bluuebunny/crossref_metadata_2025 huggingface dataset:
Reporting of paediatric exercise-induced respiratory symptoms by physicians and parents
Authors: Pedersen Eva SL , Glick Sarah , de Jong Carmen CM , Ardura-Garcia Cristina , Jochmann Anja , Casaulta Carmen , Hartog Katharina , Marangu-Boore Diana , Mueller-Suter Dominik , Regamey Nicolas , Singer Florian , Moeller Alexander , Kuehni Claudia E
Published: May 2024

Aims of the study

Routinely collected health data are increasingly used for research, however important history items may be incomplete in medical records. We assessed clinical documentation of exercise-induced respiratory symptoms (EIS) by treating physicians and compared with parent-reported EIS for the same children.

Methods

We analysed data from the Swiss Paediatric Airway Cohort (SPAC), a multicentre observational study of children treated in Swiss outpatient pulmonology clinics. We included children 6 to 17 years of age who were referred to a paediatric pulmonologist for evaluation of EIS. Features of EIS recorded by physicians were extracted from outpatient clinical letters transmitted to the referring physician, while parent-reported EIS data were collected from a standardized questionnaire completed at SPAC enrolment. We calculated agreement between physician-documented and parent-reported EIS characteristics using Cohen’s and Fleiss’s kappa.

Results

Of 1669 children participating in SPAC (2017-2019), 193 (12%) met the inclusion criteria, of whom 48% were girls. Physicians provided detailed information on EIS in 186 (96%) outpatient clinical letters. Documented characteristics included: type of physical activity triggering EIS (69%), localisation of EIS in chest or throat (48%), respiratory phase of EIS (45%), and timing of EIS during or after exercise (37%). Previous bronchodilator use (94%) and its effect on EIS (88%) were consistently documented by physicians. The clinical letters of children diagnosed with dysfunctional breathing more often contained detailed EIS characteristics than for children diagnosed with asthma. The agreement between physician-documented and parent-reported EIS was moderate for use of bronchodilators (k=0.53) and poor to fair for all other features (k=0.01-0.36).

Conclusion

This study highlights that outpatient clinical letters may lack some details on EIS characteristics, information which parents could provide. A standardized and detailed method for documenting paediatric respiratory symptoms in the coordinated data infrastructure may enhance future analyses of routinely collected health data.
Harmonizing multisite neonatal diffusion-weighted brain MRI data for developmental neuroscience
Authors: Bonthrone Alexandra F. , Blesa Cábez Manuel , Edwards A. David , Hajnal Jo V. , Counsell Serena J. , Boardman James P.
Published: May 2024

Large diffusion-weighted brain MRI (dMRI) studies in neonates are crucial for developmental neuroscience. Our aim was to investigate the utility of ComBat, and empirical Bayes tool for multisite harmonization, for removing site effects from white matter (WM) dMRI measures in healthy infants born 37-42+6 weeks from the Theirworld Edinburgh Birth Cohort (n=86) and Developing Human Connectome Project (n=287).

Skeletonized fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD, RD) maps were harmonized. The differences between voxel-wise metrics, skeleton means and histogram widths (5th-95th percentile) were assessed before and after harmonization, as well as variance associated with gestational age at birth.

Before harmonization, large cohort differences were observed in all measures. Harmonization removed all voxel-wise differences from MD maps and all metric means and histogram widths, however small voxel-wise differences (<1.5% of voxels) remained in FA, AD and RD. We detected significant relationships between GA at birth and all metrics. When comparing single site and multi-site harmonized datasets of equal sample sizes, harmonized data resulted in smaller standardized regression coefficients.

ComBat will enable unprecedented sample sizes in developmental neuroscience, offering new horizons for biomarker discovery and validation, understanding typical and atypical brain development, and assessment of neuroprotective therapies.
The relationship between the size and asymmetry of the lateral ventricles and cortical myelin content in individuals with mood disorders
Authors: Manelis A , Hu H , Miceli R , Satz S , Lau R , Iyengar S , Swartz HA
Published: May 2024

Background

Although enlargement of the lateral ventricles was previously observed in individuals with mood disorders, the link between ventricular size and asymmetry with other indices of brain structure remains underexplored. In this study, we examined the association of lateral ventricular size and asymmetry with cortical myelin content in individuals with bipolar (BD) and depressive (DD) disorders compared to healthy controls (HC).

Methods

Magnetic resonance imaging (MRI) was used to obtain T1w and T2w images from 149 individuals (age=27.7 (SD=6.1) years, 78% female, BD=38, DD=57, HC=54). Cortical myelin content was calculated using the T1w/T2w ratio. Elastic net regularized regression identified brain regions whose myelin content was associated with ventricular size and asymmetry. A post-hoc linear regression examined how participants’ diagnosis, illness duration, and current level of depression moderated the relationship between the size and asymmetry of the lateral ventricles and levels of cortical myelin in the selected brain regions.

Results

Individuals with mood disorders had larger lateral ventricles than HC. Larger ventricles and lower asymmetry were observed in individuals with BD who had longer lifetime illness duration and more severe current depressive symptoms. A greater left asymmetry was observed in participants with DD than in those with BD (p<0.01). Elastic net revealed that both ventricular enlargement and asymmetry were associated with altered myelin content in cingulate, frontal, and sensorimotor cortices. In BD, but not other groups, ventricular enlargement was related to altered myelin content in the right insular regions.

