bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraoperative Fluorescence Imaging to Identify and Preserve the Fifth Anterior Intercostal Sensory Nerves during Inferior Pedicle Reduction Mammoplasty
Authors: Ramírez Mariano F. , Nahabedian Maurice Y. , Mendoza Santos Horacio , Rancati Agustin , Angrigiani Claudio , Dip Fernando , Rancati Alberto O.
Published: March 2024

Postoperative sensitivity of the nipple–areola complex (NAC) is an important concern for women after reduction mammoplasty. Previous studies have demonstrated that sensory branches of the fifth anterior intercostal nerve are important for innervating the NAC and that using an inferior pedicle technique is associated with improved sensory retention. The significance of this case report is that it demonstrates the importance of the fifth anterior intercostal sensory nerve branches using a prototype fluorescent imaging camera. The benefit of this device is that it can detect intraoperative auto-fluorescence of nerves and facilitate their identification and preservation, potentially facilitating the retention of sensation in the NAC and surrounding skin. The goals of this article are, therefore, to demonstrate the importance of this neurovascular pedicle when the inferior pedicle technique is used for breast reduction; and to provide demonstrative evidence of the nerve’s presence within the fifth anterior intercostal artery perforator pedicle. The case involved a woman with mammary hypertrophy who underwent bilateral reduction mammoplasty using the inferior pedicle technique. Full NAC sensation was demonstrated on postoperative day 3 with complete sensory recovery at 1- and 3-month follow-up confirmed. To our knowledge, this is the first reported instance of the fifth intercostal nerve being visualized during aesthetic breast surgery, demonstrating the importance of this neurovascular bundle for sensory preservation when an inferior pedicle reduction mammaplasty technique is used.
Intraluminal Suture Placement for Management of Hypotony After Glaucoma Drainage Device Surgery
Authors: Tang Minjia , Anchala Anupama R. , Tanna Angelo P.
Published: March 2024

Précis:

Intraluminal 3-0 Supramid stent placement can be an effective long-term solution for hypotony after glaucoma drainage device surgery. This procedure may obviate the need for conjunctival dissection. In some cases, additional procedures are required.

Purpose:

To describe the utility of implantation of a multifilament polyamide suture (Supramid) in the tube lumen to reverse hypotony after glaucoma drainage device (GDD) surgery.

Patients:

Patients who underwent tube revision with intraluminal placement of a 3-0 Supramid stent, with or without external ligature, to manage hypotony following GDD surgery between January 2010 and October 2020.

Methods:

Resolution of hypotony was defined as IOP >5 mm Hg and the absence of hypotony-related structural abnormalities. Overall success was the absence of failure criteria (IOP ≤5 mm Hg, >21 mm Hg, or <20% reduction below baseline IOP after 3 months for 2 consecutive study visits; additional glaucoma surgery; or loss of light perception), with or without adjunctive ocular hypotensive therapy.

Results:

Nine eyes of 9 patients underwent placement of a 3-0 Supramid stent with a resolution of hypotony in all eyes with a mean follow-up duration of 33.3 ±24.0 months. Overall success was achieved in 7 of 9 eyes. Four eyes required intervention after stent placement: 1 eye required selective laser trabeculoplasty followed by replacement of the original stent with a shorter 3-0 Supramid suture and external ligature; 1 eye underwent revision for tube exposure; and 2 eyes underwent laser suture lysis to release an external suture ligature.

Conclusions:

In cases of hypotony after GDD, particularly when it is desirable to reduce the extent of additional conjunctival dissection, intraluminal placement of a 3-0 Supramid stent via an intracameral approach can be an effective long-term solution. Postoperative adjustments were required in many cases.
Integrative analysis identifies molecular features of fibroblast and the significance of fibrosis on neoadjuvant chemotherapy response in breast cancer
Authors: Wang Xiaomin , Chen Bo , Zhang Hanghao , Peng Lushan , Liu Xiangyan , Zhang Qian , Wang Xiaoxiao , Peng Shuai , Wang Kuangsong , Liao Liqiu
Published: March 2024

Background:

The molecular features of fibroblasts and the role of fibrosis in neoadjuvant chemotherapy (NAC) response and breast cancer (BRCA) prognosis remain unclear. Therefore, this study aimed to investigate the impact of interstitial fibrosis on the response and prognosis of patients with BRCA undergoing NAC treatment.

Materials and Methods:

The molecular characteristics of pathologic complete response (pCR) and non-pCR (npCR) in patients with BRCA were analyzed using multiomics analysis. A clinical cohort was collected to investigate the predictive value of fibrosis in patients with BRCA.

Results:

Fibrosis-related signaling pathways were significantly upregulated in patients with npCR. npCR may be associated with distinct and highly active fibroblast subtypes. Patients with high fibrosis had lower pCR rates. The fibrosis-dependent nomogram for pCR showed efficient predictive ability [training set: area under the curve [AUC]=0.871, validation set: AUC=0.792]. Patients with low fibrosis had a significantly better prognosis than those with high fibrosis, and those with a high fibrotic focus index had significantly shorter overall and recurrence-free survival. Therefore, fibrosis can be used to predict pCR. Our findings provide a basis for decision-making in the treatment of BRCA.

