bluuebunny/crossref_metadata_2025 huggingface dataset:
BASELINE SATTLER LAYER–CHORIOCAPILLARIS COMPLEX THICKNESS CUTOFFS ASSOCIATED WITH AGE-RELATED MACULAR DEGENERATION PROGRESSION
Authors: Amato Alessia , Arrigo Alessandro , Borghesan Federico , Aragona Emanuela , Vigano' Chiara , Saladino Andrea , Bandello Francesco , Battaglia Parodi Maurizio
Published: May 2022

Purpose:

To assess the relationship between choroidal overall and sublayer thickness and age-related macular degeneration (AMD) stage progression.

Methods:

A prospective, observational case series was performed. Two hundred and sixty-two eyes of 262 patients with different stages of AMD were imaged by optical coherence tomography. Age-related macular degeneration stage, choroidal thickness, Sattler layer–choriocapillaris complex thickness (SLCCT), and Haller layer thickness were determined at the baseline visit, at a 1-year follow-up visit, at a 2-year follow up visit, and at a final visit (performed after a mean of 5 ± 1 year from the baseline visit).

Results:

Baseline AMD stages were distributed as follows: early AMD (30 eyes; 12%), intermediate AMD (97 eyes; 39%), and late AMD (126 eyes; 49%). At the final follow-up, AMD stages were so distributed: early AMD (14 eyes; 6%), intermediate AMD (83 eyes; 33%), and late AMD (156 eyes; 61%). Each group showed a statistically significant decrease in choroidal thickness values over the entire follow-up (P < 0.001), and SLCCT reduction was associated with AMD progression (P < 0.001). Moreover, SLCCT quantitative cutoffs of <20.50 µm and <10.5 µm were associated with a moderate and high probability of AMD progression, respectively, and SLCCT quantitative cutoffs of <18.50 µm and <8.50 µm implied a moderate and high probability of macular neovascularization onset, respectively.

Conclusion:

Progressive choroidal impairment contributes to AMD progression. Among choroidal layers, a reduced SLCCT is a promising biomarker of disease worsening, and its quantitative evaluation could help to identify patients at higher risk of stage advancement.
Long-Term Outcomes of Bariatric Surgery in Idiopathic Intracranial Hypertension Patients
Authors: Hermes Sam M. , Bharadwaj Madhumithaa , Miller Nick R. , Waslo Carin , Husain Farah A. , Wolfe Bruce M. , Tanne Emanuel
Published: May 2022

Background:

Idiopathic intracranial hypertension (IIH), a rare neurological disorder, has limited effective long-term treatments. Bariatric surgery has shown short-term promise as a management strategy, but long-term efficacy has not been evaluated. We investigated IIH-related outcomes 4 to 16 years postsurgery.

Materials and Methods:

This cross-sectional retrospective cohort study included Intracranial Hypertension Registry (IHR) participants with existing medical records that completed a bariatric surgery questionnaire at least 4 years postsurgery. Two physicians independently evaluated the IIH disease course at bariatric surgery and at the time of the questionnaire using detailed medical records. Determinations of improvements were based on within-participant comparisons between the 2 time points. IIH-related outcomes were then combined with bariatric surgery information and outcomes to assess the relationship between weight loss and alterations in IIH.

Results:

Among participants that underwent bariatric surgery and met study criteria (n=30) the median body mass index (BMI) at the time of surgery was 45.0 [interquartile range (IQR): 39.8-47.0], dropped to a postsurgical nadir of 27.3 (IQR: 22.8-33.1), and rose to 33.4 (IQR: 29.9-41.7) at the time of the questionnaire. Improvements in the IIH disease course at time of the questionnaire occurred in 37% of participants. However, there was a notable association between durable weight loss and IIH improvement as 90% (9 of 10) of participants that attained and maintained a BMI of 30 or below displayed improvement.

Conclusions:

Attaining and maintaining a BMI of 30 or below was associated with long-term improvement in the IIH disease course, including improved disease management and amelioration of signs and symptoms of participants of the IHR.
Menopause Hormone Therapy in the Management of Postmenopausal Osteoporosis
Authors: Rozenberg Serge , Vandromme Jean , Revercez Perrine , Valcarenghi Mathilde , Joris Aurélie
Published: May 2022

This narrative review analyzes the customization of menopause hormone therapy (MHT) for osteoporosis prevention and treatment in the context of the patients' age and menopausal age. In short, MHT is indicated in most women suffering from menopause before the age of 45 years except for breast cancer survivors. These women should be treated with MHT until the age of 50 years. For women who have entered menopause at around the age of 50 years, risks associated with MHT are low, and MHT is a safe option, provided there is an indication for it. We suggest that pursuing MHT entails different risks than initiating it, after the age of 60 years. In both cases, advantages and risks should be evaluated. We suggest using risk calculators to assess the magnitude of these risks and choosing regimens that entail the lowest breast and thrombosis risks.
Effective Image Communication of Hormone Replacement Therapy Risks and Benefits
Authors: Rifkin Erik
Published: May 2022

