bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurohistopathological Findings of the Brain Parenchyma After Long-Term Deep Brain Stimulation: Case Series and Systematic Literature Review
Authors: Vivanco-Suarez Juan , Woodiwiss Timothy , Fiock Kimberly L. , Hefti Marco M. , Narayanan Nandakumar S. , Greenlee Jeremy D. W.
Published: November 2023

Introduction

The efficacy of deep brain stimulation (DBS) has been established to treat several movement and psychiatric disorders. However, several aspects, such as the mechanism of action and tissue changes after treatment are incompletely described. Hence, we aimed to describe the neurohistopathological findings of 9 patients who underwent DBS for movement disorders. Additionally, we performed a systematic literature review on postmortem studies after DBS implantation.

Methods

We performed a retrospective study of patients who underwent DBS for movement disorders between 2000-2023 and had postmortem autopsy. Demographics, clinical features, and outcomes were collected. Levodopa equivalent daily dose (LEDD) and total electrical energy delivered (TEED) were calculated. Neurohistopathological assessments were performed from autopsies. A systematic literature review was conducted to summarize the literature.

Results

Postmortem neurohistopathologic assessment of 9 patients who underwent DBS for movement disorders (8 Parkinson’s disease [multiple system atrophy was final diagnosis in 1], and 1 parkinsonism) was performed. Median age at DBS implantation was 65 years (range, 54-69), and most were male (8 patients, 89%). Most common DBS target was the subthalamic nucleus (8 patients, 89%). Median DBS duration was 65 months (range, 7-264 months). Post-DBS reduction in LEDD was found in 7/9 patients, and TEED was increased over time in 5/7 patients. No patients died due to DBS. Neurohistopathological assessment showed gliosis in 7 (78%) patients and activated microglial infiltration in 1 (11%). Additionally, postmortem findings (after DBS) of 59 patients (between 1977-2021) were identified in the literature: 26 (44%) for Parkinson’s disease, 20 (34%) for pain, and 13 (22%) for other conditions.

Conclusion

Our findings confirm the presence of a local tissue reaction, including gliosis and activated microglial infiltration around the implanted DBS electrodes. The effect of the local changes on the clinical efficacy of DBS is not established. Further DBS postmortem studies and standardization of tissue processing are needed.
Dose-response associations of device measured sleep regularity and duration with incident dementia in 82391 UK adults
Authors: Bian Wenxin , Biswas Raaj K. , Ahmadi Matthew N. , Bin Yu Sun , Postnova Svetlana , Phillips Andrew J.K. , Koemel Nicolas A. , Chaput Jean-Philippe , Rajaratnam Shantha M.W. , Cistulli Peter A , Stamatakis Emmanuel
Published: November 2023

Objectives

To evaluate the associations of device-measured sleep duration and regularity with incident dementia, and to explore whether regular sleep might mitigate any association of sleep duration with dementia.

Methods

This population-based prospective cohort study of 82391 adults from the UK Biobank accelerometry subsample included adults aged 43 to 79 years old in England, Scotland, and Wales. Sleep duration (h/day) and Sleep Regularity Index (SRI, range 0-100) were calculated from the wrist-worn accelerometry data collected by participants over the course of one week. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and assess the independent associations between sleep and incident dementia after adjustment for common demographic and contextual covariates.

Results

Over a mean follow-up of 7.9 years, during which 694 incident dementia cases occurred, there was a U-shaped association between sleep duration and incident dementia. Short sleep (<7 h) was associated with increased dementia risk, while long sleep (≥ 8h) was not significantly associated with dementia risk. The median sleep duration for short sleepers (<7 h) of 6.5 hours was associated with an HR of 1.19 (95% CI 1.01, 1.40) for incident dementia. Sleep regularity was negatively associated with dementia risk in a near-linear fashion. The sample median SRI of approximately 73, compared to the reference point of 51, was associated with an HR of 0.76 (95%CI 0.61, 0.94). The SRI value where the risk reduction was 50% of the maximum observed of 66, was associated with an HR of 0.77 (95%CI 0.63, 0.95). Among individuals with sleep duration outside the optimal range (too short or too long), less regular sleep was associated with increased risk of dementia. Among those with optimal sleep duration (7-8h/day), there was no significant association between sleep regularity and dementia risk. Compared to the reference point (SRI: 51), an SRI value of 62 for non-optimal sleepers was associated with a 25% reduction in risk for dementia (HR: 0.75; 95% CI 0.63, 0.90).

Conclusions

A regular sleep pattern may mitigate some adverse effects of inadequate sleep duration, suggesting that interventions aimed at improving sleep regularity may be a suitable option for people not able to achieve the recommended hours of sleep.
Sales of over the counter (OTC) codeine-containing products in the United Kingdom: a retrospective observational study
Authors: Richards Georgia C. , Martus Isabella , Aronson Jeffrey K. , Heneghan Carl
Published: November 2023

Background

Codeine is a widely available opioid medicine that is on the World Health Organisation’s list of essential medicines. However, widespread access to codeine has led to its misuse, abuse, dependence, and deaths. Some countries, including France and Australia, have successfully reclassified codeine to prescription only, which is encouraging other regulators, including the UK, to reconsider the status of codeine. However, little is known about how much codeine is sold in the UK.