Conclusions

Lateral ventricular enlargement and asymmetry are linked to myelin content imbalance, thus, potentially leading to emotional and cognitive dysfunction in mood disorders.
Pharmacologic and genetic evidence converge on mechanisms of psychotic illness
Authors: Fennessy Brian , Cotter Liam , Simons Nicole W. , Liharska Lora E. , Nadkarni Girish N. , Ruderfer Douglas M. , Charney Alexander W.
Published: May 2024

Idiopathic and substance-induced forms of psychotic illness afflict millions of people worldwide, and it is largely unknown whether these two forms emerge through the same molecular mechanisms. Though genetic studies have implicated thousands of genes in idiopathic psychotic illnesses (e.g., schizophrenia), consensus is lacking regarding which of these genes are most likely to treat psychotic illness when modulated pharmacologically and, as a result, antipsychotic medications targeting these genes have yet to be developed. Previous studies suggest that one way to determine if a candidate target gene is likely to lead to an effective treatment for a given illness is if the gene is implicated by multiple lines of evidence (e.g., genetic, pharmacologic). Here, pharmacologic, genetic, and clinical data were leveraged to determine if the idiopathic and substance-induced forms of psychotic illness are related to one another through a common set of genes. A set of medications that cause psychotic illness as a side effect (“propsychotics”) were identified by analyzing 15 million medication side effects reports from over 100 countries. There was a significant overlap of target genes among propsychotics and antipsychotics and for many of the shared target genes propsychotics act through a mechanism that was qualitatively the opposite of the mechanism through which antipsychotics act (e.g., activation vs. inhibition). Propsychotic and antipsychotic target genes were significantly enriched for genes implicated in schizophrenia by rare loss-of-function genetic variation but not for genes implicated in schizophrenia by common genetic variation. Only one gene –GRIN2A, encoding the GluN2A subunit of the NMDA glutamate receptor – was implicated in psychotic illness by propsychotics, rare loss-of-function genetic variation, and common genetic variation. Mining genetic data from a diverse cohort of 30,000 adults treated in a New York City health system, a carrier of a rare loss-of-function variant inGRIN2Awith severe psychotic illness was identified with a clinical course notable for psychotic symptoms and cognitive deficits that are not targeted by current antipsychotics. Altogether, this report shows how integrating pharmacologic, genetic, and clinical data from large cohorts can prioritize target genes for novel drug development and align the prioritized targets with specific clinical presentations.
A multi-centre cross-sectional study on hepatitis B vaccination coverage and associated factors among personnel working in health facilities in Kumasi, Ghana
Authors: Okwan Daniel Kobina , Scott Godfred Yawson , Takyi Pius , Boateng Clinton Owusu , Antwi Philemon Boasiako , Abrampah Akwasi Amponsah , Obeng Michael Agyemang
Published: May 2024

As part of efforts to reach the elimination target by 2030, the WHO and CDC recommend that all HCWs adhere to the 3-dose hepatitis B vaccination schedule to protect themselves against the infection. This study assessed Hepatitis B vaccination coverage and associated factors among personnel working in health facilities in Kumasi, Ghana.

A cross-sectional study involving 530 HCWs was conducted in four hospitals in Kumasi from September to November, 2023. An investigator-administered questionnaire was employed in gathering participant demographics and other information related to vaccination coverage. IBM SPSS version 26.0 and GraphPad prism 8.0 were used for analysing the data.

Even though, majority (70.6%) reported having taken at least one dose of the vaccine, only 43.6% were fully vaccinated (≥ 3 doses). More than a quarter (29.4%) had not taken any dose of the HBV vaccine. Close to a quarter (23.6%) had not screened or tested for HBV infection in their lifetime. The Statistically significant variables influencing vaccination status were age, marital status, profession and status in the hospital. Majority (44.9%) of the participants who have not taken the vaccine reported they do not have reason for not taking the vaccine and high proportion (80.1%) were willing to take the vaccine when given for free.

To combat the low hepatitis B vaccination coverage among healthcare workers in Kumasi, Ghana, amidst the significant public health threat of HBV infection, comprehensive measures are necessary. These include implementing infection prevention control programmes, enhancing occupational health and safety, and conducting health promotion campaigns in healthcare facilities. Extending and intensifying hepatitis B screening and vaccination initiatives to tertiary institutions and encouraging employers, supervisors or team leaders to provide these services nationwide are also recommended.
The effectiveness of telemedicine in the prevention of type 2 diabetes: a systematic review and meta-analysis of interventions
Authors: Suhlrie Laura , Ayyagari Raga , Mba Camille , Olsson Kjell , Torres-Aparcana Harold , James Steven , Vounzoulaki Elpida , Ibsen Daniel B.
Published: May 2024

Objective

To evaluate the effectiveness of telemedicine-delivered diet and/or exercise interventions to prevent type 2 diabetes (T2D) in people at risk.

Methods

Embase (via Ovid), Medline (via Ovid), Web of Science, CINAHL, Scopus and SciELO were searched from January 2010-December 2020 for intervention studies using a diet and/or exercise intervention delivered through telemedicine for T2D prevention in people at risk. Parallel randomised controlled trials were meta-analyzed and other intervention designs narratively synthesised.

