bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuromuscular Adaptations Related to Medial Knee Osteoarthritis and Influence of Unloader Braces on Neuromuscular Activity in Knee Osteoarthritis Subjects—A Systematic Review
Authors: Rogoschin Jana , Komnik Igor , Potthast Wolfgang
Published: May 2024

Unloader braces are a treatment modality for medial compartment knee osteoarthritis. The functional mechanisms involved are not yet fully understood. Therefore, this two-part systematic review examines the following research questions: How is muscle activation altered by medial compartment knee osteoarthritis, and do medial tibio-femoral compartment unloader braces alter muscle activation? If so, could this alteration be part of the unloading mechanism by affecting the altered muscle activity in medial compartment knee osteoarthritis?

A systematic literature search was conducted using PubMed, LIVIVO, Web of Science, Google Scholar, and CENTRAL for articles published until August 2023. The first systematic review, examining neuromuscular alterations, identified 703 articles, with a final inclusion of 20. The second systematic review, which evaluated the neuromuscular effects of unloader braces, identified 123 articles with the final inclusion of 3. Individuals with medial compartment knee osteoarthritis demonstrated increased activity and co-contraction of the periarticular knee muscles, whereas medial tibio-femoral compartment unloader braces seemed to reduce activity and co-contraction. In contrast to the belief that unloader braces result in muscle weakness as they decrease muscle activity and co-contraction, our limited insights indicate that they rather might reduce the pathological increase. This may result in joint load reduction due to lower compressive forces. However, further investigation is required.
Brief Report: Depression, Substance Use, and Factors Associated With Sexual Risk Behaviors Among Adults Living With HIV in the Asia-Pacific Region
Authors: Ross Jeremy L. , Teeraananchai Sirinya , Avihingsanon Anchalee , Lee Man Po , Ditangco Rossana , Rajasuriar Reena , Kim Jung Ho , Gatechompol Sivaporn , Chan Iris , Melgar Maria Isabel Echanis , Chong Meng Li , Jiamsakul Awachana , Sohn Annette H. , Law Matthew , Choi Jun Yong ,   on behalf of the Substance Use, Stigma, Depression and Disability (S2D2) Study Group of IeDEA Asia-Pacific
Published: May 2024

Background:

Mental health and substance use disorders are common among people living with HIV and are associated with high-risk sexual behaviors, such as unprotected sex and multiple sexual partners, but Asia-Pacific data are limited.

Methods:

Adults living with HIV in care at 5 Asia-Pacific HIV clinics were enrolled at routine clinic visits between July 2019 and June 2020. Depression, substance use, sexual practice, and sociodemographic data were collected using the Patient Health Questionnaire-9, Alcohol, Smoking, and Substance Involvement Screening Test, and a study-specific questionnaire. Clinical data were accessed from medical records. Risk factors for medium- to high-risk sexual practices, defined based on total scores from the sexual practice questionnaire assessing number of sexual partners and condom use, were analyzed using logistic regression. Moderate-to-severe depression was defined as a Patient Health Questionnaire-9 score >9 and moderate- to high-risk substance use as an Alcohol, Smoking, and Substance Involvement Screening Test score ≥11 for alcohol or ≥4 for other substances.

Results:

Among 723 participants, the median age was 38 years, 89% were men, 99% were on antiretroviral therapy and 37% had medium- to high-risk sexual practices. Medium- to high-risk sexual practices were more common among those ≤30 years old, unemployed, and those with HIV status disclosed and were more likely in participants with moderate-to-severe depression (aOR 2.09, 95% CI: 1.17 to 3.74) compared with none-to-minimal depression, and moderate- to high-risk substance use (aOR 1.73, 95% CI: 1.23 to 2.44) compared with those without.