This article focuses on the value of a unique graphic/image designed to communicate health risks and benefits related to the administration of hormone replacement therapy. It will demonstrate why equations, technical terms, and confusing rhetoric need not be used for communication to patients and others. The use of a “familiar” theater graphic (given the name Benefit/Risk Characterization Theater) will allow physicians and patients to share decision-making by visualizing tradeoffs through the use of a clearer format: example Benefit/Risk Characterization Theaters: breast cancer risks associated with hormone replacement therapy, effectiveness of estrogen in treating menopausal symptoms, and thromboembolic risk of taking estrogen for postmenopausal women. The article describes a practical, simple methodology that can be used in many countries to facilitate doctor-patient communication.
Individual Benefits and Risks of Intravaginal Estrogen and Systemic Testosterone in the Management of Women in the Menopause, With a Discussion of Any Associated Risks for Cancer Development
Authors: Laing Abbie J. , Newson Louise , Simon James A.
Published: May 2022

Several formulations of intravaginal oestrogen are available for the treatment of genitourinary syndrome of menopause (GSM). These are safe and effective treatments for the symptoms of GSM. Licensed doses of intravaginal oestrogen do not elevate systemic estradiol levels above the normal postmenopausal range with long term use and there is no evidence of an increased risk of coronary heart disease, stroke, thromboembolism, colorectal cancer, endometrial cancer, breast cancer or breast cancer recurrence with their use. This should reassure both women and their healthcare professionals and should lead to more women receiving these localised, vaginally administered hormonal treatments. Available evidence also suggests a positive safety profile for transdermal testosterone treatment when delivered at physiological concentrations.
Percutaneous auricular nerve stimulation (neuromodulation) for the treatment of pain: A proof-of-concept case report using total joint arthroplasty as a surrogate for battlefield trauma
Authors: Ilfeld Brian M. , Finneran John J. , Said Engy T. , Cidambi Krishna R. , Ball Scott T.
Published: May 2022

BACKGROUND

There are few effective pain treatments following trauma on the battlefield other than opioids, which are limited by respiratory depression. Ultrasound-guided percutaneous peripheral nerve stimulation (“neuromodulation”) has been proposed as an analgesic, but requires physician-level skills, advanced equipment, and an hour to administer. In contrast, percutaneous auricular neuromodulation may be placed by a medic in the field under nonsterile conditions in a few minutes, theoretically provides analgesia for any anatomic location, has no side effects, and no significant risks. It therefore offers the potential to be applied quickly on the battlefield without any of the limitations of opioids. We propose total joint replacement as a surrogate for battlefield trauma and here present a case report to demonstrate proof of concept.

METHODS

Following open total knee or hip arthroplasty under spinal anesthesia, two patients had an auricular neuromodulation device applied within the recovery room. Patients were discharged with the unit and contacted daily for 7 days.

RESULTS

The devices were each applied in under 3 minutes without difficulty, were well tolerated during use, and removed without complication at home on Day 5. During use, neither patient experienced pain while lying, sitting, or ambulating. Neither required analgesics other than scheduled celecoxib; and a single tablet (50 mg) of tramadol for one patient on postoperative Days 3 and 4 for pain while lowering herself to a seated position. On Days 6 and 7, both patients experienced an increase in pain, one of whom required around-the-clock tramadol.

CONCLUSION

Ambulatory postoperative percutaneous auricular neuromodulation is feasible. In these two cases, it appears to have markedly reduced pain scores and opioid requirements free of systemic side effects during the week following major orthopedic surgery. Considering the potential of this modality to treat trauma on the battlefield without systemic side effects, additional investigation appears warranted.

LEVEL OF EVIDENCE

Therapeutic/care management; Level V.
Effect of exercise from a very early stage after intracerebral hemorrhage on microglial and macrophage reactivity states in rats
Authors: Tamakoshi Keigo , Maeda Madoka , Murohashi Nae , Saito Ami
Published: May 2022

Objective

This study investigated the effects of exercise, starting very early after intracerebral hemorrhage (ICH), on microglia and macrophages in a rat model. Collagenase solution was injected into the left striatum to induce ICH.

Methods

Rats were randomly assigned to receive placebo surgery without exercise (sham surgery), ICH without exercise (ICH), or ICH with very early exercise (ICH + VET). The ICH + VET group was subjected to treadmill running 6 h, 24 h, and days 2–6 after ICH. Motor function assessment was performed using the ladder test and rotarod test 3 h, 25 h, and 7 days after ICH. Postexercise brain tissue was collected on day 8 after surgery to investigate the lesion volume. Very early exercise temporarily worsened motor dysfunction. The protein expression levels of the macrophage and microglial markers CD80, CD163, and TMEM119 were analyzed 6 h, 24 h, and 8 days after ICH. Protein analysis of NeuN, GFAP, and PSD95 was also performed on day 8 after ICH.

Results

There was no significant difference in lesion volume between the ICH and ICH + VET groups on day 8 after ICH. Exercise from very early stage prevented elevated CD163 protein expression.

Conclusion

Very early exercise may inhibit the activation of anti-inflammatory-associated macrophages/microglia.
eEF1A2 knockdown impairs neuronal proliferation and inhibits neurite outgrowth of differentiating neurons
Authors: Rumpansuwon Kanitin , Prommahom Athinan , Dharmasaroja Permphan
Published: May 2022

Objectives

The translation elongation factor-1, alpha-2 (eEF1A2) plays an important role in protein synthesis. Mutations in this gene have been described in individuals with neurodevelopmental disorders. Here, we silenced the expression of eEFA2 in human SH-SY5Y neuroblastoma cells and observed its roles in neuronal proliferation and differentiation upon induction with retinoic acid.