Results

We identified 11,645 studies via database searches, of which 226 were full text screened, and 52 interventions included; 32 were included in the meta-analysis and 20 in the narrative synthesis. Telemedicine interventions reduced body weight (mean difference (MD): -1.66 kg, 95% confidence interval (CI) -2.48,-0.90, I2=81%, nstudies=17), body mass index (MD -0.71 kg/m2, 95% CI -1.06,-0.37, I2=70%, nstudies=11), waist circumference (MD -2.82 cm, 95% CI -5.16,-2.35, I2=84%, nstudies=7) and HbA1c (MD -0.07%, 95% CI -0.14,0.00, I2=71%, nstudies=11). No significant effects were found for other clinical outcomes. The narrative synthesis supported the results.

Conclusions

Our study highlights the potential for telemedicine-delivered interventions in preventing T2D in people at risk.
Overexpression of miR-3168 impairs angiogenesis in Pulmonary Arterial Hypertension: Insights from circulating miRNA analysis
Authors: Lago-Docampo Mauro , Iglesias-López Ainhoa , Vilariño Carlos , Baloira Adolfo , Barberá Joan Albert , Blanco Isabel , Valverde Diana
Published: May 2024

Background

Pulmonary Arterial Hypertension (PAH) is a rare disease where the thickening of the precapillary pulmonary arteries ends up inducing right heart failure. Nowadays, obtaining an early diagnosis is challenging and typically delayed until undergoing right-heart catheterization.

Methods

We performed small RNA sequencing (microRNA-seq) in the plasma of idiopathic PAH patients and controls, that we validated by qPCR. We then interrogated the role of miR-3168 in HUVECs by performing western-blot, flow cytometry and tube formation assays.

Results

We found 29 differentially expressed microRNAs and validate 7 of them let-(7a-5p, let-7b-5p, let-7c-5p, let-7f-5p, miR-9-5p, miR-31-5p, miR-3168) in a nationwide cohort of 120 patients and 110 controls. We then used classification models to analyze their potential as PAH predictor. In the first half of our cohort, we obtained a model with an AUC of 0.888. Although, this value lowered to 0.738 after using this model in the whole cohort of patients. Additionally, we validated the effect of miR-3168, a novel upregulated miRNA in PAH patients which targetsBMPR2,and impairs angiogenesis, as assessed by the tube formation assay.

Conclusion

We identified novel downregulated and upregulated microRNAs in idiopathic PAH patients, developed a 3-microRNA signature for diagnosis, and validatedin vitrothat miR-3168 targetsBMPR2,thereby impairing angiogenesis.
Biomarkers Correspond with Echocardiographic Phenotypes in Heart Failure with Preserved Ejection Fraction: A Secondary Analysis of the RELAX Trial
Authors: Hyson Peter R. , Kao David P.
Published: May 2024

Background

Little is known about the relationship between structural phenotypes in in heart failure with preserved ejection fraction (HFpEF) and cardiac biomarkers. We used cluster analysis to identify cardiac structural phenotypes and their relationships to biomarkers in HFpEF.

Methods and results

Latent class analysis (LCA) was applied to echocardiographic data including left atrial enlargement (LAE), diastolic dysfunction (DD), E/e’, EF≤55%, and right ventricular dysfunction from 216 patients enrolled in the RELAX trial. Three structural phenotypes were identified. Phenotype A had the most grade II DD. Phenotype B had the most grade III DD, worst LAE, elevated E/e’ and right ventricular dysfunction. Phenotype C had the least DD and moderate LAE. Phenotypes B and C had prevalent atrial fibrillation (AF). Phenotype B patients had increased carboxy-terminal telopeptide of collagen type I (CITP), cystatin-c (CYSTC), endothelin-1 (ET1), NT-proBNP, and high-sensitivity troponin I (TNI). Type A had the next highest CITP and CYSTC levels while Type C had next highest NT-proBNP.

Conclusions

Structural HFpEF phenotypes demonstrated different characteristics including cardiac biomarkers. These findings may help explain phenotype-specific differences in natural history and prognosis, and they may represent phenotype-specific pathophysiology that could be amenable to targeted therapy.
Strategies for motion- and respiration-robust estimation of fMRI intrinsic neural timescales
Authors: Goldberg Andrew , Rosario Isabella , Power Jonathan , Horga Guillermo , Wengler Kenneth
Published: May 2024