Conclusions:

Further integration of comprehensive sexual risk reduction strategies, mental health services, and substance use harm reduction within HIV clinical settings in the region is needed.
Maxillary Bone Necrosis in Post-COVID-19 Patients: Possibility of Medication-Related Osteonecrosis of Jaws (MRONJ) Induced by Tocilizumab
Authors: Roh Taeho , Jo Hyeongyu , Kim Jun-Young
Published: May 2024

Medication-related osteonecrosis of the jaws (MRONJ) is a serious condition often linked with antiresorptive, immune modulating, and antiangiogenic drugs, initially associated with bisphosphonates but now including a broader range of medications. Tocilizumab, an interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody used for conditions like rheumatoid arthritis and recently for COVID-19 to reduce IL-6 activity and alleviate symptoms, has raised concerns over its potential to induce MRONJ, particularly in post-COVID-19 patients. A case involving a 36-year-old male who developed tooth mobility and pain in the right maxillary posterior region after COVID-19 treatment with tocilizumab and dexamethasone is highlighted. Despite treatments like antibiotics, the necrosis persisted until more extensive surgery was performed, leading to improvement without recurrence over 2 years. This case emphasizes the need for awareness and research into the risk of MRONJ in patients treated with tocilizumab after COVID-19, underlining the importance for healthcare professionals to recognize and manage this complication.
Determination of Mouth Width for Facial Reconstruction Based on Statistical Regression Model
Authors: Zhang MeiLing , Xu Huiming , Biao Yan , Lee KyungMin Clara
Published: May 2024

Introduction:

It is important to generate predictable statistical models by increasing the number of variables on the human skeletal and soft tissue structures on the face to increase the accuracy of human facial reconstructions. The purpose of this study was to determine mouth width 3-dimensionally based on statistical regression model.

Material and Methods:

Cone-beam computed tomography scan data from 130 individuals were used to measure the horizontal and vertical dimensions of orbital and nasal structures and intercanine width. The correlation between these hard tissue variables and the mouth width was evaluated using the statistical regression model.

Results:

Orbital width, nasal width, and intercanine width were found to be strong predictors of the mouth width determination and were used to generate the regression formulae to find the most approximate position of the mouth.

Conclusion:

These specific variables may contribute to improving the accuracy of mouth width determination for oral and maxillofacial reconstructions.
Zygomatic Implant Length Measurement Without Excessive Flap Release: A Human Cadaver Study
Authors: Şahin Onur , Rizaj Xhini , Bilge Okan , Çelik Servet , Hacilar Mustafa , Bakar Olcay
Published: May 2024

One of the most important steps in zygomatic implant surgery is to determine the implant length. This cadaver study aims to identify an alternative technique for determining the length of the implant in zygoma surgery without excessive elevation of the flap. A total of 30 cadavers were included in this study. Measurements were made with a probe by seeing the exit point of the drills from the lateral aspect of the zygomatic bone. Secondly, without excessive flap release, the distance that the depth probe first raises the skin over the lateral border of the zygoma is measured. The average difference between the measurements made without excessive elevation of the flap and with a retractor placed on the zygomaticofrontal notch was found to be 5.41 ± 0.94 mm (range: 5–7.5 mm). According to the results of this study, the zygomatic implant should be placed at least 5 mm shorter than the length at which the depth probe first raises the skin over the lateral border of the zygomatic bone.
Morphometric Analysis of the Sella Turcica on Cone-Beam Computed Tomography Images
Authors: Ince Rümeysa , Cihan Ömer F. , Bahşi İlhan , Yalçin Eda D.
Published: May 2024

Introduction:

Sella turcica is an important anatomic formation that contains the pituitary gland and is in a close neighborhood with many vital structures. It is important to know the morphometry of the sella turcica, as it is a transition point during surgical interventions such as the endoscopic endonasal transsphenoidal approach to the region. The findings obtained are thought to be useful in the examination of sella turcica and surrounding structures and will contribute to the literature by knowing the morphometry of the region for the surgical method.

Method:

In this study, cone-beam computed tomography images of 400 individuals, 200 females and 200 males, aged between 18 and 65 years, who did not have craniofacial pathology, who applied to Gaziantep University, Faculty of Dentistry between 2015 and 2020 for any reason, were evaluated retrospectively. In the sagittal section, 8 parameters were examined, 6 of which were transverse.

Results:

The length () of the sella turcica in the sagittal plane is 10.19±1.77 mm, the diameter of the sella turcica is 11.6±1.69 mm, the anterior height of the sella turcica is 7.88±1.56 mm, the median height of the sella turcica 8.18±1.42 mm, posterior height of sella turcica 6.98±1.31 mm, width of sella turcica 11.10±1.6 mm. The distance between anterior clinoid processes in the transverse plane was 24.93±2.57 mm, and the distance between posterior clinoid processes was 14.92±2.46 mm.