Methods

eEF1A2 were silenced using siRNA transfection. Cell proliferation was qualitatively evaluated by Ki-67 immunocytochemistry. Neuronal differentiation was induced with retinoic acid for 3, 5, 7 and 10 days. Neurite length was measured. The expression of microtubule-associated protein 2 (MAP2) was analyzed by western blotting. Tyrosine hydroxylase expression was visualized by immunofluorescence. Cytotoxicity to a neurotoxin, 1-methyl-4-phenylpyridinium (MPP+), was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and western blotting of cleaved caspase-3.

Results

eEF1A2 knockdown suppressed the proliferative activity of undifferentiated SH-SY5Y cells as shown by decreased Ki-67 immunostaining. Upon retinoic acid-induction, differentiated neurons with eEF1A2 knockdown exhibited shorter neurite length than untransfected cells, which was associated with the reduction of tyrosine hydroxylase and suppression of MAP2 at 10 days of differentiation. eEF1A2 knockdown decreased the survival of neurons, which was clearly observed in undifferentiated and short-term differentiated cells. Upon treatment with MPP+, cells with eEF1A2 knockdown showed a further reduction in cell survival and an increase of cleaved caspase-3 protein.

Conclusions

Our results suggest that eEF1A2 may be required for neuronal proliferation and differentiation of SH-SY5Y cells. Increased cell death susceptibility against MPP+ in eEF1A2-knockdown neurons may imply the neuroprotective role of eEF1A2.
The presence of occlusion affects electroencephalogram activity patterns when the target is occluded and immediately before occlusion
Authors: Koshizawa Ryo , Oki Kazuma , Takayose Masaki
Published: May 2022

Objective

The objective of this study was to clarify the differences in electroencephalogram (EEG) activity patterns during the eye movements required to trace visible and occluded moving targets with millisecond temporal resolution.

Methods

To achieve this objective, we simultaneously measured EEG and eye-tracking during a task that required tracking moving targets that were partially occluded. These EEG and eye tracker parameters were compared with those of a nonoccluded task, a control task in which the moving target was fully visible.

Results

Differences in EEG activity patterns in the parietal eye field and posterior parietal lobe were observed during the occluded sections in the occluded task compared with the nonoccluded task. Under the same conditions, differences in EEG activity patterns in the middle temporal visual area, posterior parietal lobe, premotor, primary motor cortex, and temporal lobe were observed during visible sections in the occluded task compared with the nonoccluded task.

Conclusion

These results indicate that the presence of occlusion affects EEG activity patterns not only when the target is occluded but also immediately before occlusion.
Volumetric changes in specific neurofunctional subfields of the hippocampus in major depressive disorder
Authors: Wang Yuning , Wang Yi , Zhou Jing , Ge Chenjin , Shi Yin , Hu Zhihai
Published: May 2022

Objective

There is evidence that hippocampal volume is abnormal in patients with major depressive disorder (MDD), but there have been no studies on volumetric changes in different subfields based on functional topography. This was investigated in the present study by comparing hippocampal neurofunctional subfield volumes between MDD patients and healthy control (HC) subjects.

Methods

Patients with MDD (n = 44) and HCs (n = 27) recruited at Shanghai Traditional Chinese Medicine Integrated Hospital underwent a T1-weighted anatomical MRI scan in the sagittal orientation, and the data were used to calculate hippocampal subfield volumes. Logistic regression was used to evaluate the association between the volumes and risk of MDD. A nomogram for predicting MDD risk based on volume changes in different subfields was developed, and its predictive power was evaluated by calculating the concordance (C)-index.

Results

Compared with HCs, MDD patients showed reduced volume in hippocampal neurofunctional subfields, specifically in left (L)1, right (R)1, and R2 (related to emotion) and L2, L3, and R4 (related to cognition and perception). The logistic regression analysis revealed that the risk of MDD was 4.59-, 5.8-, 8.33-, and 6.92-fold higher with atrophies of L1, L2, L3, and R4, respectively. A nomogram for predicting MDD risk was developed based on age; sex; and hippocampal L1, L2, L3, and R4 subfield volumes and showed good accuracy, with a C-index of 0.784.

Conclusion

Volumetric changes in the neurofunctional subfield of the hippocampus are potential imaging markers that can predict the occurrence of MDD.
Alterations in white matter microstructural properties after lingual strength exercise in patients with dysphagia
Authors: Krekeler Brittany N , Hou Jiancheng , Nair Veena A. , Prabhakaran Vivek , Rusche Nicole , Rogus-Pulia Nicole , Robbins JoAnne
Published: May 2022

Objectives

Central nervous system effects of lingual strengthening exercise to treat dysphagia remain largely unknown. This pilot study measured changes in microstructural white matter to capture alterations in neural signal processing following lingual strengthening exercise.

Methods

Diffusion-weighted images were acquired from seven participants with dysphagia of varying etiologies, before and after lingual strengthening exercise (20 reps, 3×/day, 3 days/week, 8 weeks), using a 10-min diffusion sequence (9 b0, 56 directions with b1000) on GE750 3T scanner. Tract-Based Spatial Statistics evaluated voxel-based group differences for fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity and local diffusion homogeneity (LDH). Paired t-tests evaluated treatment differences on each metric (P < 0.05).