Intrinsic neural timescale (INT) is a resting-state fMRI (rs-fMRI) measure that reflects the time window of neural integration within a brain region. Despite the potential relevance of INT to cognition, brain organization, and neuropsychiatric illness, the influences of physiological artifacts on INT have not been systematically considered. Two artifacts, head motion and respiration, pose serious issues in rs-fMRI studies. Here, we described their impact on INT estimation and tested the ability of two denoising strategies for mitigating these artifacts, high-motion frame censoring and global signal regression (GSR). We used a subset of the HCP Young Adult dataset with runs annotated for breathing patterns (Lynch et al., 2020) and at least one “clean” (reference) run that had minimal head motion and no respiration artifacts; other runs from the same participants (n = 46) were labeled as “non-clean.” We found that non-clean runs exhibited brain-wide increases in INT compared to their respective clean runs and the magnitude of error in INT between non-clean and clean runs correlated with the amount of head motion. Importantly, effect sizes were comparable to INT effects reported in the clinical literature. GSR and high-motion frame censoring improved the similarity between INT maps from non-clean runs and their respective clean run. Using a pseudo-random frame-censoring approach, there was a relationship between the amount of censored frames and both the mean INT and mean error, suggesting that frame censoring itself biases INT estimation. A group-level correction procedure reduced this bias and improved similarity between non-clean runs and their respective clean run. Based on our findings, we offer recommendations for rs-fMRI INT studies, which include implementing GSR and high-motion frame censoring with Lomb-Scargle interpolation of censored data, and performing group-level correction of the bias introduced by frame censoring.
Association of bidirectional network cores in the brain with perceptual awareness and cognition
Authors: Taguchi Tomoya , Kitazono Jun , Sasai Shuntaro , Oizumi Masafumi
Published: May 2024

The brain comprises a complex network of interacting regions. To understand the roles and mechanisms of this intricate network, it is crucial to elucidate its structural features related to cognitive functions. Recent empirical evidence suggests that both feedforward and feedback signals are necessary for conscious perception, emphasizing the importance of subnetworks with bidirectional interactions. However, the link between such subnetworks and conscious perception remains unclear due to the complexity of brain networks. In this study, we propose a framework for extracting subnetworks with strong bidirectional interactions---termed the "cores" of a network---from brain activity. We applied this framework to resting-state and task-based human fMRI data from participants of both sexes to identify regions forming strongly bidirectional cores. We then explored the association of these cores with conscious perception and cognitive functions. We found that the extracted central cores predominantly included cerebral cortical regions rather than subcortical regions. Additionally, regarding their relation to conscious perception, we demonstrated that the cores tend to include regions previously reported to be affected by electrical stimulation that altered conscious perception, although the results are not statistically robust due to the small sample size. Furthermore, in relation to cognitive functions, based on a meta-analysis and comparison of the core structure with a cortical functional connectivity gradient, we found that the central cores were related to unimodal sensorimotor functions. The proposed framework provides novel insights into the roles of network cores with strong bidirectional interactions in conscious perception and unimodal sensorimotor functions.
Thalamocortical interactions reflecting the intensity of flicker light-induced visual hallucinatory phenomena
Authors: Amaya Ioanna A. , Nierhaus Till , Schmidt Timo T.
Published: May 2024

The thalamus has a critical role in the orchestration of cortical activity. Aberrant thalamocortical connectivity occurs together with visual hallucinations in various pathologies and drug-induced states, highlighting the need to better understand how thalamocortical interactions may contribute to hallucinatory phenomena. However, concurring symptoms and physiological changes that occur during psychopathologies and pharmacological interventions make it difficult to distil the specific neural correlates of hallucinatory experiences. Flicker light stimulation (FLS) at 10 Hz reliably and selectively induces transient visual hallucinations in healthy participants. Arrhythmic flicker elicits fewer hallucinatory effects while delivering equal amounts of visual stimulation, together facilitating a well-controlled experimental setup to investigate the neural correlates of visual hallucinations driven by flicker rhythmicity. In this study, we implemented rhythmic and arrhythmic FLS during fMRI scanning to test the elicited changes in cortical activation and thalamocortical functional connectivity. We found that rhythmic FLS elicited stronger activation in higher-order visual cortices compared to arrhythmic control. Consistently, we found that rhythmic flicker selectively increased connectivity between ventroanterior thalamic nuclei and higher-order visual cortices compared to arrhythmic control, which was also found be positively associated with the subjective intensity of visual hallucinatory effects. As these thalamic and cortical areas do not receive primary visual inputs, it suggests that the thalamocortical connectivity changes relate to a higher-order function of the thalamus, such as in the coordination of cortical activity. In sum, we present novel evidence for the role of specific thalamocortical interactions with ventroanterior nuclei within visual hallucinatory experiences. Importantly, this can inform future clinical research into the mechanistic underpinnings of pathologic hallucinations.
Evolutionary convergence of sensory circuits in the pallium of amniotes
Authors: Rueda-Alaña Eneritz , Senovilla-Ganzo Rodrigo , Grillo Marco , Vázquez Enrique , Marco-Salas Sergio , Gallego-Flores Tatiana , Ftara Artemis , Escobar Laura , Benguría Alberto , Quintas-Gorozarri Ana , Dopazo Ana , Rábano Miriam , dM Vivanco María , Aransay Ana María , Garrigos Daniel , Toval Ángel , Ferrán José Luis , Nilsson Mats , Encinas Juan Manuel , De Pitta Maurizio , García-Moreno Fernando
Published: May 2024