Conclusion:

It was determined that there was an increase in many parameters with age, and length of the sella turcica and anterior clinoid processes were statistically significantly higher in males.
Long-term Follow-up of Implant Installation Following Multiple Distraction Osteogenesis in Maxillofacial Gunshot Wounds
Authors: Li Haoyun , Eo Mi Young , Mustakim Kezia Rachellea , Kim Soung Min
Published: May 2024

Distraction osteogenesis (DO) is a reconstruction technique developed in the fields of oral and maxillofacial surgery and plastic surgery, addressing both vertical and horizontal bone deficiencies and enhancing soft tissue volume to facilitate subsequent dental implant placement. In this treatment method, devices are placed to stretch the bone gradually to stimulate the formation of new bone, effectively filling the existing defect to treat maxillofacial deformities or repair posttraumatic injuries. This case report presents an almost 20-year long-term follow-up of jaw defect reconstruction resulting from a gunshot injury, using DO with multiple distractors. Details on the frequency, period of DO, and subsequent implant installation in the distracted anterior jaw area are outlined. This case exhibits DO treatments that reconstructed effectively severe bone defects in the jaws. The quality of bone generated during the DO process was both functionally and esthetically satisfactory for subsequent implant rehabilitation.
Pediatric Canalicular Lacerations: Epidemiology and Surgical Outcomes
Authors: Güçlü Emin S. , Özer Ömer
Published: May 2024

Background:

The aim of this study was to report the epidemiology and surgical outcomes of canalicular lacerations in the pediatric age group.

Methods:

All pediatric patients who underwent repair of canalicular lacerations of any cause were included in this study. Age, sex, mechanism of trauma, and type of stent used were recorded.

Results:

The study group consisted of 47 patients with a median age of 6.4 years (22 mo–17 y). Thirty of the patients were male (63.8%). The lower canaliculus was affected in 76.6% (n=36), the upper canaliculus in 40.4% (n=19), and both canaliculi in 17% (n=8). The most common cause of canalicular laceration was sharp objects (n=33, 70.2%).

Conclusion:

Canalicular laceration most commonly affects boys and especially involves the lower canaliculus. There was no difference in functional success between monocanalicular and bicanalicular stents. Prevention of canalicular lacerations should be the main focus.
Mandibular Notch Contouring in Temporomandibular Joint Replacement. Technical Note
Authors: Olate Sergio , Ravelo Victor , Muñoz Gonzalo , Huentequeo Claudio
Published: May 2024

Temporomandibular Joint Replacement (TMJ-R) is used to treat maxillomandibular disease related to condylar head augmentation, condylar head reduction, absence of the condylar head and TMJ reconstruction. In most of the cases, TMJ-R could be used together with orthognathic surgery. In cases with facial asymmetry related to overgrowth of the mandibular condyle as in the cases of osteochondroma, there is a progressive facial asymmetry with enlargement of the unilateral mandibular ramus and mandibular body, creating strong mandibular contouring when comparing to the contralateral side. Usually, in this case, a lack is observed in the antegonial notch. ​The aim of this technical note ​is to provide the strategy to obtain facial symmetry using the TMJ prosthesis and contouring osteotomy in the same procedure.
Three-Dimensional Analysis of Bone Remodeling After Closed Treatment for Mandibular Condylar Head Fracture
Authors: Sim You Song , Park Won-Jong , Jung Seunggon , Kook Min-Suk , Park Hong-Ju , Oh Hee-Kyun , Han Jeong Joon
Published: May 2024