Aim

To assess national trends in sales and expenditure of codeine-containing products sold over the counter (OTC) between 2013 and 2019.

Methods

We conducted a retrospective observational study using electronic point-of-sales data from the human data science companyIQVIAand population statistics from the UK’s Office of National Statistics (ONS). Descriptive statistics were used to examine the quantity, trends over time, and types of OTC codeine-containing products sold.

Results

4.75 billion dosage units of codeine were sold OTC in the UK between April 2013 and March 2019, an average of 72 dosage units per UK resident. Over time, sales of codeine fell by 8%, from 12.54 dosage units per resident in 2013 to 11.48 dosage units per resident in 2019. Codeine was often sold in combination with other analgesics, amounting to 1711 tonnes of paracetamol and 96 tonnes of ibuprofen. The public spent £638 million on OTC codeine-containing products, which increased by 12% over the study period. There were 83 different types of codeine-containing products sold.

Conclusion

Large volumes of codeine-containing products were purchased OTC in the UK in 2013-19. To improve the safety of opioids, OTC codeine sales data should be made accessible for public health surveillance. The trends presented in this study should inform policy for the future status of codeine availability in the UK.

Principal Investigator statement

The authors confirm that the Principal Investigator for this paper is Dr Georgia Richards and that they had direct responsibility for the conduct of this study.
Longitudinal tracking of intra-breath respiratory impedance in preschool children
Authors: Wong Matthew D , Blake Tamara , Zahir Syeda Farah , Suresh Sadasivam , Hantos Zoltán , Grimwood Keith , Lambert Stephen B , Ware Robert S , Sly Peter D
Published: November 2023

Background

Longitudinal measurements of intra-breath respiratory impedance (Zrs) in preschool-aged children may be able to distinguish abnormal lung function trajectories in children with a history of wheezing compared to healthy ones.

Methods

Children from a prospective, longitudinal community-based cohort performed annual intra-breath oscillometry (IB-OSC) measurements from age 3-years to 7-years. IB-OSC was performed using a single 10 Hz sinusoid while clinically asymptomatic. Linear mixed-effects models were developed to explore the effects of wheezing phenotypes, growth, and sex on seven IB-OSC outcome variables over time: resistance at end-expiration (ReE), resistance at end-inspiration (ReI), the tidal change in resistance (ΔR=ReE-ReI), reactance at end-expiration (XeE), reactance at end-inspiration (XeI), the tidal change in reactance (ΔX=XeE-XeI), and ΔX normalised by tidal volume (ΔX/VT).

Results

Eighty-five children produced 375 acceptable IB-OSC measurements. Subjects were classified into one of three wheeze groups: never (n=36), transient (n=35), or persistent (n=14). After adjusting for height, children with persistent wheezing, compared to those who never wheezed, had -0.669 hPa·s·L-1XeE (95% confidence interval [CI] -1.102 to -0.237, p<0.01), -0.465 hPa·s·L-1ΔX (95%CI -0.772 to -0.159, p<0.01) and +1.433 hPa·s·L-1ΔX/VT(95%CI +0.492 to +2.374, p<0.01). Increasing subject height had a significant effect on all IB-OSC resistance and reactance variables when adjusted for the effect of preschool wheezing.

Conclusions

IB-OSC is feasible for tracking lung function in preschool-aged children, and intra-breath reactance outcomes may allow abnormal lung function to be identified early in asymptomatic children with a history of persistent wheeze.
RAG-17: A Novel siRNA Conjugate Demonstrating Efficacy in Late-Stage Treatment of SOD1G93AALS mice
Authors: Duan Chunling , Kang Moorim , Liu Kunshan , Gan Zubao , Li Guanlin , Chen Junnan , Schacht Ian , Place Robert F. , Li Long-Cheng
Published: November 2023

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by rapid progression and high mortality. With genetic mutations, particularly in the SOD1 gene, playing a significant role in ALS pathogenesis, targeted therapies have become a primary focus. This study introduces RD-12500 (RAG-17), a novel siRNA-ACO (Accessory Oligonucleotide) conjugate designed to address the challenges of delivering duplex RNAs to the central nervous system (CNS). RD-12500 exhibits remarkablein vitrostability and target specificity with minimal immunostimulation.In vivostudies demonstrate its extensive CNS biodistribution, sustained accumulation post-intrathecal administration, and a robust dose-exposure-activity correlation. Notably, RD-12500 significantly reduces cerebrospinal fluid (CSF) SOD1 protein levels, indicating potent SOD1 mRNA and protein knockdown in cynomolgus monkeys. Most notably, our study breaks new ground by demonstrating the effectiveness of RD-12500 in late-stage treatment scenarios. In SOD1G93AALS mice, post-onset administration of RD-12500 significantly delayed disease progression, improved motor function, and extended survival, marking a significant advancement over other treatments which are typically initiated pre-symptomatically in the same model mice. These findings suggest RD-12500’s potential to provide therapeutic benefits not only to pre-symptomatic but also to post-symptomatic and late-stage SOD1-ALS patients.
A bird’s eye view to the homeostatic, Alzheimer and Glioblastoma attractors
Authors: Nieves Joan , Gil Gabriel , Gonzalez Augusto
Published: November 2023