The amniote pallium contains sensory circuits structurally and functionally equivalent, yet their evolutionary relationship remains unresolved. Our study employs birthdating analysis, single-cell RNA and spatial transcriptomics, and mathematical modeling to compare the development and evolution of known pallial circuits across birds (chick), lizards (gecko) and mammals (mouse). We reveal that neurons within these circuits’ stations are generated at varying developmental times and brain regions across species, and found an early developmental divergence in the transcriptomic progression of glutamatergic neurons. Together, we show divergent developmental and evolutionary trajectories in the pallial cell types of sauropsids and mammals. Our research highlights significant differences in circuit construction rules among species and pallial regions. Interestingly, despite these developmental distinctions, the sensory circuits in birds and mammals appear functionally similar, which suggest the convergence of high-order sensory processing across amniote lineages.
Action potential propagation speed compensates for traveling distance in the human retina
Authors: Bucci Annalisa , Büttner Marc , Domdei Niklas , Rosselli Federica Bianca , Znidaric Matej , Diggelmann Roland , De Gennaro Martina , Cowan Cameron S. , Harmening Wolf , Hierlemann Andreas , Roska Botond , Franke Felix
Published: May 2024

Neural information processing requires accurately timed action potentials arriving from presynaptic neurons at the postsynaptic neuron. However, axons of ganglion cells in the human retina feature low axonal conduction speeds and vastly different lengths, which poses a challenge to the brain for constructing a temporally coherent image over the visual field. Combining results from microelectrode array recordings, human behavioral measurements, transmission electron microscopy, and mathematical modelling of the retinal nerve fiber layer, we demonstrate that axonal propagation speeds compensate for variations in axonal length across the human retina including the fovea. The human brain synchronizes the arrival times of action potentials at the optic disc by increasing the diameters of longer axons, which increases their propagation speeds.
Ventral pallidal GABAergic neurons drive consumption in male, but not female rats
Authors: Scott Alexandra , Paulson Anika , Prill Collin , Kermoade Klaiten , Newell Bailey , Richard Jocelyn M.
Published: May 2024

Food intake is controlled by multiple converging signals: hormonal signals that provide information about energy homeostasis, but also hedonic and motivational aspects of food and food cues that can drive non-homeostatic or “hedonic “feeding. The ventral pallidum (VP) is a brain region implicated in the hedonic and motivational impact of food and foods cues, as well as consumption of rewards. Disinhibition of VP neurons has been shown to generate intense hyperphagia, or overconsumption. While VP gamma-Aminobutyric acidergic (GABA) neurons have been implicated in cue-elicited reward seeking and motivation, the role of these neurons in the hyperphagia resulting from VP activation remains unclear. Here, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to activate or inhibit VP GABA neurons in sated male and female rats during chow and sucrose consumption. We found that activation of VP GABA neurons increases consumption of chow and sucrose in male rats, but not female rats. We also found that, while inhibition of VP GABA neurons tended to decrease sucrose consumption, this effect was not statistically significant. Together, these findings suggest that activation of VP GABA neurons can stimulate consumption of routine or highly palatable rewards selectively in male rats.
Reversal of Obesity by Enhancing Slow-wave Sleep via a Prokineticin Receptor Neural Circuit
Authors: Han Yong , Xia Guobin , Harris Lauren , Liu Panpan , Guan Dongyin , Wu Qi
Published: May 2024

Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and exacerbates diet-induced obesity (DIO). However, the neural circuit and signaling mechanism underlying the reciprocal control of appetite and sleep is yet not elucidated. Here, we report a neural circuit where prokineticin receptor 2 (PROKR2)-expressing neurons within the parabrachial nucleus (PBN) of the brainstem received direct projections from neuropeptide Y receptor Y2 (NPY2R)-expressing neurons within the lateral preoptic area (LPO) of the hypothalamus. The RNA-Seq results revealedProkr2in the PBN is the most regulated GPCR signaling gene that is responsible for comorbidity of obesity and sleep dysfunction. Furthermore, those NPY2RLPOneurons are minimally active during NREM sleep and maximally active during wakefulness and REM sleep. Activation of the NPY2RLPO→PBN circuit or the postsynaptic PROKR2PBNneurons suppressed feeding of a high-fat diet and abrogated morbid sleep patterns in DIO mice. Further studies showed that genetic ablation of the PROKR2 signaling within PROKR2PBNneurons alleviated the hyperphagia and weight gain, and restored sleep dysfunction in DIO mice. We further discovered pterostilbene, a plant-derived stilbenoid, is a powerful anti-obesity and sleep-improving agent, robustly suppressed hyperphagia and promoted reconstruction of a healthier sleep architecture, thereby leading to significant weight loss. Collectively, our results unveil a neural mechanism for the reciprocal control of appetite and sleep, through which pterostilbene, along with a class of similarly structured compounds, may be developed as effective therapeutics for tackling obesity and sleep disorders.
Representation of navigational affordances and ego-motion in the occipital place area
Authors: Kamps Frederik S. , Chen Emily M. , Kanwisher Nancy , Saxe Rebecca
Published: May 2024