Closed treatment of mandibular condylar fractures has been used for its indications based on the fracture site, fracture status, and patient age. Posttreatment mandibular condyle size is associated with mandibular function; however, a few studies have reported bone remodeling patterns and volume changes in the condyle and glenoid fossa after mandibular condylar head fractures (CHFs). Therefore, volumetric changes in the mandibular condyle and glenoid fossa were analyzed in the present study, and bone remodeling patterns were evaluated after mandibular CHFs. The present study included 16 condyles from 12 patients who received closed treatment for CHF. After reconstruction of a 3-dimensional skull model, including the mandible, using computed tomography data taken immediately after injury and 6 months after treatment, volume changes in the mandibular condyle and glenoid fossa were analyzed. The condylar volume increased by 0.32±0.66 cm3 during the 6-month healing period without statistical significance (P=0.093). Regarding the glenoid fossa, the fossa showed a statistically significant volume increase of 0.41±0.59 cm3 (P=0.021), and 12 glenoid fossae (75%) showed downward bone apposition; however, no change or only mild bone resorption was observed in 4 glenoid fossae (25%). The results of this study indicated that the volume changes in the mandibular condyle after closed treatment of a mandibular CHF are not significant, and the glenoid fossa adapts to the displaced mandibular condyle through downward growth accompanied by volume increase.
The Long-Term Natural History of Fibrous Dysplasia
Authors: Ishida Kaori , Sakamoto Yoshiaki , Kosugi Kenzo , Miwa Tomoru , Toda Masahiro
Published: May 2024

Fibrous dysplasia (FD), a developmental, nonfamilial, benign anomaly of bone development, is characterized by the replacement of normal bone by proliferating fibro-osseous tissue. Marked craniofacial deformities, functional disturbances, and emotional stress are major indications for treatment, and various surgical procedures have been performed; however, excision and regrowth issues have also been reported. While several treatment options are available, no studies have reported the natural history of untreated FD. Here, we report 2 patients, aged 73 and 50 years, respectively, who had not received treatment. Both patients presented to the hospital complaining of noise when moving their heads. Computed tomography scans showed niveau with honeycomb cavities in both patients, indicating abscess formation, and resection was performed. Relatively large cranial FD leads to the development of central necrosis over time. In such cases, surgical intervention should be performed at an early disease stage.
Ambulatory Cardiology or General Internal Medicine Assessment Prior to Scheduled Major Vascular Surgery is Associated with Improved Outcomes
Authors: de Mestral Charles , Abdel-Qadir Husam M , Austin Peter C , Chong Alice S , McAlister Finlay A , Lindsay Thomas F , Ross Heather J , Oreopoulos George , Wijeysundera Duminda N , Lee Douglas S
Published: May 2024

Objective:

To characterize the association between ambulatory cardiology or general internal medicine (GIM) assessment prior to surgery and outcomes following scheduled major vascular surgery.

Background:

Cardiovascular risk assessment and management prior to high-risk surgery remains an evolving area of care.

Methods:

This is population-based retrospective cohort study of all adults who underwent scheduled major vascular surgery in Ontario, Canada, April 1, 2004-March 31, 2019. Patients who had an ambulatory cardiology and/or GIM assessment within 6 months prior to surgery were compared to those who did not. The primary outcome was 30-day mortality. Secondary outcomes included: composite of 30-day mortality, myocardial infarction or stroke; 30-day cardiovascular death; 1-year mortality; composite of 1-year mortality, myocardial infarction or stroke; and 1-year cardiovascular death. Cox proportional hazard regression using inverse probability of treatment weighting (IPTW) was used to mitigate confounding by indication.

Results:

Among 50,228 patients, 20,484 (40.8%) underwent an ambulatory assessment prior to surgery: 11,074 (54.1%) with cardiology, 8,071 (39.4%) with GIM and 1,339 (6.5%) with both. Compared to patients who did not, those who underwent an assessment had a higher Revised Cardiac Risk Index (N with Index over 2= 4,989[24.4%] vs. 4,587[15.4%], P<0.001) and more frequent pre-operative cardiac testing (N=7,772[37.9%] vs. 6,113[20.6%], P<0.001) but, lower 30-day mortality (N=551[2.7%] vs. 970[3.3%], P<0.001). After application of IPTW, cardiology or GIM assessment prior to surgery remained associated with a lower 30-day mortality (weighted Hazard Ratio [95%CI] = 0.73 [0.65-0.82]) and a lower rate of all secondary outcomes.