Conclusions:

npCR is associated with a distinct and highly active fibroblast subtype. Furthermore, patients with high fibrosis have lower pCR rates and shorter long-term survival. Therefore, fibrosis can predict pCR. A nomogram that includes fibrosis can provide a basis for decision-making in the treatment of BRCA.
Evidence on docosahexaenoic acid and arachidonic acid supplementation for preterm infants
Authors: Lapillonne Alexandre , Lembo Chiara , Moltu Sissel J.
Published: March 2024

Purpose of review

For many decades, docosahexaenoic acid (DHA) supplementation was tested in premature infants to achieve an intake equivalent to the average level in breast milk, but this approach has led to conflicting results in terms of development and health outcomes. Higher doses of DHA closer to fetal accumulation may be needed.

Recent findings

The efficacy of DHA supplementation for preterm infants at a dose equivalent to the estimated fetal accumulation rate is still under investigation, but this may be a promising approach, especially in conjunction with arachidonic acid supplementation. Current data suggest benefit for some outcomes, such as brain maturation, long-term cognitive function, and the prevention of retinopathy of prematurity. The possibility that supplementation with highly unsaturated oils increases the risk of neonatal morbidities should not be ruled out, but current meta-analyzes do not support a significant risk.

The published literature supports a DHA intake in preterm infants that is closer to the fetal accumulation rate than the average breast milk content. Supplementation with DHA at this level in combination with arachidonic acid is currently being investigated and appears promising.
Use of Sequential Hot-Deck Imputation for Missing Health Care Systems Data for Population Health Research
Authors: Chrenka Ella A. , Dehmer Steven P. , Maciosek Michael V. , Essien Inih J. , Westgard Bjorn C.
Published: March 2024

Electronic medical record (EMR) data present many opportunities for population health research. The use of EMR data for population risk models can be impeded by the high proportion of missingness in key patient variables. Common approaches like complete case analysis and multiple imputation may not be appropriate for some population health initiatives that require a single, complete analytic data set. In this study, we demonstrate a sequential hot-deck imputation (HDI) procedure to address missingness in a set of cardiometabolic measures in an EMR data set. We assessed the performance of sequential HDI within the individual variables and a commonly used composite risk score. A data set of cardiometabolic measures based on EMR data from 2 large urban hospitals was used to create a benchmark data set with simulated missingness. Sequential HDI was applied, and the resulting data were used to calculate atherosclerotic cardiovascular disease risk scores. The performance of the imputation approach was assessed using a set of metrics to evaluate the distribution and validity of the imputed data. Of the 567,841 patients, 65% had at least 1 missing cardiometabolic measure. Sequential HDI resulted in the distribution of variables and risk scores that reflected those in the simulated data while retaining correlation. When stratified by age and sex, risk scores were plausible and captured patterns expected in the general population. The use of sequential HDI was shown to be a suitable approach to multivariate missingness in EMR data. Sequential HDI could benefit population health research by providing a straightforward, computationally nonintensive approach to missing EMR data that results in a single analytic data set.
Update on ischemic hepatitis
Authors: Smith Jessica Elizabeth , Rockey Don C.
Published: March 2024

Purpose of review

Ischemic hepatitis (IH) refers to diffuse liver injury secondary to hypoperfusion. The condition is usually seen in the critical care setting and is associated with significant mortality. IH typically occurs in the setting of systemic hypotension superimposed on some form of underlying cardiac dysfunction. This review aims to report what is known and what is new about the etiology, pathophysiology, and clinical features associated with IH.

Recent findings

In recent years, studies on IH have largely confirmed earlier reports regarding etiologies, comorbid conditions, and associated mortality. Recent study has also shed light on the potential treatment of IH with N-acetyl-cysteine (NAC).

IH is typically associated with underlying cardiac disease, and patients with IH have a very high mortality rate. Treatment remains largely supportive, although the utility of agents such as NAC are being explored.
Swallowing after total laryngectomy surgery: where are we after 150 years?
Authors: O’Connor Laura M. , Maclean Julia C.F.
Published: March 2024

Purpose of review

Recent findings

Dysphagia is a common sequela following total laryngectomy surgery; however, there is significant variability in its assessment and management. Manometry enables an accurate understanding of the underlying mechanism of dysphagia and precise assessment of any oesophageal dysfunction. EndoFLIP is a useful tool to better understand dysfunction of the upper oesophageal sphincter particularly to detect stricture.

Following total laryngectomy surgery, dysphagia is common; clinicians need to be alert to early indicators of dysfunction and understand the tools to comprehensively characterize swallow function. Accurate diagnosis of a stricture is important, as this aspect of dysfunction can be modified, and may alleviate surrogate problems such as a leaking voice prosthesis. Clinicians should have a low threshold to examine patients for oesophageal dysfunction due to the high prevalence of dysmotility following a laryngectomy.
Enhanced Recovery After Surgery Orthopaedics Program in a Community-Based Health Care System
Authors: Schams Peter J. , Tradewell Matthew W. , Nolte Charles P. , Feller Christine A. , Elsen Sandra J. , Ludlum Jamie L. , Jagim Andrew R. , Schollmeier Micaela M.
Published: March 2024

