of the general population (e.g. hospitalised patients).

Results

Of the 488 screened studies, 76 studies reporting on 50 different seroassays were included in the analysis. Sensitivity decay depends strongly on the antigen and the analytic technique used by the assay, with average sensitivities ranging between 26% and 98% at 6 months after infection, depending on assay characteristics. We find that a third of the included assays depart considerably from manufacturer specifications after 6 months.

Conclusions

Seroassay sensitivity decay depends on assay characteristics, and for some types of assays it can make manufacturer specifications highly unreliable. We provide a tool to correct for this phenomenon, and to assess the risk of decay for a given assay. Our analysis can guide the design and interpretation of serosurveys for SARS-CoV-2 and other pathogens, and quantify systematic biases in the existing serology literature.
Postpartum estrogen withdrawal induces deficits in affective behaviors and increases ΔFosB in D1 and D2 neurons in the nucleus accumbens core in mice
Authors: Foster William B. , Beach Katherine F. , Carson Paige F. , Harris Kagan C. , Alonso Brandon L. , Costa Leo T. , Simamora Roy C. , Corbin Jaclyn E. , Hoag Keegan F. , Mercado Sophia I. , Bernhard Anya G. , Leung Cary H. , Nestler Eric J. , Been Laura E.
Published: September 2022

In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an “estrogen withdrawal” state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estrogen withdrawal on several behavioral measures of anxiety and motivation. We found that estrogen withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estrogen withdrawal. In the social motivation test, estrogen withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of ΔFosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher ΔFosB expression in the nucleus accumbens core. Using transgenic reporter mice, we found that this increase in ΔFosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases ΔFosB in the NAc core.
Synergising single-cell resolution and 4sU labelling boosts inference of transcriptional bursting
Authors: Edwards David M , Davies Philip , Hebenstreit Daniel
Published: September 2022

Despite the recent rise of RNA-seq datasets combining single-cell (sc) resolution with 4-thiouridine (4sU) labelling, analytical methods exploiting their power to dissect transcriptional bursting are lacking. Here, we present a mathematical model and Bayesian inference implementation to facilitate genome-wide joint parameter estimation and confidence quantification. We demonstrate that, unlike conventional scRNA-seq, 4sU scRNA-seq resolves temporal parameters and furthermore boosts inference of dimensionless parameters via a synergy between single-cell resolution and 4sU labelling. We applied our method to published 4sU scRNA-seq data and linked with ChIP-seq data, uncovering previously obscured associations between different parameters and histone modifications.
Adaptive encoding speed in working memory
Authors: de Jong Joost , van Rijn Hedderik , Akyurek Elkan
Published: September 2022

Humans can adapt when complex patterns unfold at a faster or slower pace, for instance when remembering a grocery list that is dictated at an increasingly fast pace. Integrating information over such timescales crucially depends on working memory, but although recent findings have shown that working memory capacity can be flexibly adapted, such adaptations have not yet been demonstrated for encoding speed. In a series of experiments, we found that young adults encoded at a faster rate when they were adapted to overall and recent rate of incoming information. Interestingly, our participants were unable to use explicit cues to speed up encoding, even though these cues were objectively more informative than statistical information. Our findings suggest that adaptive tuning of encoding speed in working memory is a fundamental but largely implicit mechanism underlying our ability to keep up with the pace of our surroundings.

Significance Statement

Humans can store information very quickly. For instance, when we hear someone speak twice as fast as normal, we can still follow quite well. How is this possible? We hypothesized that when humans expect limited time to store a piece of information (e.g. when listening to a sped-up podcast) they would ideally store that information more quickly before it’s gone. Indeed, we found that young adults encoded more information per second when they implicitly expect that they have little time to do so. However, they were unable to use explicit cues about how much time they have. It seems that young adults can, at least implicitly, tune the pace at which they store information.
A genome-wide CRISPR functional survey of the human phagocytosis molecular machinery
Authors: Essletzbichler Patrick , Sedlyarov Vitaly , Frommelt Fabian , Soulat Didier , Heinz Leonhard X , Stefanovic Adrijana , Neumayer Benedikt , Superti-Furga Giulio
Published: September 2022