Conclusions:

Major vascular surgery patients assessed by a cardiology or GIM physician prior to surgery have better outcomes than those who are not. Further research is needed to better understand potential mechanisms of benefit.
A Method for Continuous Surgeon Improvement in Rectal Cancer
Authors: Ferrari Davide , Violante Tommaso , Merchea Amit , Dozois Eric , Vierkant Robert A. , Larson David W.
Published: May 2024

Objective:

To develop and analyze a risk-adjusted cumulative sum (RA-CUSUM) chart as a potential method to monitor individual surgeon performance in robotic total mesorectal excision (TME) for rectal cancer.

Summary Background Data:

Currently, surgeons lack real-time tools to monitor and enhance their performance beyond residency completion. While national quality programs exist, granular, individual-level data is crucial for continuous improvement. Previous studies suggest CUSUM charts hold promise in identifying performance trends and outliers.

Methods:

This retrospective study analyzed data from 640 robotic TME cases performed by 12 surgeons at two institutions. RA-CUSUM charts were generated for three outcomes: complications, operative time, and length of stay.

Results:

The overall RA-CUSUM curves for operative time and complications showed an initial learning phase followed by a plateau or downward slope, indicating proficiency or improvement. However, individual surgeon curves revealed significant heterogeneity. Three surgeons consistently excelled in operative time, while five minimized complications most effectively. Potential quality improvement could be implemented to drive performance toward positive outliers. No differences were found in unadjusted outcomes, including conversion, number of lymph nodes harvested, and positive circumferential margins.

Conclusions:

The RA-CUSUM chart is a promising method for identifying individual surgeon performance in robotic TME. It could help surgeons, teams, and leaders identify improvement areas and benchmark themselves against positive outliers. Further studies are needed to explore the potential of RA-CUSUM for implementing interventions to improve surgical quality.
Postoperative Activity Restrictions After Slings: A Randomized Controlled Trial
Authors: Lai Erica , McDonald Katherine , Chopra Vini , Robinson Lindsay , Alvarez Alejandro , O’Shaughnessy Danielle , Pillalamarri Nirmala , Polland Allison , Shalom Dara , Winkler Harvey
Published: May 2024

Importance

Restricting activity after midurethral slings is an unproven practice.

Objective

The objective of this study was to evaluate the effect of postoperative activity restriction on satisfaction and outcomes after slings.

Study Design

This was a multicenter, 2-arm, noninferiority randomized controlled trial. Patients aged 18–85 years undergoing treatment with a midurethral sling were randomized 1:1 to postoperative activity restriction or liberal activity. Restrictions included avoidance of strenuous exercise and heavy lifting. The liberal group was allowed to resume activity at their discretion. Our primary outcome was satisfaction with postoperative instruction at 2 weeks. Secondary outcomes included surgical failure, mesh exposure rates, and other adverse events.

Results

In total, 158 patients were randomized with 80 to the liberal group and 78 to the restricted group. At 2 weeks, 54 (80.6%) of patients in the liberal group and 48 (73.9%) of patients in the restricted group were satisfied. We found statistical evidence supporting the hypothesis that postoperative liberal activity instruction is noninferior to activity restriction with regard to patient satisfaction (P = 0.0281). There was no significant difference in strenuous activity at 2 weeks (P = 0.0824). The liberal group reported significantly more moderate activity at 2 weeks (P = 0.0384) and more strenuous activity at 6 weeks and 6 months (P = 0.0171, P = 0.0118, respectively). The rate of recurrent or persistent stress incontinence for liberal versus restricted groups was 18.52% versus 23.53% (P = 0.635). There were no statistically significant differences in complication rates.

Conclusions

Postoperative liberal activity was noninferior to activity restriction with regard to patients’ satisfaction. There was no evidence supporting a statistically significant association between postoperative instruction and negative surgical outcomes.
A phylogeny of extant coleoid cephalopods with brain data
Authors: Basava Kiran , Bendixen Theiss , Birk Sørensen Alexander Leonhard , George Nicole , Vanhersecke Zoé , Omotosho Joshua , Mather Jennifer , Muthukrishna Michael
Published: May 2024