Available data for white matter of the brain allows to locate the normal (homeostatic), Glioblastoma and Alzheimer’s disease attractors in gene expression space and to identify paths related to transitions like carcinogenesis or Alzheimer’s disease onset. A predefined path for aging is also apparent, which is consistent with the hypothesis of programmatic aging. In addition, reasonable assumptions about the relative strengths of attractors allow to draw a schematic landscape of fitness: a Wright’s diagram. These simple diagrams reproduce known relations between aging, Glioblastoma and Alzheimer’s disease, and rise interesting questions like the possible connection between programmatic aging and Glioblastoma in this tissue. We anticipate that similar multiple diagrams in other tissues could be useful in the understanding of the biology of apparently unrelated diseases or disorders, and in the discovery of unexpected clues for their treatment.

Graphical abstract

In brief

Aging, carcinogenesis and Alzheimer’s disease onset in white matter of the brain are shown as paths or directions in gene-expression space, a simple view that allows the analysis of their mutual relations and to rise interesting questions such as whether programmatic aging could be related to avoiding the Glioblastoma.

Highlights

Normal homeostatic, Glioblastoma and Alzheimer’s disease attractors are apparent in gene-expression space

The relative disposition of paths for carcinogenesis and Alzheimer’s disease onset reproduce known relations between these diseases

The observed corridor for aging is consistent with programmatic aging

Avoiding the fall into the huge basin of the Glioblastoma could be the subject of selection pressure

Aged normal samples could be captured by the weak Alzheimer’s disease attractor
Screening the MMV Pathogen Box reveals the mitochondrialbc1-complex as a drug target in matureToxoplasma gondiibradyzoites
Authors: Maus Deborah , Putrianti Elyzana , Hoffmann Tobias , Laue Michael , Seeber Frank , Blume Martin
Published: November 2023

The apicomplexan parasiteToxoplasma gondiiinfects 25-30% of the global human population and can cause life-threatening diseases in immunocompromised patients. The chronically infectious forms of the parasite, bradyzoites, persist within cysts in brain and muscle tissue and are responsible for its transmission and remission of the disease. Currently available treatment options are very limited and are only effective against the fast-replicating tachyzoites but fail to eradicate the chronic stages ofT. gondii. The cause of these treatment failures remains unclear. Here, we utilized our recently developed human myotube-based culture model to screen compounds from the MMV Pathogen Box against pan-resistant in vitro bradyzoites and identified multiple compounds with simultaneous activity against tachyzoites and bradyzoites. Stable isotope-resolved metabolic profiling on tachyzoites and bradyzoites identified the mitochondrialbc1-complex as a target of bradyzocidal compounds and defines their metabolic impacts on both parasite forms. Our data suggest that mature bradyzoites rely on mitochondrial ATP production.
Perceptual error based on Bayesian cue combination drives implicit motor adaptation
Authors: Zhang Zhaoran , Wang Huijun , Zhang Tianyang , Nie Zixuan , Wei Kunlin
Published: November 2023

The sensorimotor system can recalibrate itself without our conscious awareness, a type of procedural learning whose computational mechanism remains undefined. Recent findings on implicit motor adaptation, such as over-learning from small perturbations and fast saturation for increasing perturbation size, challenge existing theories based on sensory errors. We argue that perceptual error, arising from the optimal combination of movement-related cues, is the primary driver of implicit adaptation. Central to our theory is the increasing sensory uncertainty of visual cues with increasing perturbations, which was validated through perceptual psychophysics (Experiment 1). Our theory predicts the learning dynamics of implicit adaptation across a spectrum of perturbation sizes on a trial-by-trial basis (Experiment 2). It explains proprioception changes and their relation to visual perturbation (Experiment 3). By modulating visual uncertainty in perturbation, we induced unique adaptation responses in line with our model predictions (Experiment 4). Overall, our perceptual error framework outperforms existing models based on sensory errors, suggesting that perceptual error in locating one’s effector, supported by Bayesian cue integration, underpins the sensorimotor system’s implicit adaptation.
Predictive phage therapy forEscherichia coliurinary tract infections: cocktail selection for therapy based on machine learning models
Authors: Keith Marianne , Park de la Torriente Alba , Chalka Antonia , Vallejo-Trujillo Adriana , McAteer Sean P. , Paterson Gavin K. , Low Alison S. , Gally David L.
Published: November 2023

This study supports the development of predictive bacteriophage (phage) therapy: the concept of phage cocktail selection to treat a bacterial infection based on machine learning models (MLM). For this purpose, MLM were trained on thousands of measured interactions between a panel of phage and sequenced bacterial isolates. The concept was applied toEscherichia coli(E. coli) associated with urinary tract infections. This is an important common infection in humans and companion animals from which multi-drug resistant (MDR) bloodstream infections can originate. The global threat of MDR infection has reinvigorated international efforts into alternatives to antibiotics including phage therapy.E. coliexhibit extensive genome-level variation due to horizontal gene transfer via phage and plasmids. Associated with this, phage selection forE. coliis difficult as individual isolates can exhibit considerable variation in phage susceptibility due to differences in factors important to phage infection including phage receptor profiles and resistance mechanisms. The activity of 31 phage were measured on 314 isolates with growth curves in artificial urine. Random Forest models were built for each phage from bacterial genome features and the more generalist phage, acting on over 20% of the bacterial population, exhibited F1 scores of >0.6 and could be used to predict phage cocktails effective against previously untested strains. The study demonstrates the potential of predictive models which integrate bacterial genomics with phage activity datasets allowing their use on data derived from direct sequencing of clinical samples to inform rapid and effective phage therapy.