Results

After lingual strengthening exercise, lingual pressure generation increased (avg increase = 46.1 hPa; nonsignificant P = 0.52) with these changes in imaging metrics: (1) decrease in fractional anisotropy, forceps minor; (2) increase in mean diffusivity, right inferior fronto-occipital fasciculus (IFOF); (3) decrease in mean diffusivity, left uncinate fasciculus; (4) decrease in axial diffusivity, both left IFOF and left uncinate fasciculus; (5) increase in LDH, right anterior thalamic radiation and (6) decrease in LDH, temporal portion of right superior longitudinal fasciculus. There was a positive correlation between diffusion tensor imaging metrics and change in lingual pressure generation in left IFOF and the temporal portion of right superior longitudinal fasciculus.

Conclusions

These findings suggest that lingual strengthening exercise can induce changes in white matter structural and functional properties in a small group of patients with dysphagia of heterogeneous etiologies. These procedures should be repeated with a larger group of patients to improve interpretation of overall lingual strengthening exercise effects on cortical structure and function.
Impact of hierarchical processing levels on division of labor: neural electrophysiological evidence from a joint rule shifting
Authors: Han Jiahui , Guan Lei , Zhu Chengdong
Published: May 2022

Objectives

Although previous studies have revealed the behavioral and neural mechanisms underlying cognitive control, the neural electrophysiological process in joint task switching has rarely been discussed. Moreover, the hierarchy process remains unclear. Therefore, the present study aimed to explore the neural mechanism of a target when two actors use division of labor between action selections in a joint hierarchical rule-shifting situation.

Methods

The present study employed a joint hierarchical rule shifting paradigm, and each participant was responsible for the selection of one type of action (left key and right key). The cue was the letter ‘R’ with three features, which indicated the hierarchical rule of the current trial. The target was an Arabic numeral (1–9, except 5). Participants made a magnitude judgement or a parity judgment based on the high and low hierarchical features of cues.

Results

The P2 component was smaller in the high-shift condition than in the repeat condition; however, the high-shift condition elicited a larger N2 amplitude than the low-shift and repeat conditions. We believe that the current P2 is related to selective attention to the hierarchical features of rules, and N2 is related to conflict control. In addition, the high-shift condition had the largest P3 amplitude, which indicates that this condition has the largest extent of update and leads to the most unstable association between rule and stimuli.

Conclusions

The study demonstrated that participants had dynamic brain responses to target stimuli in the joint rule-shifting situation. In other words, participants first confirmed the actor of the current target and then processed the target stimuli themselves.
Rotavirus exploits SREBP pathway for hyper lipid biogenesis during replication
Authors: Naveed Ahsan , Naveed Muhammad Ammar , Akram Lubna , Sharif Muhammad , Kang Mun-Il , Park Sang-Ik
Published: May 2022

Species A rotavirus (RVA) is one of the pathogens causing severe acute gastroenteritis in young children and animals worldwide. RVA replicates and assembles its immature particle within electron dense compartments known as viroplasm. Despite the importance of lipid droplet (LD) formation in the RVA viroplasm, the upstream molecules modulating LD formation have remained elusive. Here, we demonstrate that RVA infection reprogrammes sterol regulatory element binding proteins (SREBPs)-dependent lipogenic pathways in virus-infected cells. Interestingly, silencing of SREBPs significantly reduced RVA protein synthesis, genome replication and progeny virus production. Moreover, knockout of SREBP-1c gene conferred resistance to RVA-induced diarrhoea, reduction of RVA replication, and mitigation of small intestinal pathology in mice. This study identifies SREBPs-mediated lipogenic reprogramming in RVA-infected host cells for facilitating virus replication and SREBPs as a potential target for developing therapeutics against RVA infection.
The role of sigma factor competition in bacterial adaptation under prolonged starvation
Authors: Nandy Pabitra
Published: May 2022

The study of adaptive microbial evolution in the laboratory can illuminate the genetic mechanisms of gaining fitness under a pre-defined set of selection factors. Laboratory evolution of bacteria under long-term starvation has gained importance in recent years because of its ability to uncover adaptive strategies that overcome prolonged nutrient limitation, a condition often encountered by natural microbes. In this evolutionary paradigm, bacteria are maintained in an energy-restricted environment in a growth phase called long-term stationary phase (LTSP). This phase is characterized by a stable, viable population size and highly dynamic genetic changes. Multiple independent iterations of LTSP evolution experiments have given rise to mutants that are slow-growing compared to the ancestor. Although the antagonistic regulation between rapid growth and the stress response is well-known in bacteria (especially

Escherichia coli

), the growth deficit of many LTSP-adapted mutants has not been explored in detail. In this review, I pinpoint the trade-off between growth and stress response as a dominant driver of evolutionary strategies under prolonged starvation. Focusing on mainly

E. coli

-based research, I discuss the various affectors and regulators of the competition between sigma factors to occupy their targets on the genome, and assess its effect on growth advantage in stationary phase (GASP). Finally, I comment on some crucial issues that hinder the progress of the field, including identification of novel metabolites in nutrient-depleted media, and the importance of using multidisciplinary research to resolve them.
First direct observation of ‘elongated’ conformational states in α-synuclein upon liquid-liquid phase separation
Authors: Ubbiali Daniele , Fratini Marta , Piersimoni Lolita , Ihling Christian H. , Kipping Marc , Heilmann Ingo , Iacobucci Claudio , Sinz Andrea
Published: May 2022