Enhanced Recovery After Surgery programs are common among healthcare systems and various surgical disciplines. Although evidence supporting the physiological rationale of multiple nutrition, physical activity, and pain control strategies before, during, and after surgical procedures is accumulating, implementing such strategies may pose a substantial challenge. The purpose of this quality improvement initiative was to outline the development, workflow, and implementation of an Enhanced Recovery After Surgery program for same-day total joint replacement procedures in a rural healthcare setting. This was not just an academic exercise. Our leadership had a strong desire to support our patients by identifying ways to hasten their recovery so that they can return to their preferred activities.
Development of a Group Curriculum for Children With Congenital Upper Limb Difference (CULD) and Their Caregivers
Authors: Nelson Danielle , Hauschild Maia , Johns Alexis L. , Lightdale-Miric Nina R.
Published: March 2024

Caring for patients with congenital upper limb differences (CULD) requires an understanding of unique psychosocial challenges. The study purpose was to describe the needs of children with CULD and their caregivers to develop a group curriculum. This mixed-method study included 13 mothers and one father of children with CULD (age 3 months to 14 years; mean 7.2 ± 4.3 years) using Patient-Reported Outcomes Measurement Information System Parent Proxy Reports and caregiver interviews. Patient-Reported Outcomes Measurement Information System Peer Relationships (M = 48.1 ± 10.9) and Pain Interference (M = 44.5 ± 7.5) T-scores were average with below average scores for Physical Function: Upper Extremity (M = 31.9 ± 12.1). Caregivers expressed high interest in groups to create community and mutual support covering themes of responding to questions from strangers, social and coping skills, building self-confidence, accessing resources, advocacy skills, and advice from adults with CULD. Access to a support group with a curriculum addressing CULD-related patient and family needs may improve care.
Implementation of Group-Based Exercise Programs in Physiotherapy
Authors: Le Berre Mélanie , Forest Lauriane , Dumoulin Chantale
Published: March 2024

This review synthesized implementation literature on group-based exercise programs in physiotherapy. MEDLINE and Embase databases were searched for English and French articles published between 2000 and 2022. Through a two-step process (titles/abstracts and full text), two independent reviewers selected studies. The independent reviewers then extracted data and assessed study quality using the Mixed Methods Appraisal Tool. A total of 31 studies involving 4555 participants were included. Data on the group-based programs were extracted using the Consensus on Exercise Reporting Template and reported narratively. Implementation outcomes were reported narratively. The most frequently reported constructs pertained to feasibility and acceptability. Overall, the implementation of group-based programs appeared to be feasible, yielding high rates of adherence and attendance (between 36% and 91%), moderate-to-high completion rates (between 46% and 100%), low-to-moderate dropout rates (between 4.5% and 35.9%), and high satisfaction (satisfaction scores generally ranging above 7/10). The present findings also indicate a high acceptability for group-based physiotherapy exercise programs among patients. This review provided an overview of the literature on the implementation of group-based exercise programs in physiotherapy. In addition, it identified the need for more evidence on fidelity and costs. Future research should address these gaps to better inform healthcare stakeholders.
Assessing Scar Outcomes Using Objective Scar Measurement Tools: An Adjunct to Validated Scar Evaluation Scales
Authors: Bernabe Rendell M. , Madrigal Paloma , Choe Deborah , Pham Christopher , Yenikomshian Haig A. , Gillenwater Justin
Published: March 2024

Background:

The assessment of scar outcomes is important to both patient care and research focused on understanding the results of medical and surgical interventions. The Vancouver Scar Scale (VSS) and Patient and Observer Scar Assessment Scale (POSAS) are validated and simple instruments to assess scars. However, these subjective scales have shortcomings. The VSS fails to capture patient perception and has indeterminate validity and reliability. The POSAS captures patient perception, but the observer scale has been shown to have moderate amounts of interrater variability. Studies highlighting the ability of objective scar assessment tools to produce reliable and reproducible results are needed. In this study, the authors aimed to validate the use of the FibroMeter, ElastiMeter, and SkinColorCatch as objective adjuncts in the assessment of hypertrophic scar and keloid outcomes.

Methods:

In this prospective single-center study, scars were assessed using the VSS, the POSAS, and the objective study tools (FibroMeter, ElastiMeter, and SkinColorCatch). Correlations between the different methods of scar assessment were measured.

Results:

The FibroMeter and SkinColorCatch showed significant correlations with the VSS total and the observer POSAS total. The ElastiMeter showed significant correlations with both the patient and observer POSAS totals. Unexpected correlations between ElastiMeter measurements and the vascularity or pigmentation of scars indicate that scoring of these categories may be influenced by how severe the scar looks to the observer subjectively, underscoring the need for reliable objective scar assessment tools.

Conclusion:

The results highlight the ability of the FibroMeter, ElastiMeter, and SkinColorCatch to assess scars, and demonstrate their potential in serving as important adjuncts to previously validated scar assessment scales.
Defining the Role of Social Vulnerability in Treatment and Survival in Localized Colon Cancer
Authors: Meier Jennie , Murimwa Gilbert , Nehrubabu Mithin , Yopp Adam , DiMartino Lisa , Singal Amit G. , Zeh Herbert J. , Polanco Patricio
Published: March 2024

Objective:

To determine whether variations in Social Vulnerability Index (SVI) are associated with disparities in colon cancer surgery and mortality.

Summary Background Data:

Colon cancer mortality is influenced by health care access, which is affected by individual and community-level factors. Prior studies have not used the SVI to compare surgical access and survival in localized colon cancer patients. Further, it is unclear if those above 65 years are more vulnerable to variations in SVI.