Extant coleoid cephalopods include over 800 species of octopuses, squid, and cuttlefish, which have drawn scientific and public interest for their complex behavior and cognition. Of these, approximately 10% (79) species have adult specimens with recorded measures of central nervous system size distributed across various sources. Here, we use a combination of topological placements from previous phylogenetic studies, along with mitochondrial and nuclear gene sequences obtained from GenBank, to build a composite phylogenetic tree with estimated branch lengths of all species with available brain measurements. This phylogeny is used for analyses in a forthcoming paper on cephalopod brain evolution, and ideally will be of use to other researchers interested in conducting comparative studies of coleoid cephalopod brains.
Non Parametric Differential Network Analysis: A Tool for Unveiling Specific Molecular Signatures
Authors: Guzzi Pietro Hiram , Arkaprava Roy , Milano Marianna , Veltri Pierangelo
Published: May 2024

The rewiring of molecular interactions in various conditions leads to distinct phenotypic outcomes. Differential Network Analysis (DNA) is dedicated to exploring these rewirings within gene and protein networks. Leveraging statistical learning and graph theory, DNA algorithms scrutinize alterations in interaction patterns derived from experimental data. Introducing a novel approach to differential network analysis, we incorporate differential gene expression based on sex and gender attributes. We hypothesize that gene expression can be accurately represented through non-Gaussian processes. Our methodology involves quantifying changes in non-parametric correlations among gene pairs and expression levels of individual genes. Applying our method to public expression datasets concerning diabetes mellitus and atherosclerosis in liver tissue, we identify gender-specific differential networks. Results underscore the biological relevance of our approach in uncovering meaningful molecular distinctions.

Author summary

This paper explores a novel technique for Differential Network Analysis (DNA) that considers sex-based variations. DNA compares biological networks under different conditions, like healthy vs. diseased states. Our method tackles the limitations of traditional DNA approaches, which often assume specific data distributions. We propose a non-parametric DNA methodology that integrates sex differences and identifies differential edges between networks. This approach utilizes data on gene expression levels and sex to construct a more accurate picture of the molecular mechanisms underlying diseases, particularly those exhibiting sex-dependent variations. Our method paves the way for a deeper understanding of how sex and age influence disease processes at the molecular level.
SMC complex unidirectionally translocates DNA by coupling segment capture with an asymmetric kleisin path
Authors: Yamauchi Masataka , Brandani Giovanni B. , Terakawa Tsuyoshi , Takada Shoji
Published: May 2024

SMC (structural maintenance of chromosomes) protein complexes are ring-shaped molecular motors essential for genome folding. Despite recent progress, the detailed molecular mechanism of DNA translocation in concert with the ATP-driven conformational changes of the complex remains to be clarified. In this study, we elucidated the mechanisms of SMC action on DNA using multiscale molecular dynamics simulations. We first created a near-atomic full-length model of prokaryotic SMC-kleisin complex that implemented protein-DNA hydrogen bond interactions derived from fully atomistic simulations and emulated ATP-dependent conformational changes. Extensive simulations of the SMC complex with 800 base pairs of duplex DNA over the ATP cycle revealed unidirectional DNA translocation via the DNA segment capture mechanism. The process exhibited a step size of ∼200 base pairs, wherein the complex captured a DNA segment of about the same size within the SMC ring in the engaged state, followed by its pumping into the kleisin ring as ATP was hydrolyzed. We found that the hinge-DNA interaction is not critical for the DNA translocation. On the other hand, analysis of trajectories identified the asymmetric path of the kleisin as a critical factor for the observed unidirectionality.

SIGNIFICANCE STATEMENT

Ring-shaped SMC (structural maintenance of chromosomes) protein complexes, which are highly conserved across all three domains of life, play an essential role in chromosome organization through a process called DNA loop extrusion. However, the molecular mechanism underlying the ATP-dependent motor activity of SMC complexes remains unclear. Using all-atom and residue-resolution coarse-grained molecular dynamics simulations, we revealed that prokaryotic SMC complexes translocate unidirectionally along DNA via a segment capture mechanism. We found that the unidirectionality arises from the kleisin subunit breaking the symmetry of the ring-shaped SMC complex structure. Our findings provide insights into the molecular motor mechanisms shared by SMC complexes.
Mechanical characterization of soft biomaterials: which time and spatial scale to choose?
Authors: Krivega E.S. , Kotova S.L. , Timashev P.S. , Efremov Y.M.
Published: May 2024