Significance Statement

With the growing challenge of antimicrobial resistance there is an urgency for alternative treatments for common bacterial diseases including urinary tract infections (UTIs).Escherichia coliis the main causative agent of UTIs in both humans and companion animals with multidrug resistant strains such as the globally disseminated ST131 becoming more common. Bacteriophage (phage) are natural predators of bacteria and potentially an alternative therapy. However, a major barrier for phage therapy is the specificity of phage on target bacteria and therefore difficulty efficiently selecting the appropriate phage. Here, we demonstrate a genomics driven approach using machine learning prediction models combined with phage activity clustering to select phage cocktails based only on the genome sequence of the infecting bacterial strain.
Anatomical insights into the vascular lay-out of the barley rachis: implications for transport and spikelet connection
Authors: Rutten Twan , Thirulogachandar Venkatasubbu , Huang Yongyu , Shanmugaraj Nandhakumar , Koppolu Ravi , Ortleb Stefan , Hensel Götz , Kumlehn Jochen , Melzer Michael , Schnurbusch Thorsten
Published: November 2023

Background and aims

Vascular patterning is intimately related to plant form and function. However, morphologic a l studies on the vascular anatomy of cereal crops, and inflorescences in particular, are scarce despite their importance for grain yield determination. Here, using barley (Hordeum vulgare) as a model, we study the vascular anatomy of the spike-type inflorescence. Our goal is to clarify the relationship between rachis (spike axis) vasculature and spike size, the implications for transport capacity and its interaction with the spikelets.

Methods

We employed serial transversal internode sections in multiple barley lines with different spike size, and investigated the internode diameter, vascular area and vein number size along the mature barley rachis. We then modeled the vascular dynamics along the main spike axis, and analyzed their relationship with spike size.

Key results

Internode diameter and total vascular area have a clear positive correlation with spike size whereas vascular number is only weakly correlated. While the lateral periphery of the rachis contains large mature veins of constant diameter the central part is occupied by a staggered array of small immature veins. This underlines the importance of minimizing transport resistance and suggests that transport and distribution of nutrients are spatially separated. Spikelet-derived veins enter the rachis either in the central area, where they often merge with the immature rachis veins, or in the periphery where they do not merge with the large mature veins. An increase in floret fertility through the conversion of a two-rowed barley into an isogenic six-rowed line, as well a decrease in floret fertility due to enhanced pre-anthesis tip degeneration caused by the mutationtip sterile 2.b(tst2.b) significantly affected vein size, but had limited to no effects on vein number or rachis diameter. Comparative analysis of a wild barley accession suggests that the domestication of barley may have favored plants with enhanced rachis transport capacity.

Conclusions

The rachis vasculature is the result of a two-step process involving an initial lay-out followed by size adjustment according to floret fertility/spike size. The functional processes of long distance transport and local supply to spikelets are spatially separated while a vascular continuity between rachis and spikelets appears non-essential.
The Drosophila cancer-germline, head-to-head gene pairTrxTanddhdis dispensable for normal brain development but plays a major role inl(3)malignant brain tumourgrowth
Authors: Molnar Cristina , Heinen Jan Peter , Reina Jose , Llamazares Salud , Palumbo Emilio , Pollarolo Giulia , Gonzalez Cayetano
Published: November 2023

Drosophila thioredoxins Deadhead (Dhd) and Thioredoxin-T (TrxT) are encoded by a head-to-head gene pair in the X chromosome. Akin to human cancer-germline (CG) genes,dhdandTrxTexpression is normally sex and germline specific, but becomes upregulated in brain tumours of either sex caused by mutation inl(3)malignant brain tumour(l(3)mbt).

Using CRISPR/Cas9-mediated knock-out alleles and RNA-seq, we show that while bothTrxTanddhdare dispensable for normal brain development, each of them has a significant but partial effect onl(3)mbtbrain tumour development as well as on tumour-linked transcriptomic signatures. Moreover, this effect is enhanced by the concomitant removal of both thioredoxins that strongly inhibitsl(3)mbtlarval brain tumour traits, reduces gene expression differences between tumour and wild-type tissue, and essentially erases all traces of gene expression differences between tumours from larvae of different sex. These results show thatTrxTanddhdplay a major synergistic role in the emergence ofl(3)mbttumour-linked transcriptomic signatures and tumour development, which is remarkable taking into account that these two genes are never expressed together under normal conditions. We have also found thatTrxTis crucial butdhdhas no effect on the growth of male-derivedl(3)mbtallografts, hence suggesting that the initial stages of tumour development and sustained, long-term tumour growth may depend upon different molecular pathways.