Phagocytosis, the process of engulfing large particles by cells, is a multilayered biological activity driving tissue clearance and host defense. Dysregulation of phagocytosis is connected to autoimmunity, accumulation of toxic disease proteins, and increased risks for infections. Despite its importance and multiple roles, we lack a full understanding of the cellular machinery involved in executing and regulating the process, including the coordination with other cellular events. To create a functional map in human cells, we performed a reporter- and FACS-based genome-wide CRISPR/Cas9 knock-out screen that identified 716 genes. Mapping the gene hits to a comprehensive protein-protein interaction network annotated for functional cellular processes, allowed to highlight those protein complexes identified multiple times, to identify missing components of the cellular phagocytosis network, and to suggest functional partition among complexes. We validate complexes known to be involved, such as the Arp2/3 complex, the vacuolar-ATPase-Rag machinery, and the Wave-2 complex, as well as processes previously not or only poorly associated with phagocytosis. Among the novel, phagocytosis-relevant cellular functions validated are the oligosaccharyltransferase complex (MAGT1/SLC58A1, DDOST, STT3B, and RPN2) as well as the hypusine pathway (eIF5A, DHPS, and DOHH). Overall, our network of phagocytosis regulators and effectors maps elements of cargo uptake, cargo shuffling and cargo biotransformation through the cell, providing a valuable resource for the identification of potential novel drivers for diseases of the endo-lysosomal system. We further propose that our approach of mining and integrating publicly available protein-protein interaction data with datasets derived from reporter-based genome-wide screens offers a broadly applicable way to functionally map biological processes onto the molecular machinery of the cell.

Summary blurb

The validation and interpretation of a FACS reporter-based genome-wide CRISPR/Cas9 knock-out screen through protein-protein interaction data yields a comprehensive view of the molecular network regulating and executing phagocytosis in human cells.
Genomic and ecologic characteristics of the airway microbial-mucosal complex
Authors: Cuthbertson Leah , Löber Ulrike , Ish-Horowicz Jonathan S. , McBrien Claire N. , Churchward Colin , Parker Jeremy C. , Olanipekun Michael T. , Burke Conor , O’Carroll Orla , Faul John , Davies Gwyneth A. , Lewis Keir E. , Hopkin Julian M. , Creaser-Thomas Joy , Goshal Robin , Chung Kian Fan , Piatek Stefan , Willis-Owen Saffron A.G. , Bartolomaeus Theda U. P. , Birkner Till , Dwyer Sarah , Kumar Nitin , Turek Elena M. , Musk A. William , Hui Jenni , Hunter Michael , James Alan , Dumas Marc-Emmanuel , Filippi Sarah , Cox Michael J. , Lawley Trevor D. , Forslund Sofia K. , Moffatt Miriam F. , Cookson William O.C.
Published: September 2022

Summary paragraph

Lung diseases due to infection and dysbiosis affect hundreds of millions of people world-wide1-4. Microbial communities at the airway mucosal barrier are conserved and highly ordered5, reflecting symbiosis and co-evolution with human host factors6. Freed of selection to digest nutrients for the host, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the results of the first systematic culture and whole-genome sequencing of the principal airway bacterial species, identifying abundant novel organisms within the genera Streptococcus, Pauljensenia, Neisseria and Gemella. Bacterial genomes were enriched for genes encoding antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. RNA-targeting CRISPR elements in some taxa suggest the potential to prevent or treat specific viral infections. Homologues of human RO60 present in Neisseria spp. provide a possible respiratory primer for autoimmunity in systemic lupus erythematosus (SLE) and Sjögren syndrome. We interpret the structure and biogeography of airway microbial communities from clinical surveys in the context of whole-genome content, identifying features of airway dysbiosis that may presage breakdown of homeostasis during acute attacks of asthma and chronic obstructive pulmonary disease (COPD). We match the gene content of isolates to human transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways that can sustain host interactions with the microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosal immunity in lung diseases of global significance.
Extraction and characterization of cellulose from invasive weeds from central Nepal: A potential prospect of environmental management
Authors: Dhakal Samyog , Tiwari Achyut , Adhikari Archana , Shrestha Shyam Kumar , Adhikari Bikash
Published: September 2022

The cellulose is made up of long chains of polysaccharide of glucose molecules. Microfibrils are formed when numerous hydrogen-bonded cellulose chains unite, they are extremely stiff and contribute to physical stability, due to this general ability of forming these microfibrils to form long chains, cellulose is an ideal molecule for the manufacturing of packaging materials and bioplastics. On the other hand, Invasive plant species are one of the major constituents for environmental degradation and its application seems outmost. The main purpose of this study is to extract and identify the composition of cellulose fiber and characterize the fiber of invasive plant species that could be used as a replacement for plastics and textiles in some cases. In this study, Cellulose was isolated from 6 invasive species collected in Nepal’s Ramechhap district using various techniques, the composition of the fiber was identified using AOAC method 973.18, ASTM method D1106-96 and ASTM method E1755-01 and characterized using FTIR spectroscopy with weight analyses. Acid hydrolysis, chlorination, alkaline extraction, and bleaching were among the chemical methods adopted. In all of the samples, there were two primary absorbance peaks. The first occurred at low wavelengths in the 700−1,800 cm−1 range, while the second occurred at higher wavelengths in the 2,700–3,500 cm−1 range.The percentage of lignin within the final sample was determined in the range of 4.4-3.1% and the percentage yield of cellulose was determined within the range of 78-62%.The study shows that the cellulose can be extracted from the taken invasive plant species and can be used for further applications.
CTCF is a DNA-tension-dependent barrier to cohesin-mediated DNA loop extrusion
Authors: Davidson Iain F. , Barth Roman , Zaczek Maciej , van der Torre Jaco , Tang Wen , Nagasaka Kota , Janissen Richard , Kerssemakers Jacob , Wutz Gordana , Dekker Cees , Peters Jan-Michael
Published: September 2022