Methods:

We queried the Texas and California Cancer Registries from 2004-2017 to identify patients with localized colonic adenocarcinoma and categorized patients into <65 and ≥65 years. Our outcomes were survival and access to surgical intervention. The independent variable was census tract social vulnerability index, with higher scores indicating more social vulnerability. We used multivariable logistic regression and Cox proportional hazards for analysis.

Results:

We included 73,923 patients with a mean age of 68.6 years (SD 13.0), mean SVI of 47.2 (SD 27.6), and 51.1% male. After adjustment, increasing SVI was associated with reduced odds of undergoing surgery (OR 0.996; 95% CI 0.995-0.997; P < 0.0001 and increased mortality (HR 1.002; 95% CI 1.001-1.002; P < 0.0001). Patients < 65 years were more sensitive to variation in SVI.

Conclusions:

Increased social vulnerability was associated with reduced odds of receiving surgery for early-stage colon cancer as well as increased mortality. These findings amplify the need for policy changes at the local, state, and federal level to address community-level vulnerability to improve access to surgical care and reduce mortality.
Vitamin D is a biomarker of clinical disease severity in oral lichen planus
Authors: Unnikrishnan Sreedevi P. , Boggon Janice , Mclaughlin Bernice , Cruickshank Maggie E. , Abu-Eid Rasha , Hijazi Karolin
Published: March 2024

Oral lichen planus (OLP) is a chronic inflammatory condition known to adversely impact patient quality of life and is associated with an increased risk of cancer. The diverse clinical presentation and poor knowledge of clinical factors that determine the course of disease are amongst the main challenges that hinder effective and personalised treatment for OLP patients.

This study aimed to systematically identify clinical predictors of disease severity in OLP patients. A cohort of patients with histologically confirmed OLP (n=89) was recruited in a cross-sectional and single site study. A comprehensive assessment of clinical characteristics, medical and social history, haematological parameters, vitamin D levels, and Perceived Stress Scale (PSS-10) was carried out. Hierarchical linear regression identified the predictive value of clinical factors to OLP disease severity measured by the Oral Disease Severity Score (ODSS) and the Reticular/hyperkeratotic, Erosive/erythematous, Ulcerative (REU) scoring system.

Findings revealed that extraoral lichen planus and insufficient vitamin D levels were significant predictors of both overall and gingival disease severity of OLP. Specifically, patients with lichen planus affecting the skin or other mucosal sites had a 5.766-unit higher OLP severity score (β=5.766, 95% CI=.744-10.788, p=.025) than those without extraoral involvement as measured by ODSS. Patients with insufficient vitamin D levels exhibited 5.490-unit increase in OLP severity (β=5.490, 95% CI=1.136-9.844, p=.014) compared to those with adequate vitamin D levels. The presence of dental plaque-induced gingivitis (β=4.833, 95% CI=.974-8.692, p=.015), was found to be a significant factor affecting gingival disease severity.

This study revealed the importance of adequate vitamin D levels in OLP patients and suggests embedding vitamin D pre-treatment screening to optimise management of OLP. Future research should focus on elucidating the biological mechanisms underlying the protective effects of vitamin D in OLP.
Base editing ofPtbp1in neurons alleviates symptoms in a mouse model of Parkinson’s disease
Authors: Böck Desirée , Wilhelm Maria , Mumenthaler Jonas , Carpanese Daniel Fabio , Kulcsár Peter I. , d‘Aquin Simon , Cremonesi Alessio , Rassi Anahita , Häberle Johannes , Patriarchi Tommaso , Schwank Gerald
Published: March 2024

Parkinson’s disease (PD) is a multifactorial disease caused by irreversible progressive loss of dopaminergic neurons (DANs). Recent studies have reported successful conversion of astrocytes into DANs by repressing polypyrimidine tract binding protein 1 (PTBP1), which led to the rescue of motor symptoms in a chemically-induced mouse model of PD. However, several follow-up studies have questioned the validity of this astrocyte to DAN conversion model. In this study, we devised an adenine base editing strategy to downregulate PTBP1 in astrocytes and neurons in a chemically-induced PD mouse model. While PTBP1 downregulation in astrocytes had no effect, we observed that PTBP1 downregulation in neurons of the substantia nigra pars compacta and striatum resulted in the expression of the DAN marker tyrosine hydroxylase (TH) in non-dividing neurons, which was associated with an increase in striatal dopamine concentrations and a rescue of forelimb akinesia and spontaneous rotations. Phenotypic analysis using multiplexed iterative immunofluorescence imaging further revealed that most of the TH-positive cells in the striatum co-expressed the dopaminergic marker DAT and the pan-neuronal marker NEUN, with the majority of these triple-positive cells being classified as mature GABAergic neurons. Additional research is needed to fully elucidate the molecular mechanisms underlying the expression of the observed markers and understand how the formation of these cells contributes to the rescue of spontaneous motor behaviors. Nevertheless, our findings support a model where neuronal, but not astrocytic, downregulation of PTBP1 can mitigate symptoms in PD mice.
Perception - action dissociations depend on factors that affect multisensory processing
Authors: Bruno Nicola , Uccelli Stefano
Published: March 2024