In humans, head-to-head inverted gene pairs are abundant among the CG genes that map to the X chromosome, some of which have been shown to work as a unit cancer. Our results identify the first instance of an X-linked, head-to-head CG gene pair in Drosophila and underpin the potential of such CG genes that are dispensable for normal development and homeostasis of somatic tissue, as targets to curtail malignant growth with minimal impact on overall health.
Neuromodulator-induced Temperature Robustness in a Motor Pattern: a Comparative Study Between two Decapod Crustaceans
Authors: Stein Wolfgang , Städele Carola
Published: November 2023

While temperature fluctuations pose significant challenges to the nervous system, many vital neuronal systems in poikilothermic animals function over a broad temperature range. Using the gastric mill pattern generator in the Jonah crab, we previously demonstrated that temperature-induced increases in leak conductance disrupt neuronal function and that neuropeptide modulation provides thermal protection. Here, we show that neuropeptide modulation also increases temperature robustness in Dungeness and Green crabs. Like in Jonah crabs, higher temperatures increased leak conductance in both species’ pattern-generating neuron LG and terminated rhythmic gastric mill activity. Likewise, increasing descending modulatory projection neuron activity or neuropeptide transmitter application rescued rhythms at elevated temperatures. However, decreasing input resistance using dynamic clamp only restored the rhythm in half of the experiments.

Thus, neuropeptide modulation increased temperature robustness in both species, demonstrating that neuropeptide-mediated temperature compensation is not limited to one species, although the underlying cellular compensation mechanisms may be distinct.

Summary statement

This study shows that the release of neuropeptide from modulatory projection neurons plays a crucial role in maintaining neuron and circuit function at elevated temperatures across crustacean species.
Evolving patterns of extreme publishing behavior across science
Authors: Ioannidis John P.A. , Collins Thomas A. , Baas Jeroen
Published: November 2023

Extreme publishing behavior may reflect a combination of some authors with genuinely high publication output and of other people who have their names listed too frequently in publications because of consortium agreements, gift authorship or other spurious practices. We aimed to evaluate the evolution of extreme publishing behavior across countries and scientific fields during 2000-2022. Extreme publishing behavior was defined as having >60 full articles (original articles, reviews, conference papers) in a single calendar year and indexed in Scopus. We identified 3,191 authors with extreme publishing behavior across science excluding Physics and 12,624 such authors in Physics. While Physics had much higher numbers of extreme publishing authors in the past, in 2022 extreme publishing authors was almost as numerous in non-Physics and Physics disciplines (1,226 vs. 1,480). Excluding Physics, China had the largest number of extreme publishing authors, followed by the USA. The largest fold-wise increases between 2016 and 2022 (5-19-fold) occurred in Thailand, Saudi Arabia, Spain, India, Italy, Russia, Pakistan, and South Korea. Excluding Physics, most extreme publishing authors were in Clinical Medicine, but from 2016 to 2022 the largest relative increases (>6-fold) were seen in Agriculture, Fisheries & Forestry, Biology, and Mathematics and Statistics. Extreme publishing authors accounted for 4,360 of the 10,000 most-cited authors (based on raw citation count) across science. While most Physics authors with extreme publishing behavior had modest citation impact in a composite citation indicator that adjusts for co-authorship and author positions, 67% of authors with extreme publishing behavior in non-Physics fields remained within the top-2% according to that indicator among all authors with >=5 full articles. Extreme publishing behavior has become worryingly common across scientific fields with rapidly increasing rates in some countries and settings and may herald a rapid depreciation of authorship standards.
Plant Phenolics Inhibit Focal Adhesion Kinase and Suppress Host Cell Invasion by UropathogenicEscherichia coli
Authors: Lewis Adam J. , Richards Amanda C. , Mendez Alejandra A. , Dhakal Bijaya K. , Jones Tiffani A. , Sundsbak Jamie L. , Eto Danelle S. , Mulvey Matthew A.
Published: November 2023

Traditional folk treatments for the prevention and management of urinary tract infections (UTIs) and other infectious diseases often include plants and plant extracts that are rich in phenolic and polyphenolic compounds. These have been ascribed a variety of activities, including inhibition of bacterial interactions with host cells. Here we tested a panel of four well-studied phenolic compounds – caffeic acid phenethyl ester (CAPE), resveratrol, catechin, and epigallocatechin gallate – for effects on host cell adherence and invasion by uropathogenicEscherichia coli(UPEC). These bacteria, which are the leading cause of UTIs, can bind and subsequently invade bladder epithelial cells via an actin-dependent process. Intracellular UPEC reservoirs within the bladder are often protected from antibiotics and host defenses, and likely contribute to the development of chronic and recurrent infections. Using cell culture-based assays, we found that only resveratrol had a notable negative effect on UPEC adherence to bladder cells. However, both CAPE and resveratrol significantly inhibited UPEC entry into the host cells, coordinate with attenuated phosphorylation of the host actin regulator Focal Adhesion Kinase (FAK, or PTK2) and marked increases in the numbers of focal adhesion structures. We further show that the intravesical delivery of resveratrol inhibits UPEC infiltration of the bladder mucosa in a murine UTI model, and that resveratrol and CAPE can disrupt the ability of other invasive pathogens to enter host cells. Together, these results highlight the therapeutic potential of molecules like CAPE and resveratrol, which could be used to augment antibiotic treatments by restricting pathogen access to protective intracellular niches.