α-Synuclein (α-syn) is an intrinsically disordered protein (IDP) that undergoes liquid-liquid phase separation (LLPS), fibrillation, and forms insoluble intracellular Lewy’s bodies in neurons, which are the hallmark of Parkinson’s Disease (PD). Neurotoxicity precedes the formation of aggregates and is probably related to LLPS of α-syn in the cell. The molecular mechanisms underlying the early stages of LLPS are still elusive. To obtain structural insights into α-syn upon LLPS, we take advantage of cross-linking/mass spectrometry (XL-MS) and introduce an innovative approach, termed COMPASS (COMPetitive PAiring StatisticS). COMPASS unravels transient interactions between α-syn molecules in liquid droplets. In this work, we show that the conformational ensemble of α-syn shifts from a ‘hairpin-like’ structure towards more ‘elongated’ conformational states upon LLPS. We obtain insights into the critical initial stages of PD and establish a novel mass spectrometry-based approach that will aid to solve open questions in LLPS structural biology.
Evolutionarily conserved effects of Notch signaling drive intestinal graft-versus-host disease in mice and non-human primates
Authors: Tkachev Victor , Vanderbeck Ashley , Perkey Eric , Furlan Scott N. , McGuckin Connor , Atria Daniela Gómez , Gerdemann Ulrike , Rui Xianliang , Lane Jennifer , Hunt Daniel J. , Zheng Hengqi , Colonna Lucrezia , Hoffman Michelle , Yu Alison , Kelly Samantha , Allman Anneka , Burbach Brandon , Shimizu Yoji , Panoskaltsis-Mortari Angela , Chen Guoying , Carpenter Stephen M. , Harari Olivier , Kuhnert Frank , Thurston Gavin , Blazar Bruce R. , Kean Leslie S. , Maillard Ivan
Published: May 2022

Notch signaling promotes T-cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like ligand DLL4. To assess if Notch’s effects are evolutionarily conserved and identify key mechanisms, we studied antibody-mediated DLL4 blockade in a non-human primate model similar to human allo-HCT. Short-term DLL4 blockade improved post-transplant survival with striking, durable protection from gastrointestinal GVHD, out of proportion to other disease sites. Unlike prior immunosuppressive strategies, anti-DLL4 interfered with a T-cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin a4b7 in conventional T-cells via b1 competition for a4 binding, while preserving a4b7 in regulatory T-cells. Thereby, DLL4/Notch blockade decreased effector T-cell infiltration into the gut, with increased regulatory to conventional T-cell ratios early after allo-HCT. Our results identify a conserved, biologically unique and targetable role of DLL4/Notch signaling in GVHD.

One Sentence Summary

Notch signaling promotes pathogenic effector T cell infiltration of the intestine during acute graft-versus-host disease.
Mixture Margin Random-effects Copula Models for Inferring Temporally Conserved Microbial Co-variation Networks from Longitudinal Data
Authors: Deek Rebecca A. , Li Hongzhe
Published: May 2022

Longitudinal microbiome studies, in which data on a single subject is collected repeatedly over time, are becoming increasingly common in biomedical research. Such studies provide an opportunity to study the inherently dynamic nature of a microbiome in a way that cannot be done using cross-sectional studies. In this paper, we develop random-effects copula models with mixed zero-beta margins to identify biologically meaningful temporally conserved co-variation between two bacterial taxa, while accounting for the excessive zeros seen in 16S rRNA and metagenomic sequencing data. The model assumes a random-effects model for the dependence parameter in the copulas, which captures the conserved microbial co-variation while allowing for a time-specific dependence parameters. We develop a Monte Carlo EM algorithm for efficient estimation of model parameters and a corresponding Monte Carlo likelihood ratio test for the mean dependence parameter. Simulation studies show that our test controls the Type I error rate and provides an unbiased estimate of the mean dependence parameter. Additionally, we apply our method to a longitudinal pediatric cohort and identify changes in both local and global patterns of microbial co-variation networks in infants treated with antibiotics. Our analysis shows that the no antibiotics network is less dependent on individual taxon, thus making it more stable than the antibiotics network and more robust to both targeted and random attacks.

Author summary

Identification of co-variation between two microbes in microbial communities provides important insights into the community structure and stability. The commonly used measures of co-variation do not handle excessive zeros observed in the data and cannot be applied to longitudinal microbiome data directly. In this paper, we develop random-effects copula models with mixed zero-beta margins to identify biologically meaningful temporally conserved co-variation between two bacterial taxa, while accounting for the excessive zeros seen in 16S rRNA and metagenomic sequencing data. The model captures the conserved microbial co-variations while allowing for a time-specific dependence parameters. We develop an efficient Monte Carlo-based algorithm for parameter estimation and statistical inference. We analyze the data from a pediatric longitudinal cohort and identify changes in both local and global patterns of microbial co-variation networks in infants treated with antibiotics.
Long-term imaging reveals behavioral plasticity during C. elegans dauer exit
Authors: Preusser Friedrich , Neuschulz Anika , Junker Jan Philipp , Rajewsky Nikolaus , Preibisch Stephan
Published: May 2022