In eukaryotes, genomic DNA is extruded into loops by cohesin1. By restraining this process, the DNA-binding protein CTCF generates topologically associating domains (TADs)2-4 that play key roles in gene regulation and recombination during development and disease1,5-8. How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unknown9. To address these questions, we visualize interactions of single CTCF and cohesin molecules on DNA in vitro. We show that CTCF is sufficient to block diffusing cohesin, possibly reflecting how cohesive cohesin accumulates at TAD boundaries, as well as to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted, but unexpectedly is dependent on DNA tension. Moreover, CTCF regulates cohesin’s loop extrusion activity by changing its direction and by inducing loop shrinkage. Our data indicate that CTCF is not, as previously assumed, simply a barrier to cohesin-mediated loop extrusion but is an active regulator of this process, where the permeability of TAD boundaries can be modulated by DNA tension. These results reveal mechanistic principles of how CTCF controls loop extrusion and genome architecture.
Researchers and their experimental models: A pilot survey
Authors: Del Pace Lorenzo , Viviani Laura , Straccia Marco
Published: September 2022

A significant debate is ongoing on the effectiveness of animal experimentation due to the increasing reports of failure in the translation of results from preclinical animal experiments to human patients. Scientific, ethical, social and economic considerations linked to the use of animals raise concerns in a variety of societal contributors (regulators, policy makers, non-governmental organisations, industry, etc.).

The aim of this study was to record researchers’ voice about their vision on this science evolution, to reconstruct as truthful as possible an image of the reality of health and life science research, by using a key instrument in the hands of the researcher: the experimental models.

Hence, we surveyed European-based health and life sciences researchers, to reconstruct and decipher the varying orientations and opinions of this community over these large transformations. In the interest of advancing the public debate and more accurately guide the policy of research, it is important that policy makers, society, scientists and all stakeholders (1) mature as comprehensive as possible an understanding of the researchers perspectives on the selection and establishment of the experimental models, and (2) publicly share research community opinions, regarding the external factors influencing their professional work. Our results highlighted a general homogeneity of answers from the 117 respondents. However some discrepancies on specific key issues and topics were registered in the subgroups. These recorded divergent views might prove useful to research policy makers and regulators to calibrate their agenda and shape the future of the European health and life science research.
Attentional enhancement of tracked stimuli in early visual cortex has limited capacity
Authors: Adamian Nika , Andersen Søren. K.
Published: September 2022

Keeping track of the location of multiple simultaneously moving objects is one of the well documented functions of visual spatial attention. However, the mechanism of attentional selection that supports continuous tracking of several items is unclear. In particular, it has been proposed that target selection in early visual cortex occurs in parallel, with tracking errors arising due to attentional limitations at later processing stages. Here we examine whether, instead, total attentional capacity for enhancement of early visual processing of tracked targets is shared between all attended stimuli. If the magnitude of attentional facilitation of multiple tracked targets was a key limiting factor of tracking ability, then one should expect it to drop systematically with increasing set-size of tracked targets. Human observers (male and female) were instructed to track two, four, or six moving objects among a pool of identical distractors. Steady-state visual evoked potentials (SSVEPs) recorded during the tracking period revealed that the processing of tracked targets was consistently amplified compared to the processing of the distractors. The magnitude of this amplification decreased with increasing set size, and at lateral occipital electrodes it closely followed inverse proportionality to the number of tracked items, suggesting that limited attentional resources must be shared among the tracked stimuli. Accordingly, the magnitude of attentional facilitation predicted the behavioural outcome at the end of the trial. Together, these findings demonstrate that the limitations of multiple object tracking across set-sizes stem from the limitations of top-down selective attention already at the early stages of visual processing.