Behavioral perception-action dissociations are widely used to test models of high-level vision, but debates concerning their interpretation have underestimated the role of multisensory mechanisms in such tests. Sensorimotor tasks engage multisensory processing in fundamentally different ways in comparison to perceptual tasks, and these differences can modulate the effects of illusion in specific ways in accord with the features of the experimental task. To test this idea, we compared perception and action using a well-understood size-contrast effect, the Uznadze illusion, and manipulated both unimodal and crossmodal stimulation as well as conditions that are known to favor or hinder multisensory integration. Results demonstrate that varying such conditions can cause a visual task to be affected by the illusion, or remain fully unaffected, whereas a visuomotor task can be affected by the illusion, remain immune from the illusion, or, unexpectedly, even show a robust reverse effect. Thus, similar or dissociable effects on perception and action can be observed depending on factors that are known to affect multisensory processing.These findings provide a novel perspective on a long standing debate in behavioral cognitive neuroscience.
Roles for RERE in lymphatic endothelial cell proliferation and survival, and human cystic lymphatic malformations
Authors: Rogerson Daniella M. , Muley Ajit , Giordano Jessica , Vogel Zoe , Wapner Ronald , Shawber Carrie J.
Published: March 2024

Human congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development. During a genetic study of fetuses with LAs, we identified a heterozygous pathogenic truncating variant inREREin a fetus with a cystic lymphatic malformation (CLM). RERE is a transcriptional regulator which interacts with several key lymphangiogenic factors, including Notch and Coup-TFII. RERE also modulates retinoic acid signaling, which is essential for lymphatic vascular development. Thus, we hypothesized that RERE functions in lymphatic endothelial cells (LECs) and its loss contributes to LEC dysfunction and CLM pathogenesis. RERE was found to be expressed in the lymphatic endothelium during human development.REREknockdown in human LECs reduced proliferation and induced apoptosis, increased expression of key lymphangiogenic genes,PROX1, COUP-TFIIandVEGFR3, and altered expression of Notch target genes. RERE expression was elevated in LECs isolated from CLMs with pathogenicPIK3CAvariants. These findings support a novel role for RERE in LECs, where RERE regulates LEC proliferation, LEC survival, lymphangiogenic gene expression and Notch signaling, which in turn suggests its loss contributes to CLM pathogenesis.
In silico exploration of potent flavonoids for dengue therapeutics
Authors: Phunyal Anuraj , Adhikari Subin Jhashanath , Adhikari Achyut
Published: March 2024

Dengue poses a persistent and widespread threat with no effective antiviral drug available till now. Several inhibitors have been developed by targeting the viral non-structural proteins including methyl transferase (NS5) of the dengue virus with possible therapeutic values. In this work, virtual screening, molecular docking, molecular dynamics simulations (200 ns), and assessments of free energy changes to identify potential candidates from a database of flavonoids (ca. 2000) that may have good curative potential from the disease. The binding affinity of flavonoids, namely Genistein-7-glucoside (FLD1), 6’–O-Acetylgenistin (FLD2), 5,6-dihydroxy-2-(4-hydroxyphenyl)-7-[3,4,5-trihydroxy-6-(hydroxymethyl)oxane-2-yl]oxychromen-4-one (FLD3), Glucoliquiritigenin (FLD4), and Chrysin-7-O-glucoronide (FLD5) showed the binding affinities of −10.2, −10.2, −10.1, −10.1, −9.9 kcal/mol, respectively, and possessed better values than that of the native ligand with showed (−7.6 kcal/mol) and diclofenac sodium (−7.3 kcal/mol). Drug-likeness of these compounds was acceptable and no toxicity was hinted by ADMET predictions. The stability of the protein-ligand complexes was accessed from 200 ns molecular dynamics simulation in terms of various geometrical parameters; RMSD, RMSF of residues, Rg, SASA, and H-bond of the protein-ligand complexes. The binding free energy changes of these compounds were calculated by the MM-PBSA solvation model with negative values (less than −38.01±7.53 kcal/mol) indicating the spontaneity of the forward reaction and favorability of the product formation. The geometrical and thermodynamic parameters infer that the flavonoid binds at the orthosteric site of the target protein of DENV-2 and could inhibit its functioning resulting in the prevention of the disease. Overall, this study highlights the anti-DENV activity of five flavonoids, positioning them as promising candidates for further development as antiviral agents against dengue infection.
Single-Molecule Orientation Imaging Reveals the Nano-Architecture of Amyloid Fibrils Undergoing Growth and Decay
Authors: Sun Brian , Ding Tianben , Zhou Weiyan , Porter Tara S. , Lew Matthew D.
Published: March 2024

Amyloid-beta (Aβ42) aggregates are characteristic signatures of Alzheimer’s disease, but probing how their nanoscale architectures influence their growth and decay remains challenging using current technologies. Here, we apply time-lapse single-molecule orientation-localization microscopy (SMOLM) to measure the orientations and rotational “wobble” of Nile blue (NB) molecules transiently binding to Aβ42 fibrils. We quantify correlations between fibril architectures, measured by SMOLM, and their growth and decay visualized by single-molecule localization microscopy (SMLM). We discover that stable Aβ42 fibrils tend to be well-ordered, signified by well-aligned NB orientations and small wobble. SMOLM also shows that increasing order and disorder are signatures of growing and decaying Aβ42 fibrils, respectively. We also observe SMLM-invisible fibril remodeling, including steady growth and decay patterns that conserve β-sheet organization. SMOLM reveals that increased heterogeneity in fibril architectures is correlated with more dynamic remodeling and that large-scale fibril remodeling tends to originate from local regions that exhibit strong heterogeneity.
Assessing the Feasibility of Processing a Paper-based Multilingual Social Needs Screening Questionnaire Using Artificial Intelligence
Authors: Ekekezie Obinna I.
Published: March 2024