During their lifetime, animals must adapt their behavior to survive in changing environments. This ability requires the nervous system to adjust through dynamic expression of neurotransmitters and receptors but also through growth, spatial reorganization and connectivity while integrating external stimuli. For instance, despite having a fixed neuronal cell lineage, the nematode Caenorhabditis elegans’ nervous system remains plastic throughout its development. Here, we focus on a specific example of nervous system plasticity, the C. elegans dauer exit decision. Under unfavorable conditions, larvae will enter the non-feeding and non-reproductive dauer stage and adapt their behavior to cope with a new environment. Upon improved conditions, this stress resistant developmental stage is actively reversed to resume reproductive development. However, how different environmental stimuli regulate the exit decision mechanism and thereby drive the larva’s behavioral change is unknown. To fill this gap, we developed a new open hardware method for long-term imaging (12h) of C. elegans larvae. We identified dauer-specific behavioral motifs and characterized the behavioral trajectory of dauer exit in different environments to identify key decision points. Combining long-term behavioral imaging with transcriptomics, we find that bacterial ingestion triggers a change in neuropeptide gene expression to establish post-dauer behavior. Taken together, we show how a developing nervous system can robustly integrate environmental changes, activate a developmental switch and adapt the organism’s behavior to a new environment.
Computational modeling of posteroanterior lumbar traction by an automated massage bed: predicting intervertebral disc stresses and deformation
Authors: Cardoso Luis , Khadka Niranjan , Dmochowski Jacek , Meneses Edson , Jin Youngsoo , Bikson Marom
Published: May 2022

Spinal traction is a physical intervention that provides constant or intermittent stretching axial force to the lumbar vertebrae to gradually distract spinal tissues into better alignment, reduce intervertebral disc (IVD) pressure, and manage lower back pain (LBP). However, such axial traction may change the normal lordotic curvature, and result in unwanted side effects and/or inefficient reduction of the IVD pressure. An alternative to axial traction has been recently tested, consisting of posteroanterior (PA) traction in supine posture, which was recently shown effective to increase the intervertebral space and lordotic angle using MRI. PA traction aims to maintain the lumbar lordosis curvature throughout the spinal traction therapy while reducing the intradiscal pressure. In this study, we developed finite element simulations of mechanical therapy produced by a commercial thermo-mechanical massage bed capable of spinal PA traction. The stress relief produced on the lumbar discs by the posteroanterior traction system was investigated on human subject models with different BMI (normal, overweight, moderate obese and extreme obese BMI cases). We predict typical traction levels lead to significant distraction stresses in the lumbar discs, thus producing a stress relief by reducing the compression stresses normally experienced by these tissues. Also, the stress relief experienced by the lumbar discs was effective in all BMI models, and it was found maximal in the normal BMI model. These results are consistent with prior observations of therapeutic benefits derived from spinal AP traction.
Identification of Dynamic Microbial Signatures in Longitudinal Studies
Authors: Calle M.Luz , Susin Antoni
Published: May 2022

The study of microbiome dynamics is key for unveiling the role of the microbiome in human health. Addressing the compositional structure of microbiome data is particularly critical in longitudinal studies where compositions measured at different times can yield to different subcompositions.

We propose a new compositional data analysis (CoDA) algorithm for inferring dynamic microbial signatures. The algorithm performs penalized regression over the summary of the log-ratio trajectories (the area under these trajectories) and the inferred microbial signature is expressed as a log-contrast model. Graphical representations of the results are provided to facilitate the interpretation of the analysis: plot of the log-ratio trajectories, plot of the signature and plot of the prediction accuracy of the model. The new proposal is illustrated with data on the developing microbiome of infants.

The algorithm is implemented in the R package “code4microbiome” (https://cran.r-project.org/web/packages/coda4microbiome/) that is accompanied with a vignette with a detailed description of the functions. The website of the project contains several tutorials: https://malucalle.github.io/coda4microbiome/
Huntington’s Disease Produces Multiplexed Transcriptional Vulnerabilities of Striatal D1-D2 and Striosome-Matrix Neurons
Authors: Matsushima Ayano , Pineda Sergio Sebastian , Crittenden Jill R. , Lee Hyeseung , Galani Kyriakitsa , Mantero Julio , Kellis Manolis , Heiman Myriam , Graybiel Ann M.
Published: May 2022

Striatal cell-type-specific vulnerability in Huntington’s disease (HD) preferentially affects dopamine D2R-expressing projection neurons (SPNs), compatible with manifest motor symptomatology in HD. Transcriptional studies of striatal striosome-matrix compartmentalization in HD are, however, limited, despite pathologic evidence for striosome vulnerability aligning with early mood symptomatology. We used single-nucleus RNA-sequencing on striatal samples from two murine models, and rare Grade 1 HD patient tissues, to examine striosome and matrix sub-clusters within parent D1 and D2 SPN clusters. In human HD, striosomal SPNs were the most depleted SPN population. Surprisingly, for both mouse models, transcriptomic distinctiveness was diminished more for striosome-matrix SPNs than for D1-D2 SPNs. Compartmental markers were dysregulated so as to cancel endogenous identities as striosomal or matrix SPNs, but markers for D1-D2 exhibited less identity obscuring. The canonical striosome-matrix as well as D1-D2 organizations of the striatum thus are both strongly, but differentially, compromised in HD and are targets for therapeutics.
Biophysical, Molecular and Proteomic profiling of Human Retinal Organoids derived Exosomes
Authors: Arthur Peggy , Kandoi Sangeetha , Sun Li , Kalvala Anil , Kutlehria Shallu , Bhattacharya Santanu , Kulkarni Tanmay , Nimma Ramesh , Li Yan , Lamba Deepak A. , Singh Mandip
Published: May 2022