Significance statement

The ability to selectively attend to relevant features or objects is the key to flexibility of perception and action in the continuously changing environment. This ability is demonstrated in the Multiple Object Tracking task where observers monitor multiple independently moving objects at different locations in the visual field. The role of early attentional enhancement in tracking was previously acknowledged in the literature, however, the limitations on tracking were thought to arise during later stages of processing. Here, we demonstrate that the strength of attentional facilitation depends on the number of tracked objects and predicts successful tracking performance. Thus, it is the limitations of attentional enhancement at the early stages of visual processing that determine behavioral performance limits.
RTK signalling promotes epithelial columnar cell shape and apical junction maintenance in human lung progenitor cells
Authors: Liu Shuyu , Sun Dawei , Butler Richard , Rawlins Emma L.
Published: September 2022

Multipotent epithelial progenitor cells can be expanded from human embryonic lungs as organoids. and maintained in a self-renewing state using a defined medium. The organoid cells are columnar, resembling the cell morphology of the developing lung tip epithelium in vivo. Cell shape dynamics and fate are tightly coordinated during development. We therefore used the organoid system to identify signalling pathways that maintain the columnar shape of human lung tip progenitors. We found that EGF, FGF7 and FGF10 have distinct functions in lung tip progenitors. FGF7 activates MAPK/ERK and PI3K/AKT signalling and is sufficient to promote columnar cell shape in primary tip progenitors. Inhibitor experiments show that MAPK/ERK and PI3K/AKT signalling are key downstream pathways, regulating cell proliferation, columnar cell shape and cell junctions. We identified integrin signalling as a key pathway downstream of MAPK/ERK in the tip progenitors; disrupting integrin alters polarity, cell adhesion and tight junction assembly. By contrast, stimulation with FGF10 or EGF alone is not sufficient to maintain organoid columnar cell shape. This study employs organoids to provide insight into the cellular mechanisms regulating human lung development.

Summary statement

RTK signalling activated MAPK/ERK and PI3K/AKT signalling regulates the shape and junctional structure of human lung epithelial progenitor cells during branching.
Multiscale assessment of oviposition habitat associations and implications for management in the spotted lanternfly (Lycorma delicatula), an emerging invasive pest
Authors: Ramirez Victoria A. , De Bona Sebastiano , Helmus Matthew R. , Behm Jocelyn E.
Published: September 2022

Control of incipient invaders—established invasive species in the early stages of spreading— can be inhibited by incomplete knowledge of the species’ habitat use. By identifying consistent habitat associations for incipient invaders early, control efforts can be more effective. Yet, because habitat associations are the result of multiscale processes, approaches are needed for integrating data collected across scales to identify them.

We employed a hierarchical, multiscale approach to identify oviposition habitat associations in the spotted lanternfly (Lycorma delicatula) an incipient invasive species of high concern in the United States. We targeted the oviposition habitat spatial scales most likely to be used by lanternflies and the spatial scales of explanatory environmental variables most easily used by managers to locate egg masses to control. We explored whether habitat associations exist for oviposition habitat use and how well habitat use is explained by the duration sites have been invaded. Finally, because habitat associations are likely driven by fitness, we determined if the use of any habitat types were associated with higher fitness as measured by the number of eggs per egg mass (i.e., fecundity).

Spotted lanternflies exhibited oviposition habitat associations at the landscape, site, and tree scales. Overall, lanternflies oviposited more frequently at sites and on trees with low canopy cover in the surrounding landscape, on trees from the Acer genus, and in the crowns of larger trees beyond the reach of managers without special equipment. The duration a site had been invaded had opposing effects at the site and tree scales which indicates the need for scale-dependent management approaches.

Despite the consistent habitat associations identified, no environmental variables explained variation in lanternfly fecundity, indicating more work is needed to identify environmental drivers of spotted lanternfly fitness.

Synthesis and applications. Our results indicate a multiscale approach is needed for spotted lanternfly control with unique strategies for locating egg masses at sites and on trees that vary in invasion duration. Additionally, our results suggest that multiscale investigations of habitat associations would likely inform the control of other invasive species as well.
A conserved glutathione binding site in poliovirus is a target for antivirals and vaccine stabilisation
Authors: Bahar Mohammad W. , Nasta Veronica , Fox Helen , Sherry Lee , Grehan Keith , Porta Claudine , Macadam Andrew J. , Stonehouse Nicola J. , Rowlands David J. , Fry Elizabeth E. , Stuart David I.
Published: September 2022

Strategies to prevent the recurrence of poliovirus (PV) after eradication may utilise non-infectious, recombinant virus-like particle (VLP) vaccines. Despite clear advantages over inactivated or attenuated virus vaccines, instability of VLPs can compromise their immunogenicity. Glutathione (GSH), an important cellular reducing agent, is a crucial co-factor for the morphogenesis of enteroviruses, including PV. We report cryo-EM structures of GSH bound to PV serotype 3 VLPs showing that it can enhance particle stability. GSH binds the positively charged pocket at the interprotomer interface shown recently to bind GSH in enterovirus F3 and putative antiviral benzene sulphonamide compounds in other enteroviruses. We show, using high-resolution cryo-EM, the binding of a benzene sulphonamide compound with a PV serotype 2 VLP, consistent with antiviral activity through over-stabilizing the interprotomer pocket, preventing the capsid rearrangements necessary for viral infection. Collectively, these results suggest GSH or an analogous tight-binding antiviral offers the potential for stabilizing VLP vaccines.