The collection of Social Determinants of Health (SDoH) data is increasingly mandated by healthcare payers, yet traditional paper-based methods pose challenges in terms of cost effectiveness, accuracy, and completeness when manually entered into Electronic Health Records (EHRs). This study explores the application of artificial intelligence (AI), specifically using a document understanding model (Microsoft Azure Document Intelligence) and large language models (OpenAI’s GPT-4 Turbo and GPT-3.5 Turbo), to automate the conversion of paper-based Social Determinants of Health (SDoH) questionnaires into structured, machine-readable formats that could theoretically be incorporated into EHRs. Using a dataset of synthetic and scanned examples, the study compares the performance of the GPT-3.5 and 4 Turbo base models and fine-tuned GPT-3.5 Turbo models on this task. Findings indicate that GPT-4 Turbo outperforms GPT-3.5 Turbo in accuracy and consistency, with fine-tuning enhancing GPT-3.5 Turbo’s performance and consistency in several languages. These results suggest that AI could prove to be an accurate alternative to manual data entry, with important implications for improving how SDoH data is incorporated into EHRs. Future research should address data privacy, security concerns, cost considerations, and the technical aspects of incorporating AI-generated data into EHRs.

Description

This study explores the application of artificial intelligence (AI), specifically using a document understanding model (Microsoft Azure Document Intelligence) and large language models (OpenAI’s GPT-4 Turbo and GPT-3.5 Turbo), to automate the conversion of paper-based Social Determinants of Health (SDoH) questionnaires into structured, machine-readable formats that could theoretically be incorporated into a patient’s electronic health records (EHRs).
The Bambisana Study Protocol: A mixed methods pre- and post- test study assessing community and social media influence to increase influenza vaccination uptake among youth in Soweto, South Africa
Authors: Dietrich Janan J. , Hill Catherine , Tshabalala Gugulethu , Msibi Tshepiso , Vermaak Stefanie , Myburgh Nellie , Malycha Sarah , Goldstein Izzy , Grainger Elliot , Alam Prima , Gutu Kimberley , Otwombe Kennedy , Larson Heidi J. , Dangor Ziyaad
Published: March 2024

Background

Seasonal influenza has an estimated global reach of 3 to 5 million infections with 290 000 to 650 000 influenza-related deaths yearly. Despite its efficacy in reducing morbidity and mortality, influenza vaccination rates remain low globally and in South Africa. Youth between the ages of 18-34 years are not prioritised for influenza vaccines although influenza surveillance in South Africa shows that individuals aged 19 to 44 present the highest asymptomatic episodes and the lowest medically attended illness. This creates an opportunity to investigate if and how vaccine demand can be created in the absence of clear imperatives to vaccinate. The study tests the effectiveness of tailored, context-specific education, community engagement, including community and social media to increase influenza vaccination uptake.Tailored, context-specific education, community engagement, reliable vaccine supply and free, localised access are all critical for improving perceptions of, increasing confidence in, and motivating uptake of vaccination. This study explores strategies to increase vaccine uptake amongst marginalised youth 18-34 years old in Soweto, South Africa, where influenza vaccines are not universally accessible through the public health system for this age group.

Methods

The Bambisana Study uses an innovative approach - including community influencers and social media - to increase uptake of influenza vaccines through designing and testing an integrated communications strategy targeted at marginalised youth in Soweto, South Africa. The Bambisana study uses a mixed methods pre-test, post-test intervention design to test the effects of the interventions.

Conclusion and Significance

Enhancing perceptions of, bolstering confidence in, and fostering uptake of vaccination relies heavily on the efficacy of yearly influenza vaccination initiatives, personalized education tailored to specific contexts, active community involvement, consistent vaccine availability, and easily accessible, cost-free distribution channels at the local level.
Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated Proteomes Between Tauopathies
Authors: Morderer Dmytro , Wren Melissa C. , Liu Feilin , Kouri Naomi , Maistrenko Anastasiia , Khalil Bilal , Pobitzer Nora , Salemi Michelle , Phinney Brett S. , Dickson Dennis W. , Murray Melissa E. , Rossoll Wilfried
Published: March 2024

Tauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation of the microtubule-associated protein tau. Despite extensive research, the precise mechanisms underlying the complexity of different types of tau pathology remain incompletely understood. Here we describe an approach for proteomic profiling of aggregate-associated proteomes on slides with formalin-fixed, paraffin-embedded (FFPE) tissue that utilizes proximity labelling upon high preservation of aggregate morphology, which permits the profiling of pathological aggregates regardless of their size. To comprehensively investigate the common and unique protein interactors associated with the variety of tau lesions present across different human tauopathies, Alzheimer’s disease (AD), corticobasal degeneration (CBD), Pick’s disease (PiD), and progressive supranuclear palsy (PSP), were selected to represent the major tauopathy diseases. Implementation of our widely applicable Probe-dependent Proximity Profiling (ProPPr) strategy, using the AT8 antibody, permitted identification and quantification of proteins associated with phospho-tau lesions in well-characterized human post-mortem tissue. The analysis revealed both common and disease-specific proteins associated with phospho-tau aggregates, highlighting potential targets for therapeutic intervention and biomarker development. Candidate validation through high-resolution co-immunofluorescence of distinct aggregates across disease and control cases, confirmed the association of retromer complex protein VPS35 with phospho-tau lesions across the studied tauopathies. Furthermore, we discovered disease-specific associations of proteins including ferritin light chain (FTL) and the neuropeptide precursor VGF within distinct pathological lesions. Notably, examination of FTL-positive microglia in CBD astrocytic plaques indicate a potential role for microglial involvement in the pathogenesis of these tau lesions. Our findings provide valuable insights into the proteomic landscape of tauopathies, shedding light on the molecular mechanisms underlying tau pathology. This first comprehensive characterization of tau-associated proteomes across different tauopathies enhances our understanding of disease heterogeneity and provides a resource for future functional investigation, as well as development of targeted therapies and diagnostic biomarkers.
Identification and characterization of nanobodies acting as molecular chaperones for glucocerebrosidase through a novel allosteric mechanism
Authors: Maso Thomas Dal , Sinisgalli Chiara , Zilio Gianluca , Tessari Isabella , Pardon Els , Steyaert Jan , Ballet Steven , Greggio Elisa , Versées Wim , Plotegher Nicoletta
Published: March 2024

The enzyme glucocerebrosidase (GCase) catalyses the hydrolysis of glucosylceramide to glucose and ceramide within lysosomes. Homozygous or compound heterozygous mutations in the GCase-sencodingGBA1gene cause the lysosomal storage disorder Gaucher disease, while heterozygous mutations are the most frequent genetic risk factor for Parkinson’s disease. These mutations commonly affect GCase stability, trafficking or activity. Here, we report the development and characterization of nanobodies (Nbs) targeting and acting as chaperones for GCase. We identified several Nb families that bind with nanomolar affinity to GCase. Based on biochemical characterization, we grouped the Nbs in two classes: Nbs that improve the activity of the enzyme and Nbs that increase GCase stabilityin vitro. A selection of the most promising Nbs was shown to improve GCase function in cell models and positively impact the activity of the N370S mutant GCase. These results lay the foundation for the development of new therapeutic routes.
Immunosuppression in the prostate tumor microenvironment is tied to androgen deprivation therapy-resistant club-like cells
Authors: Kiviaho Antti , Eerola Sini K. , Kallio Heini M.L. , Andersen Maria K. , Spotbeen Xander , Giesen Alexander , Parker Charles T.A. , Taavitsainen Sinja , Hantula Olli , Marttinen Mikael , Hermelo Ismaïl , Ismail Mazlina , Midtbust Elise , Wess Maximilian , Devlies Wout , Sharma Abhibhav , Krossa Sebastian , Häkkinen Tomi , Afyounian Ebrahim , Kesseli Juha , Tolonen Teemu , Tammela Teuvo L.J. , Viset Trond , Størkersen Øystein , Giskeødegård Guro F. , Rye Morten B. , Murtola Teemu , Erickson Andrew , Latonen Leena , Bova G. Steven , Mills Ian G. , Joniau Steven , Swinnen Johannes V. , Voet Thierry , Mirtti Tuomas , Attard Gerhardt , Claessens Frank , Visakorpi Tapio , Rautajoki Kirsi J. , Tessem May-Britt , Urbanucci Alfonso , Nykter Matti
Published: March 2024

Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 110 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells partake in inducing myeloid inflammation previously associated with androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.
Spermidine/spermine N1-acetyltransferase controls tissue-specific regulatory T cell function in chronic inflammation
Authors: Neuwirth Teresa , Malzl Daniel , Knapp Katja , Tsokkou Panagiota , Kleissl Lisa , Redl Anna , Freystätter Christian , Marella Nara , Kutschat Ana P. , Ponweiser Elisabeth , Haschemi Arvand , Seruggia Davide , Menche Jörg , Wagner Erwin F. , Stary Georg
Published: March 2024

Regulatory T cells (Tregs) are a critical immune component guarding against excessive inflammatory responses. During chronic inflammation, Tregsfail to control effector T cell responses. The causes of Tregdysfunction in these diseases are poorly characterized and therapies are aimed at blocking aberrant effector responses rather than rescuing Tregfunction. Here we utilized single-cell RNA sequencing data from patients suffering from chronic skin and colon inflammation to uncoverSAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a novel marker and driver of skin-specific Tregdysfunction during TH17-mediated inflammation. TregsexpressingSAT1exhibit a tissue-specific inflammation signature and show a proinflammatory effector-like profile. In CRISPRa on healthy human skin-derived Tregsincreased expression ofSAT1leads to a loss of suppressive function and a switch to a TH17-like phenotype. This phenotype is induced by co-receptor expression on keratinocytes exposed to a TH17 microenvironment. Finally, the potential therapeutic impact of targeting SSAT was demonstrated in a mouse model of skin inflammation by inhibiting SSAT pharmacologically, which rescued Tregnumber and function in the skin and systemically. Together, these data show thatSAT1expression has severe functional consequences on Tregsand provides a novel target to treat chronic inflammatory skin disease.
Mutational synergy withCREBBPloss in lymphomagenesis identified through forward insertional mutagenesis in a new DLBCL mouse model
Authors: Sakakini Nathalie , Straver Roy , Azazi Dhoyazan M. A , Horton Sarah J. , Asby Ryan , Richardson Simon E. , Madrigal Pedro , Soilleux Elizabeth J , Bashford-Rogers Rachael , de Ridder Jeroen , Huntly Brian J. P
Published: March 2024