Extracellular vesicles (EVs) are phospholipid bilayer-bound particles released by cells that play a role in cell-cell communication, signal transduction, and extracellular matrix remodeling. There is a growing interest in EVs for ocular applications as therapeutics, biomarkers, and drug delivery vehicles. EVs secreted from mesenchymal stem cells (MSCs) have shown to provide therapeutic benefits in ocular conditions. However, very little is known about the properties of bioreactors cultured-3D human retinal organoids secreted EVs. This study provides a comprehensive morphological, nanomechanical, molecular, and proteomic characterization of retinal organoid EVs and compares it with human umbilical cord (hUC) MSCs. Nanoparticle tracking analysis indicated the average size of EV as 100–250 nm. Atomic force microscopy showed that retinal organoid EVs are softer and rougher than the hUCMSC EVs. Gene expression analysis by qPCR showed a high expression of exosome biogenesis genes in late retinal organoids derived EVs (>120 days). Immunoblot analysis showed highly expressed exosomal markers Alix, CD63, Flotillin-2, HRS and Hsp70 in late retinal organoids compared to early retinal organoids EVs (<120 days). Protein profiling of retinal organoid EVs displayed a higher differential expression of retinal function-related proteins and EV biogenesis/marker proteins than hUCMSC EVs, implicating that the use of retinal organoid EVs may have a superior therapeutic effect on retinal disorders. This study adds supplementary knowledge on the properties of EVs secreted by retinal organoids and suggests their potential use in the diagnostic and therapeutic treatments for ocular diseases.
Spatially-enhanced clusterwise inference for testing and localizing intermodal correspondence
Authors: Weinstein Sarah M. , Vandekar Simon N. , Baller Erica B. , Tu Danni , Adebimpe Azeez , Tapera Tinashe M. , Gur Ruben C. , Gur Raquel E. , Detre John A. , Raznahan Armin , Alexander-Bloch Aaron F. , Satterthwaite Theodore D. , Shinohara Russell T. , Park Jun Young
Published: May 2022

With the increasing availability of neuroimaging data from multiple modalities—each providing a different lens through which to study brain structure or function—new techniques for comparing, integrating, and interpreting information within and across modalities have emerged. Recent developments include hypothesis tests of associations between neuroimaging modalities, which can be used to determine the statistical significance of intermodal associations either throughout the entire brain or within anatomical subregions or functional networks. While these methods provide a crucial foundation for inference on intermodal relationships, they cannot be used to answer questions about where in the brain these associations are most pronounced. In this paper, we introduce a new method, called CLEAN-R, that can be used both to test intermodal correspondence throughout the brain and also to localize this correspondence. Our method involves first adjusting for the underlying spatial autocorrelation structure within each modality before aggregating information within small clusters to construct a map of enhanced test statistics. Using structural and functional magnetic resonance imaging data from a subsample of children and adolescents from the Philadelphia Neurodevelopmental Cohort, we conduct simulations and data analyses where we illustrate the high statistical power and nominal type I error levels of our method. By constructing an interpretable map of group-level correspondence using spatially-enhanced test statistics, our method offers insights beyond those provided by earlier methods.
Preterm infants show an atypical processing of the mother’s voice
Authors: Filippa Manuela , Benis Damien , Adam-Darque Alexandra , Grandjean Didier , Huppi Petra S.
Published: May 2022

To understand the consequences of prematurity on language perception it is fundamental to determine how atypical early sensory experience affects brain development. To date the neural oscillatory correlates in the time-frequency domain of voice processing as a function of atypical early sensory experience, as after premature birth, remain elusive. At term equivalent age, ten preterm and ten full-term newborns underwent high-density EEG recordings during mother or stranger speech presentation, presented in the forward (naturalistic) or backward order. A general group effect terms > preterms for the naturalistic mother’s voice is evident in the theta frequency band in the left temporal area, where only full-term newborns showed an increased activity for the mother’s voice, whereas preterm infants showed significant activation for stranger naturalistic speech. Similarly, a significant group contrast in the low and high theta in the right temporal regions indicates higher activations for the stranger’s speech in preterms. Finally, only full-term newborns presented a late gamma band increase for the maternal naturalistic speech, indicating a more mature brain response.