The mechanical properties of soft gels hold significant relevance in biomedicine and biomaterial design, including the development of tissue engineering constructs and bioequivalents. It is important to adequately characterize the gel’s mechanical properties since they play a role both in the overall structural properties of the construct and in cells’ physiological responses. The question remains which approach for mechanical characterization is most suitable for specific biomaterials. Our investigation is centered on the comparison of three types of gels and four distinct mechanical testing techniques: shear rheology, compression, microindentation, and nanoindentation by atomic force microscopy. While analyzing an elastic homogeneous synthetic hydrogel (polyacrylamide gel), we observed close mechanical results across the different testing techniques. However, our findings revealed more distinct outcomes when assessing a highly viscoelastic gel (Ecoflex) and a heterogeneous biopolymer hydrogel (enzymatically crosslinked gelatin). To ensure the precise data interpretation, we introduced correction factors to account for the boundary conditions inherent in many of the testing methods. The results of the study underscore the critical significance of considering both the temporal and spatial scales in mechanical measurements of biomaterials. Furthermore, they encourage the employment of a combination of diverse testing techniques, particularly in the characterization of heterogeneous viscoelastic materials such as biological samples. The obtained results will contribute to refining mechanical testing protocols and advance the development of soft gels for tissue engineering.
Myoglobin Inhibits Breast Cancer Cell Fatty Acid Oxidation and Migration via Heme-dependent Oxidant Production and Not Fatty Acid Binding
Authors: Johnson Aaron R. , Rao Krithika , Zhang Bob B. , Mullet Steven , Goetzman Eric , Gelhaus Stacy , Tejero Jesus , Shiva uti
Published: May 2024

The monomeric heme protein myoglobin (Mb), traditionally thought to be expressed exclusively in cardiac and skeletal muscle, is now known to be expressed in approximately 40% of breast tumors. While Mb expression is associated with better patient prognosis, the molecular mechanisms by which Mb limits cancer progression are unclear. In muscle, Mb’s predominant function is oxygen storage and delivery, which is dependent on the protein’s heme moiety. However, prior studies demonstrate that the low levels of Mb expressed in cancer cells preclude this function. Recent studies propose a novel fatty acid binding function for Mb via a lysine residue (K46) in the heme pocket. Given that cancer cells can upregulate fatty acid oxidation (FAO) to maintain energy production for cytoskeletal remodeling during cell migration, we tested whether Mb-mediated fatty acid binding modulates FAO to decrease breast cancer cell migration. We demonstrate that the stable expression of human Mb in MDA-MB-231 breast cancer cells decreases cell migration and FAO. Site-directed mutagenesis of Mb to disrupt Mb fatty acid binding did not reverse Mb-mediated attenuation of FAO or cell migration in these cells. In contrast, cells expressing Apo-Mb, in which heme incorporation was disrupted, showed a reversal of Mb-mediated attenuation of FAO and cell migration, suggesting that Mb attenuates FAO and migration via a heme-dependent mechanism rather than through fatty acid binding. To this end, we show that Mb’s heme-dependent oxidant generation propagates dysregulated gene expression of migratory genes, and this is reversed by catalase treatment. Collectively, these data demonstrate that Mb decreases breast cancer cell migration, and this effect is due to heme-mediated oxidant production rather than fatty acid binding. The implication of these results will be discussed in the context of therapeutic strategies to modulate oxidant production and Mb in tumors.

Graphical Abstract

Graphical Abstract:

Mb-dependent oxidant generation (but not fatty acid binding) dysregulates mitochondrial respiration and migratory gene expression, leading to decreased cell migration. Created with BioRender.

Highlights

Myoglobin (Mb) expression in MDA-MB-231 breast cancer cells slows migration.

Mb expression decreases mitochondrial respiration and fatty acid oxidation.

Mb-dependent fatty acid binding does not regulate cell migration or respiration.

Mb-dependent oxidant generation decreases mitochondrial metabolism and migration.