Loss-of-function mutations in the gene encoding the acetyltransferase CREBBP have been reported in numerous cancers but are particularly frequent in lymphoid malignancies. However, the functional significance of CREBBP loss in transformation and disease progression, most likely through cooperation with secondary genetic hits, has not yet been fully unravelled. Similarly, the contribution of the initial cell population sustaining CREBBP loss in the course of disease remains elusive. Here, we developed a new lymphoma mouse model integratingCrebbploss at various stages of B cell development with a transposon-based insertional mutagenesis system. We demonstrated thatCrebbploss from the HSPC compartment resulted in an aggressive DLBCL-like disease, recapitulating well-characterised histological and molecular features of the human disease, as well as the recently described enhanced CD24 expression. More importantly, we identified candidate genes functionally equivalent to patient mutated genes. Those genes, mainly related to B cell development and cellular signalling, may represent novel therapeutic targets. Overall, this new model provides a powerful resource in which to conduct future mechanistic and therapeutic studies.
Metal fluorides - multi-functional tools for the study of phosphoryl transfer enzymes
Authors: Pellegrini Erika , Juyoux Pauline , Velsen Jill von , Baxter Nicola J. , Dannatt Hugh R. W. , Yi Jin , Cliff Matthew J. , Waltho Jonathan P. , Bowler Matthew W.
Published: March 2024

Enzymes facilitating the transfer of phosphate groups constitute the most extensive protein group across all kingdoms of life, making up approximately 10% of the proteins found in the human genome. Understanding the mechanisms by which enzymes catalyse these reactions is essential in characterising the processes they regulate. Metal fluorides can be used as multifunctional tools for the study of these enzymes. These ionic species bear the same charge as phosphate and the transferring phosphoryl group and, in addition, allow the enzyme to be trapped in catalytically important states with spectroscopically sensitive atoms interacting directly with active site residues. The ionic nature of these phosphate surrogates also allows their removal and replacement with other analogues. Here, we describe the best practices to obtain these complexes, their use in NMR, X-ray crystallography, cryoEM and SAXS and describe a new metal fluoride, scandium tetrafluoride, which has significant anomalous signal with soft X-rays.

Highlights

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Enzymes that catalyse phosphoryl transfer are the largest family of enzymes and are involved in the storage and transmission of genetic information, energy transfer, signalling and cellular differentiation

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Metal fluorides form a comprehensive tool kit to study the mechanisms of these enzymes by stabilizing the active conformation; mimicking both the transition state and ground state; and placing spectroscopically sensitive atoms into the active site

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A guide is presented to the optimal formation of these complexes and their use in a wide variety of techniques in structural biology
Theoretical insights into rotary mechanism of MotAB in the bacterial flagellar motor
Authors: Kubo Shintaroh , Okada Yasushi , Takada Shoji
Published: March 2024

Many bacteria enable locomotion by rotating their flagellum. It has been suggested that this rotation is realized by the rotary motion of the stator unit, MotAB, which is driven by proton transfer across the membrane. Recent cryo-electron microscopy studies have revealed a 5:2 MotAB configuration, in which a MotB dimer is encircled by a ring-shaped MotA pentamer. While the structure implicates the rotary motion of the MotA wheel around the MotB axle, the molecular mechanisms of rotary motion and how they are coupled with proton transfer across the membrane remain elusive. In this study, we built a structure-based computational model forCampylobacter jejuniMotAB, conducted comprehensive protonation state-dependent molecular dynamics simulations, and revealed a plausible proton-transfer coupled rotation pathway. The model assumes rotation-dependent proton transfer, in which proton uptake from the periplasmic side to the conserved aspartic acid in MotB is followed by proton hopping to the MotA proton-carrying site, followed by proton export to the cytoplasm. We suggest that, by maintaining two of the proton-carrying sites of MotA in the deprotonated state, the MotA pentamer robustly rotates by ∼36° per proton transfer across the membrane. Our results provide a structure-based mechanistic model of the rotary motion of MotAB in bacterial flagellar motors and provide insights into various ion-driven rotary molecular motors.

Significance Statement

This study aims to elucidate the mechanism by which bacteria move by rotating their flagella. The driving force for flagellar rotation is predicted to be driven by protons passing through the transmembrane protein MotAB, but the actual rotation mechanism has not yet been elucidated. Using advanced computational modeling and molecular dynamics simulations, we have elucidated the detailed processes by which proton translocation achieves the rotation of the bacterial flagellar motor. This work not only sheds light on the fundamental mechanisms of bacterial motility but also provides a framework for understanding similar ion-driven rotation mechanisms in other biological systems, potentially paving the way for new bioinspired technologies.