IMPORTANCE

Urinary tract infections (UTIs) are exceptionally common and increasingly difficult to treat due to the ongoing rise and spread of antibiotic resistant pathogens. Furthermore, the primary cause of UTIs, uropathogenicEscherichia coli(UPEC), can avoid antibiotic exposure and many host defenses by invading the epithelial cells that line the bladder surface. Here we identified two plant-derived phenolic compounds that disrupt activation of the host machinery needed for UPEC entry into bladder cells. One of these compounds (resveratrol) effectively inhibited UPEC invasion of the bladder mucosa in a mouse UTI model, and both phenolic compounds significantly reduced host cell entry by other invasive pathogens. These findings suggest that select phenolic compounds can be used to supplement existing antibacterial therapeutics by denying uropathogens shelter within host cells and tissues, and help explain some of the benefits attributed to traditional plant-based medicines.
The Histopathology ofCephenemyia stimulator-Induced Nasopharyngeal Myiasis in Roe-Deers (Capreolus capreolus)
Authors: Ortiz-Leal Irene , Torres Mateo V. , López-Beceiro Ana , Sanchez-Quinteiro Pablo , Fidalgo Luis
Published: November 2023

Nasopharyngeal myiasis in European roe deer(Capreolus capreolus)is a pathological condition caused by the larval stages ofCephenemyia stimulator, a fly from the Oestridae family. These larvae reside in the host’s upper respiratory tract for months, inducing significant tissue damage and clinical symptoms. The lifecycle ofCephenemyia stimulatoris complex, involving three larval stages before maturation into adult flies, with each stage contributing to the progressive pathology observed in the host. Despite their prevalence, the histopathological effects of these larvae in the nasopharyngeal and nasal cavities have been understudied. Our study fills this knowledge gap by providing a detailed histopathological analysis of the affected tissues, using various staining techniques to reveal the extent and nature of the damage caused by these parasitic larvae. This histopathological examination reveals significant alterations within the nasopharyngeal mucosa and nasal cavity, including erythematous changes, mucosal metaplasia, fibrosis, and tissue necrosis. Parasitic cysts and eosinophilic infiltration further characterize the infestation’s impact, compromising not only the mucosal integrity but also potentially the olfactory function of the affected animals. This research is crucial for understanding the impact of myiasis on the health of roe deer populations and could have significant implications for wildlife management and conservation.
Late onset and regional heterogeneity of synaptic deficits in cortical PV interneurons ofShank3B−/−mice
Authors: Shih Yi-Chun , Nelson Lars , Janeček Michael , Peixoto Rui T.
Published: November 2023

Epilepsy and epileptiform patterns of cortical activity are highly prevalent in autism spectrum disorders (ASDs), but the neural substrates and pathophysiological mechanisms underlying the onset of cortical dysfunction in ASD remains elusive. Reduced cortical expression of Parvalbumin (PV) has been widely observed in ASD mouse models and human postmortem studies, suggesting a crucial role of PV interneurons (PVINs) in ASD pathogenesis.Shank3B−/−mice carrying a Δ13-16 deletion in SHANK3 exhibit cortical hyperactivity during postnatal development and reduced sensory responses in cortical GABAergic interneurons in adulthood. However, whether these phenotypes are associated with PVIN dysfunction is unknown. Using whole-cell electrophysiology and a viral-based strategy to label PVINs during postnatal development, we performed a developmental characterization of AMPAR miniature excitatory postsynaptic currents (mEPSCs) in PVINs and pyramidal (PYR) neurons of layer (L) 2/3 mPFC inShank3B−/−mice. Surprisingly, reduced mEPSC frequency was observed in both PYR and PVIN populations, but only in adulthood. At P15, when cortical hyperactivity is already observed, both neuron types exhibited normal mEPSC amplitude and frequency, suggesting that glutamatergic connectivity deficits in these neurons emerge as compensatory mechanisms. Additionally, we found normal mEPSCs in adult PVINs of L2/3 somatosensory cortex, revealing region-specific phenotypic differences of cortical PVINs inShank3B−/−mice. Together, these results demonstrate that loss of Shank3 alters PVIN function but suggest that PVIN glutamatergic synapses are a suboptimal therapeutic target for normalizing early cortical imbalances in SHANK3-associated disorders. More broadly, these findings underscore the complexity of interneuron dysfunction in ASDs, prompting further exploration of region and developmental stage specific phenotypes for understanding and developing effective interventions.
Structure of the human 80S ribosome at 1.9 Å resolution – the molecular role of chemical modifications and ions in RNA
Authors: Holvec Samuel , Barchet Charles , Lechner Antony , Fréchin Léo , Silva S. Nimali T. De , Hazemann Isabelle , Wolff Philippe , Loeffelholz Ottilie von , Klaholz Bruno P.
Published: November 2023