Humans effortlessly use vision to plan and guide navigation through the local environment, or “scene”. A network of three cortical regions responds selectively to visual scene information, including the occipital (OPA), parahippocampal (PPA), and medial place areas (MPA) – but how this network supports visually-guided navigation is unclear. Recent evidence suggests that one region in particular, the OPA, supports visual representations for navigation, while PPA and MPA support other aspects of scene processing. However, most previous studies tested only static scene images, which lack the dynamic experience of navigating through scenes. We used dynamic movie stimuli to test whether OPA, PPA, and MPA represent two critical kinds of navigationally-relevant information: navigational affordances (e.g., can I walk to the left, right, or both?) and ego-motion (e.g., am I walking forward or backward? turning left or right?). We found that OPA is sensitive to both affordances and ego-motion, as well as the conflict between these cues – e.g., turning toward versus away from an open doorway. These effects were significantly weaker or absent in PPA and MPA. Responses in OPA were also dissociable from those in early visual cortex, consistent with the idea that OPA responses are not merely explained by lower-level visual features. OPA responses to affordances and ego-motion were stronger in the contralateral than ipsilateral visual field, suggesting that OPA encodes navigationally relevant information within an egocentric reference frame. Taken together, these results support the hypothesis that OPA contains visual representations that are useful for planning and guiding navigation through scenes.
Bacterial Receptors but Not Anti-Phage Defence Mechanisms Determine Host Range for a Pair ofPseudomonas aeruginosaLytic Phages
Authors: Müller Dea M. , Pourtois Julie D. , Kim Minyoung Kevin , Targ Bobby , Burgener Elizabeth B. , Milla Carlos , McBride Robert , Antani Jyot D. , Turner Paul E. , Koff Jonathan L. , Bollyky Paul L.
Published: May 2024

Lytic bacteriophages (phage), viral predators of bacteria, offer a promising solution for treating bacterial infections. However, the narrow host range of phages limits the broad utility of individual phages, making the determinants of phage host range a subject of great interest. Here, we perform a genome-wide association study (GWAS) to identify bacterial genes associated with resistance or susceptibility to two lytic phages, OMKO1 and LPS-5, recently used in a clinical trial for patients with cystic fibrosis (pwCF). We analyzed 80Pseudomonas aeruginosaclinical isolates collected from pwCF. For OMKO1, genes crucial for infection were associated with biofilm formation, exopolysaccharide synthesis, metabolism, porins, and flagellum assembly. We validate a critical role for flagellum genes in transposon mutagenesis experiments and functional assays. For LPS-5, genes associated with DNA repair, metabolism, and lipopolysaccharide biosynthesis are crucial for infection. We confirme the critical role for LPS/O-antigen in susceptibility to LPS-5. Interestingly, the presence of bacterial genes encoding bacterial defence mechanisms is not predictive of phage susceptibility. Instead, the relative abundance of several known defence elements is associated with the number of temperate phages within bacterial genomes. Together, our findings highlight the central role of receptors in determining phage host range, providing valuable insights for the development of phage-based therapies against bacterial infections.
Heterogeneous local structures of the microtubule lattice revealed by cryo-ET and non-averaging analysis
Authors: Liu Hanjin , Yamaguchi Hiroshi , Kikkawa Masahide , Shima Tomohiro
Published: May 2024

Microtubule cytoskeletons play pivotal roles in various cellular processes, including cell division and locomotion, by dynamically changing their length and distribution in cells through tubulin polymerization/depolymerization. Recent structural studies have revealed the polymorphic lattice structure of microtubules closely correlate with the microtubule dynamics, but the studies were limited to averaged structures. To reveal the transient and localized structures, such as GTP-cap, we developed several non-averaging methods for cryogenic electron tomography to precisely measure the longitudinal spacing and helical twisting of individual microtubule lattices at the tubulin subunit level. Our analysis revealed that polymerizing and depolymerizing ends share a similar structure with regards to lattice spacing. The most distinctive property specific to the polymerizing plus end was left-handed twisting in the inter-dimer interface, suggesting that the twisting might accelerate fast polymerization at the plus ends. Our analysis uncovered the heterogeneity of native microtubules and will be indispensable for the study of microtubules dynamics under physiological contexts or during specific cellular events.
Evidence that minocycline treatment confounds the interpretation of neurofilament as a biomarker
Authors: Gentile Juliana E , Heiss Christina , Corridon Taylor L , Mortberg Meredith A , Fruhwürth Stefanie , Guzman Kenia , Grötschel Lana , Chan Kwan , Herring Neil C , Janicki Timothy , Nhass Rajaa , Sarathy Janani Manavala , Erickson Brian , Kunz Ryan , Erickson Alison , Braun Craig , Henry Katherine T , Bry Lynn , Arnold Steven E , Minikel Eric Vallabh , Zetterberg Henrik , Vallabh Sonia M
Published: May 2024

Neurofilament light (NfL) concentration in cerebrospinal fluid (CSF) and blood serves as an important biomarker in neurology drug development. Changes in NfL are generally assumed to reflect changes in neuronal damage, while little is known about the clearance of NfL from biofluids. We observed an NfL increase of 3.5-fold in plasma and 5.7-fold in CSF in an asymptomatic individual at risk for genetic prion disease following 6 weeks’ treatment with oral minocycline for a dermatologic indication. Other biomarkers remained normal, and proteomic analysis of CSF revealed that the spike was exquisitely specific to neurofilaments. NfL dropped nearly to normal levels 5 weeks after minocycline cessation, and the individual remained free of disease 2 years later. Plasma NfL in dermatology patients was not elevated above normal controls. Dramatically high plasma NfL (>500 pg/mL) was variably observed in some hospitalized individuals receiving minocycline. In mice, treatment with minocycline resulted in variable increases of 1.3- to 4.0-fold in plasma NfL, with complete washout 2 weeks after cessation. In neuron-microglia co-cultures, minocycline increased NfL concentration in conditioned media by 3.0-fold without any visually obvious impact on neuronal health. We hypothesize that minocycline does not cause or exacerbate neuronal damage, but instead impacts the clearance of NfL from biofluids, a potential confounder for interpretation of this biomarker.
Diversity and impact of single-stranded RNA viruses in CzechHeterobasidionpopulations
Authors: Dálya László Benedek , Černý Martin , de la Peña Marcos , Poimala Anna , Vainio Eeva J. , Hantula Jarkko , Botella Leticia
Published: May 2024