The current study based on neural time-frequency patterns, demonstrates that preterm infants lack selective brain responses to mother’s naturalistic voice typical for full-term newborns, whereas preterms are selectively responsive to stranger voices in both temporal hemispheres.
Mechanochemical signal transduction in synthetic cells
Authors: Jahnke Kevin , Illig Maja , Scheffold Marlene , Tran Mai P. , Mersdorf Ulrike , Göpfrich Kerstin
Published: May 2022

Mechanotransduction determines the adaptive response of natural cells via transmem-brane proteins1. The incorporation of membrane-spanning structures to guide cellular function and to enable transmembrane signalling is therefore a critical aim for bottom-up synthetic biology2,3,4. Here, we design membrane-spanning DNA origami signalling units (DOSUs) and mechanically couple them to DNA cytoskeletons5 encapsulated within giant unilamellar vesicles (GUVs). We verify the assembly and incorporation of the DOSUs into the GUV membranes and achieve their clustering upon external stimulation. The transmembrane-spanning DOSUs act as a pore to allow for the transport of single-stranded DNA into the GUVs. We employ this to externally trigger the reconfiguration of DNA cytoskeletons within GUVs using strand displacement reactions. In addition to chemical signalling, we achieve the mechanical coupling of the externally added DOSUs and the internal DNA cytoskeletons. We induce clustering of the DOSUs, which triggers a symmetry break in the organization of the DNA cytoskeleton which is mechanically coupled to the DOSU.Our work thus provides a mechanical and chemical transmembrane signaling module towards the assembly of stimuli-responsive and adaptive synthetic cells.
Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and C53-mediated autophagy
Authors: Picchianti Lorenzo , de Medina Hernández Víctor Sánchez , Zhan Ni , Irwin Nicholas A. T. , Stephani Madlen , Hornegger Harald , Beveridge Rebecca , Sawa-Makarska Justyna , Lendl Thomas , Grujic Nenad , Martens Sascha , Richards Thomas A. , Clausen Tim , Ramundo Silvia , Karagöz G. Elif , Dagdas Yasin
Published: May 2022

UFMylation mediates the covalent modification of substrate proteins with UFM1 (Ubiquitin-fold modifier 1) and regulates the selective degradation of endoplasmic reticulum (ER) via autophagy (ER-phagy) to maintain ER homeostasis. Specifically, collisions of the ER-bound ribosomes trigger ribosome UFMylation, which in turn activates C53-mediated autophagy that clears the toxic incomplete polypeptides. C53 has evolved non-canonical shuffled ATG8 interacting motifs (sAIMs) that are essential for ATG8 interaction and autophagy initiation. Why these non-canonical motifs were selected during evolution, instead of canonical ATG8 interacting motifs remains unknown. Here, using a phylogenomics approach, we show that UFMylation is conserved across the eukaryotes and secondarily lost in fungi and some other species. Further biochemical assays have confirmed those results and showed that the unicellular algae,Chlamydomonas reinhardtiihas a functional UFMylation machinery, overturning the assumption that this process is linked to multicellularity. Our conservation analysis also revealed that UFM1 co-evolves with the sAIMs in C53, reflecting a functional link between UFM1 and the sAIMs. Using biochemical and structural approaches, we confirmed the interaction of UFM1 with the C53 sAIMs and found that UFM1 and ATG8 bound to the sAIMs in a different mode. Conversion of sAIMs into canonical AIMs prevented binding of UFM1 to C53, while strengthening ATG8 interaction. This led to the autoactivation of the C53 pathway and sensitizedArabidopsis thalianato ER stress. Altogether, our findings reveal an ancestral toggle switch embodied in the sAIMs that regulates C53-mediated autophagy to maintain ER homeostasis.
Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer
Authors: Carpenter Michael A. , Temiz Nuri A. , Ibrahim Mahmoud A. , Jarvis Matthew C. , Brown Margaret R. , Argyris Prokopios P. , Brown William L. , Yee Douglas , Harris Reuben S.
Published: May 2022

A prominent source of mutation in cancer is single-stranded DNA cytosine deamination by cellular APOBEC3 enzymes, which results in signature C-to-T and C-to-G mutations in TCA and TCT motifs. Although multiple enzymes have been implicated, reports conflict and it is unclear which protein(s) are responsible. Here we report the development of a selectable system to quantify genome mutation and demonstrate its utility by comparing the mutagenic activities of three leading candidates - APOBEC3A, APOBEC3B, and APOBEC3H. The human cell line, HAP1, is engineered to express thethymidine kinase(TK) gene of HSV-1, which confers sensitivity to ganciclovir. Expression of APOBEC3A and APOBEC3B, but not catalytic mutant controls or APOBEC3H, triggers increased frequencies ofTKmutation and nearly indistinguishable TC-biased cytosine mutation profiles in the selectableTKreporter gene. Whole genome sequences fromTKmutant clones enabled an analysis of thousands of single base substitution mutations and extraction of local sequence preferences with APOBEC3A preferring YTCW motifs over 70% of the time and APOBEC3B just under 50% of the time (Y=C/T; W=A/T). Signature comparisons with breast tumor whole genome sequences indicate that most malignancies manifest intermediate percentages of APOBEC3 signature mutations in YTCW motifs, mostly between 50 and 70%, suggesting that both enzymes are contributing in a combinatorial manner to the overall mutation landscape. Although the vast majority of APOBEC3A- and APOBEC3B-induced single base substitution mutations occur outside of predicted chromosomal DNA hairpin structures, whole genome sequence analyses and supporting biochemical studies also indicate that both enzymes are capable of deaminating the single-stranded loop regions of DNA hairpins at elevated rates relative to control conditions. These studies combine to help resolve a long-standing etiologic debate on the source of APOBEC3 signature mutations in cancer and indicate that future diagnostic and therapeutic efforts should focus on both APOBEC3A and APOBEC3B.