The ribosomal RNA of the human protein synthesis machinery comprises numerous chemical modifications that are introduced during ribosome biogenesis. We present the 1.9 Å resolution cryo-EM structure of the 80S human ribosome resolving numerous new rRNA modifications and functionally important ions such as Zn2+, K+and Mg2+including their associated individual water molecules. 2’-O-methylation, pseudo-uridine and base modifications were confirmed by mass spectrometry resulting in a complete investigation of the > 230 sites many of which could not be addressed previously. They choreograph key interactions within the RNA and at the interface with proteins, including at the ribosomal subunit interfaces of the fully assembled 80S ribosome. Uridine isomerisation turns out to be a key mechanism for U-A base pair stabilisation in RNA in general. The structural environment of chemical modifications & ions is primordial for the RNA architecture of the mature human ribosome, hence providing a structural framework to address their role in healthy context and human diseases.
Influence of study characteristics, methodological rigor and publication bias on efficacy of pharmacotherapy in obsessive compulsive disorder: a systematic review and meta-analysis of randomized placebo-controlled trials
Authors: Cohen S.E. , Zantvoord J.B. , Storosum B.W.C. , Mattila T.K. , Daams J.G. , Wezenberg B.N. , De Boer A. , Denys D.
Published: November 2023

Question

We examined the effect of study characteristics, risk of bias and publication bias on efficacy of pharmacotherapy in randomized controlled trials (RCT’s) for obsessive-compulsive disorder (OCD).

Study selection and analysis

We conducted a systematic search for double-blinded, placebo controlled short-term RCT’s with selective serotonergic reuptake inhibitors (SSRI’s) or clomipramine. We performed a random-effect meta-analysis, using change of the Yale-Brown Obsessive-Compulsive scale (YBOCS) as primary outcome. We performed meta-regression for key study characteristics, and for risk of bias. Furthermore, we analyzed publication bias using a Bayesian selection model.

Findings

We screened 3729 articles and included 21 studies, containing 4102 participants. Meta-analysis showed an effect size of −0.59 (Hedges’ G, 95% CI −0.73 to −0.46), equaling 4.2 point reduction on the YBOCS compared to placebo. The most recent trial was performed in 2007 and most trials were at risk of bias. In our meta-regression, we found that high risk of bias was associated with a larger effect size. Clomipramine was more effective than SSRI’s, even after correcting for risk of bias. We found an indication for publication bias subsequent correction for this bias resulted in a depleted effect size.

Conclusions

Our findings reveal superiority of clomipramine over SSRIs, even after adjusting for risk of bias. Effect sizes may be attenuated when considering publication bias and methodological rigor, emphasizing the importance of robust studies to guide clinical utility of OCD pharmacotherapy.
Patterns of change in regulatory modules of chemical reaction systems induced by network modification
Authors: Hishida Atsuki , Okada Takashi , Mochizuki Atsushi
Published: November 2023

Cellular functions are realized through the dynamics of chemical reaction networks formed by thousands of chemical reactions. Numerical studies have empirically demonstrated that small differences in network structures among species or tissues can cause substantial changes in dynamics. However, the existence of a general principle for behavior changes in response to network structure modifications is not known. The chemical reaction system possesses substructures called buffering structures, which are characterized by a certain topological index being zero. It was proven that the steady-state response to modulation of reaction parameters inside a buffering structure is localized in the buffering structure [1, 2, 3]. In this study, we developed a method to systematically identify the loss or creation of buffering structures induced by the addition of a single degradation reaction from network structure alone. This makes it possible to predict the qualitative and macroscopic changes in regulation that will be caused by the network modification. This method was applied to two reaction systems: the central metabolic system and the mitogen-activated protein kinases (MAPK) signal transduction system. Our method enables identification of reactions that are important for biological functions in living systems.

Significance Statement

Dynamics of complex biological systems have been understood using mathematical models[4, 5, 6, 7]; however, various assumptions are necessary to construct models for large networks such as those found in the life sciences, and discussing the relation between the network structure and its behavior is difficult. Our study using structural sensitivity analysis [1, 2, 3] shows that directly discussing changes in the structure and behavior of a reaction network without making assumptions about kinetics is possible. This enabled the prediction of changes in behavior depending on whether a reaction is present or not and identify reactions that are essentially important for biological behavior.
Electrical impedance spectroscopy with bacterial biofilms: neuronal-like behaviour
Authors: Akabuogu Emmanuel U. , Zhang Lin , Krašovec Rok , Roberts Ian S. , Waigh Thomas A.
Published: November 2023

Negative capacitance at low frequencies for neurons was first demonstrated in 1941 (Kenneth S. Cole) using extracellular electrodes. The phenomenon subsequently was explained by Cole using the Hodgkin-Huxley model and is due to the activity of voltage-gated potassium ion channels. We show thatE. colibiofilms exhibit significant stable negative capacitances at low frequencies when they experience a small DC bias voltage in electrical impedance spectroscopy experiments. Using a frequency domain Hodgkin-Huxley model, we characterize the conditions for the emergence of this feature and demonstrate that the negative capacitance exists only in biofilms containing living cells. Furthermore, we established the importance of the voltage-gated potassium ion channel, Kch, using knock-down mutants. The experiments provide further evidence for voltage-gated ion channels inE. coliand a new, low-cost method to probe biofilm electrophysiology e.g. to understand the efficacy of antibiotics.