Heterobasidion annosumsensu lato comprises some of the most devastating conifer pathogens conifers. Exploring virocontrol as a potential strategy to mitigate economic losses caused by these fungi holds promise for the future. In this study, we conducted a comprehensive screening for viruses in a 98H. annosums.l. specimens from different regions of Czechia aiming to identify viruses inducing hypovirulence. Initial examination for dsRNA presence was followed by RNA-Seq analyses using pooled RNA libraries constructed fromH. annosumandHeterobasidion parviporum, with diverse bioinformatic pipelines employed for virus discovery. Our study uncovered 25 distinct ssRNA viruses, including two ourmia-like viruses, one mitovirus, one fusarivirus, one tobamo-like virus, one cogu-like virus, one bisegmented narna-like virus and one segment of another narna-like virus, and 17 ambi-like viruses, for which hairpin and hammerhead ribozymes were detected. Coinfections of up to 10 viruses were observed in sixHeterobasidionisolates, while another six harbored a single virus. 73% of the isolates analyzed by RNA-Seq were virus-free. These findings show that the virome ofHeterobasidionpopulations in Czechia is highly diverse and differs from that in the boreal region. We further investigated the host effects of certain identified viruses through comparisons of the mycelial growth rate and proteomic analyses and found that certain tested viruses caused growth reductions of up to 22% and significant alterations in the host proteome profile. Their intraspecific transmission rates ranged from 0% to 33%. Further studies are needed to fully understand the biocontrol potential of these virusesin planta.

Importance

First report of a fusarivirus, a tobamo- and a cogu-like virus inHeterobasidion

Certain viruses caused mycelial growth reduction inH. annosumhost strains

Viral infections lead to proteome changes inHeterobasidion
Cholesterol Metabolite 27-Hydroxycholesterol Enhances the Secretion of Cancer Promoting Extracellular Vesicles by a Mitochondrial ROS-Induced Impairment of Lysosomal Function
Authors: Das Gupta Anasuya , Park Jaena , Sorrells Janet E. , Kim Hannah , Krawczynska Natalia , Vidana Gamage Hashni Epa , Nelczyk Adam T. , Boppart Stephen A. , Boppart Marni D. , Nelson Erik R.
Published: May 2024

Extracellular vesicles (EVs) serve as crucial mediators of cell-to-cell communication in normal physiology as well as in diseased states, and have been largely studied in regard to their role in cancer progression. However, the mechanisms by which their biogenesis and secretion are regulated by metabolic or endocrine factors remain unknown. Here, we delineate a mechanism by which EV secretion is regulated by a cholesterol metabolite, 27-Hydroxycholesterol (27HC), where treatment of myeloid immune cells (RAW 264.7 and J774A.1) with 27HC impairs lysosomal homeostasis, leading to shunting of multivesicular bodies (MVBs) away from lysosomal degradation, towards secretion as EVs. This impairment of lysosomal function is caused by mitochondrial dysfunction and subsequent increase in reactive oxygen species (ROS). Interestingly, cotreatment with a mitochondria-targeted antioxidant rescued the lysosomal impairment and attenuated the 27HC-mediated increase in EV secretion. Overall, our findings establish how a cholesterol metabolite regulates EV secretion and paves the way for the development of strategies to regulate cancer progression by controlling EV secretion.
Atlas of imprinted and allele-specific DNA methylation in the human body
Authors: Rosenski Jonathan , Peretz Ayelet , Magenheim Judith , Loyfer Netanel , Shemer Ruth , Glaser Benjamin , Dor Yuval , Kaplan Tommy
Published: May 2024

Allele-specific DNA methylation, determined genetically or epigenetically, is involved in gene regulation and underlies multiple pathologies. Yet, our knowledge of this phenomenon is partial, and largely limited to blood lineages. Here, we present a comprehensive atlas of allele-specific DNA methylation, using deep whole-genome sequencing across 39 normal human cell types. We identified 325k genomic regions, covering 6% of the genome and containing 11% of all CpG sites, that show a bimodal distribution of methylated and unmethylated molecules. In 34K of these regions, genetic variations at individual alleles segregate with methylation patterns, thus validating allele-specific methylation. We also identified 460 regions showing parentally-imprinted methylation, the majority of which were not previously reported. Surprisingly, sequence-dependent and parent-dependent methylation patterns are often restricted to specific cell types, revealing unappreciated variation in the human allele-specific methylation across the human body. The atlas provides a resource for studying allele-specific methylation and regulatory mechanisms underlying imprinted expression in specific human cell types.

Highlights

A comprehensive atlas of allele-specific methylation in primary human cell types

325k genomic regions show a bimodal pattern of of hyper- and hypo-methylation of DNA

Allele-specific methylation at 34k genomic regions

Tissue-specific effects at known imprinting control regions (ICRs)

100s of novel loci exhibiting parentally-imprinted methylation

Parentally-imprinting methylation is often cell-type-specific
Engineered Ubiquitin Variants Mitigate Pathogenic Bacterial Ubiquitin Ligase Function
Authors: Dubrule Bradley E. , Wagner Ashley , Zhang Wei , Middleton Adam J. , Subramanian Adithya S. , Eitzen Gary , Sidhu Sachdev S. , Bhavsar Amit P.
Published: May 2024

During infection some pathogenic gram-negative bacteria, such asSalmonella, manipulate the host ubiquitination system through the delivery of secreted effectors known as novel E3 ubiquitin ligases (NELs). Despite the presence of NELs amongst these well-studied bacterial species, their unique structure has limited the tools that are available to probe their molecular mechanisms and explore their therapeutic potential. In this work, we report the identification of two high affinity engineered ubiquitin variants that can modulate the activity of theSalmonella entericaserovar Typhimurium encoded NEL, SspH1. We show that these ubiquitin variants suppress SspH1-mediated toxicity phenotypes inSaccharomyces cerevisiae. Additionally, we provide microscopic and flow cytometric evidence that SspH1-mediated toxicity is caused by interference withS. cerevisiaecell cycle progression that can be suppressed in the presence of ubiquitin variants.In vitroubiquitination assays revealed that these ubiquitin variants increased the amount of SspH1-mediated ubiquitin chain formation. Interestingly, despite the increase in ubiquitin chains, we observe a relative decrease in the formation of SspH1-mediated K48-linked ubiquitin chains on its substrate, PKN1. Taken together our findings suggest that SspH1 toxicity inS. cerevisiaeoccurs through cell cycle interference and that an engineered ubiquitin variant approach can be used to identify modulators of bacterially encoded ubiquitin ligases.

Author Summary

Novel E3 ligases (NELs) are a family of secreted effectors found in various pathogenic gram- negative bacteria. During infection these effectors hijack vital host ubiquitin signaling pathways to aid bacterial invasion and persistence. Despite interacting with a protein as highly conserved as ubiquitin, they have a distinct architecture relative to the eukaryotic E3 enzymes. This unique architecture combined with the indispensable role ubiquitin signaling plays in host cell survival has made hindering the contribution of NELs to bacterial infections a difficult task. Here, we applied protein engineering technology to identify two ubiquitin variants (Ubvs) with high affinity for SspH1, aSalmonella-encoded NEL. We provide evidence that these high affinity Ubvs suppress a known SspH1-meidated toxicity phenotype in the eukaryotic model systemSaccharomyces cerevisiae. We also show that this suppression occurs without interfering with host ubiquitin signaling. Furthermore, we demonstrate the ability of a Ubv to modulate the activity of SspH1in vitro, ultimately altering the lysine linkages found in SspH1-mediated ubiquitination. To our knowledge, this is the first evidence that an engineered ubiquitin variant approach can be implemented to modulate the activity of a family of previously untargetable bacterial-encoded E3 ligases.
Dysregulation of Kappa Opioid Receptor Neuromodulation of Lateral Habenula Synaptic Function following a Repetitive Mild Traumatic Brain Injury
Authors: Flerlage William J. , Simmons Sarah C. , Thomas Emily H. , Gouty Shawn , Cox Brian M. , Nugent Fereshteh S.
Published: May 2024

Mild traumatic brain injury (mTBI) increases the risk of cognitive deficits, affective disorders, anxiety and substance use disorder in affected individuals. Substantial evidence suggests a critical role for the lateral habenula (LHb) in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between persistent mTBI-induced LHb hyperactivity due to synaptic excitation/inhibition (E/I) imbalance and motivational deficits in self-care grooming behavior in young adult male mice using a repetitive closed head injury mTBI model. One of the major neuromodulatory systems that is responsive to traumatic brain and spinal cord injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function is unknown. To address this, we first used retrograde tracing to anatomically verify that the mouse LHb indeed receives Dyn/KOR expressing projections. We identified several major KOR-expressing and Dyn-expressing synaptic inputs projecting to the mouse LHb. We then functionally evaluated the effects ofin vitroKOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4week post-injury using the repetitive closed head injury mTBI model. Similar to what we previously reported in the LHb of male mTBI mice, mTBI presynaptically diminished spontaneous synaptic activity onto LHb neurons, while shifting synaptic E/I toward excitation in female mouse LHb. Furthermore, KOR activation in either mouse male/female LHb generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant reduction in E/I ratios and decreased excitatory synaptic drive to LHb neurons of male and female sham mice. Interestingly following mTBI, while responses to KOR activation at LHb glutamatergic synapses were observed comparable to those of sham, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition. Thus, in contrast to sham LHb, we observed a reduction in GABA release probability in response to KOR stimulation in mTBI LHb, resulting in a chronic loss of KOR-mediated net synaptic inhibition within the LHb. Overall, our findings uncovered the previously unknown sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. Further, we demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global suppression of excitatory synaptic drive to the mouse LHb which could act as an inhibitory braking mechanism to prevent LHb hyperexcitability. The additional engagement of KOR-mediated modulatory action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons in male and female mTBI mice.