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Comparison and benchmark of deep learning methods for non-coding RNA classification
Authors: Creux Constance , Zehraoui Farida , Radvanyi François , Tahi Fariza
Published: November 2023

The involvement of non-coding RNAs in biological processes and diseases has made the exploration of their functions crucial. Most non-coding RNAs have yet to be studied, creating the need for methods that can rapidly classify large sets of non-coding RNAs into functional groups, or classes. In recent years, the success of deep learning in various domains led to its application to non-coding RNA classification. Multiple novel architectures have been developed, but these advancements are not covered by current literature reviews. We present an exhaustive comparison of the different methods proposed in the state-of-the-art and describe their associated datasets. Moreover, the literature lacks objective benchmarks. We perform experiments to fairly evaluate the performance of various tools for non-coding RNA classification on popular datasets. The robustness of methods to non-functional sequences and sequence boundary noise is explored. We also measure computation time and CO2emissions. With regard to these results, we assess the relevance of the different architectural choices and provide recommendations to consider in future methods. Datasets and reproducible codes are available athttps://evryrna.ibisc.univ-evry.fr/evryrna/ncBench.

Author summary

RNA can either encode proteins, which perform different functions in the genome, or be non-coding. Non-coding RNAs represent around 98% of the genome, and were long thought to be non-functional. It has now been proven that non-coding RNAs can have diverse biological functions and be involved in diseases. A large proportion of non-coding RNAs has not yet been studied. The function of specific non-coding RNAs can be studied experimentally, but experiments are costly and time-consuming. One possibility to massively characterize the function of non-coding RNAs is to use computational methods to classify them into functional groups, or classes. Recent computational methods for non-coding RNA classification are all based on deep learning, as it leads to faster runtime and improved performance. Our work presents and compares the different approaches adopted in the state-of-the-art, as well as the non-coding RNA datasets that are used. We also present a comprehensive benchmark, measuring classification performance in different conditions, computation time, and CO2emissions. The descriptions and comparisons provided are meant to guide researchers in the field, whether wanting to use existing tools or to develop new ones.
Unbiased MD simulations characterize lipid binding to lipid transfer proteins
Authors: Srinivasan Sriraksha , Alvarez Lorenzo Daniel , Vanni Stefano
Published: November 2023

The molecular characterization of lipid binding to lipid transfer proteins (LTPs) is fundamental to the understanding of several aspects of their mechanistic mode of action. However, obtaining lipid-bound structures of LTPs is not straightforward owing to caveats in current experimental structural biology approaches. As a result, several structures of LTPs, and most notably almost all of those that have been proposed to act as bridges between membrane organelles, do not provide the precise location of their endogenous lipid ligands. To address this limitation, computational approaches are a powerful alternative methodology, but they are often limited by the high flexibility of lipid substrates. In this work, we develop anin silicoprotocol based on unbiased coarse grain molecular simulations in which lipids placed in bulk solvent away from the protein can spontaneously bind to LTPs. This approach accurately determines binding pockets in LTPs and provides a working hypothesis for the pathway via which lipids enter LTPs. We apply this approach to characterize lipid binding to bridge-like LTPs belonging to the Vps13-Atg2 family, for which the lipid localization inside the protein is currently unknown. Overall, our work paves the way to determine binding pockets and entry pathways for several LTPs in an inexpensive, fast, and accurate manner.
ASM Variants in the Spotlight: A Structure-Based Atlas for Unraveling Pathogenic Mechanisms in Lysosomal Acid Sphingomyelinase
Authors: Scrima Simone , Lambrughi Matteo , Tiberti Matteo , Fadda Elisa , Papaleo Elena
Published: November 2023

Lysosomal acid sphingomyelinase (ASM), a critical enzyme in lipid metabolism encoded by the SMPD1 gene, plays a crucial role in sphingomyelin hydrolysis in lysosomes. ASM deficiency leads to acid sphingomyelinase deficiency, a rare genetic disorder with diverse clinical manifestations, and the protein can be found mutated in other diseases. We employed a structure-based framework to comprehensively understand the functional implications of ASM variants, integrating pathogenicity predictions with molecular insights derived from molecular dynamics simulations in a lysosomal membrane environment. Our analysis, encompassing over 400 variants, establishes a structural atlas of missense variants of lysosomal ASM, associating mechanistic indicators with pathogenic potential. Our study highlights variants that influence structural stability or exert local and long-range effects at functional sites. To validate our predictions, we compared them to available experimental data on residual catalytic activity in 135 ASM variants. Notably, our findings also suggest applications of the resulting data for identifying cases suited for enzyme replacement therapy. This comprehensive approach enhances the understanding of ASM variants and provides valuable insights for potential therapeutic interventions.