Mb-derived oxidants dysregulate migratory gene expression.
RegulaTome: a corpus of typed, directed, and signed relations between biomedical entities in the scientific literature
Authors: Nastou Katerina , Mehryary Farrokh , Ohta Tomoko , Luoma Jouni , Pyysalo Sampo , Jensen Lars Juhl
Published: May 2024

Motivation

In the field of biomedical text mining, the ability to extract relations from literature is crucial for advancing both theoretical research and practical applications. There is a notable shortage of corpora designed to enhance the extraction of multiple types of relations, particularly focusing on proteins and protein-containing entities such as complexes and families, as well as chemicals.

Results

In this work we present RegulaTome, a corpus that overcomes the limitations of several existing biomedical relation extraction (RE) corpora, many of which concentrate on single-type relations at the sentence level. RegulaTome stands out by offering 16,962 relations annotated in over 2,500 documents, making it the most extensive dataset of its kind to date. This corpus is specifically designed to cover a broader spectrum of over 40 relation types beyond those traditionally explored, setting a new benchmark in the complexity and depth of biomedical RE tasks. Our corpus both broadens the scope of detected relations and allows for achieving noteworthy accuracy in RE. A Transformer-based model trained on this corpus has demonstrated a promising F1-score (66.6%) for a task of this complexity, underscoring the effectiveness of our approach in accurately identifying and categorizing a wide array of biological relations. This achievement highlights RegulaTome’s potential to significantly contribute to the development of more sophisticated, efficient, and accurate RE systems to tackle biomedical tasks. Finally, a run of the trained relation extraction system on all PubMed abstracts and PMC Open Access full-text documents resulted in over 18 million relations, extracted from the entire biomedical literature.

Availability

The corpus and all introduced resources are openly accessible via Zenodo (https://zenodo.org/doi/10.5281/zenodo.10808330) and GitHub (https://github.com/farmeh/RegulaTome_extraction).
Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice
Authors: Lavigna Giada , Grasso Anna , Pasini Chiara , Grande Valentina , Mignogna Laura , Restelli Elena , Masone Antonio , Fracasso Claudia , Lucchetti Jacopo , Gobbi Marco , Chiesa Roberto
Published: May 2024

There is no cure for Marinesco-Sjögren syndrome (MSS), a genetic multisystem disease linked to loss-of-function mutations in theSIL1gene, encoding a BiP co-chaperone. We previously found that the PERK kinase inhibitor GSK2606414 delayed cerebellar Purkinje cell (PC) degeneration and the onset of ataxia in the woozy mouse model of MSS. However, GSK2606414 is toxic to the pancreas and does not completely rescue the woozy phenotype. The present study tested trazodone and dibenzoylmethane (DBM), which partially inhibit PERK signaling with neuroprotective effects and no pancreatic toxicity. We also tested the chemical chaperone tauroursodeoxycholic acid (TUDCA), which can protect MSS patients’ cells from stress-induced apoptosis. Mice were chronically treated for five weeks, starting from a presymptomatic stage. Trazodone was given 40 mg/kg daily by intraperitoneal (ip) injection. DBM was given 0.5% in the diet ad libitum. TUDCA was given either 0.4% in the diet, or 500 mg/kg ip every three days. None of the treatments prevented motor dysfunction in woozy mice, assessed by the beam walking and rotarod tests. Only trazodone slightly boosted beam walking performance. However, immunohistochemistry found no reduction in the number of CHOP-positive PCs, or increased PC survival, indicating no neuroprotective inhibition of PERK signaling. Pharmacokinetic studies excluded that the lack of effect was due to altered drug metabolism in woozy mice. These results indicate that trazodone, DBM and TUDCA, at dosing regimens active in other neurodegenerative disease mouse models, have no disease-modifying effect in a preclinical model of MSS.
Forest edge landscape context affects mosquito community composition and risk of pathogen emergence
Authors: Hendy Adam , Fé Nelson Ferreira , Pedrosa Igor , Girão André , Figueira dos Santos Taly Nayandra , Mendonça Claudia Reis , Andes Júnior José Tenaçol , Assunção Flamarion Prado , Costa Edson Rodrigues , Sluydts Vincent , Gordo Marcelo , Scarpassa Vera Margarete , Buenemann Michaela , Lacerda Marcus Vinícius Guimarães de , Mourão Maria Paula Gomes , Vasilakis Nikos , Hanley Kathryn A.
Published: May 2024

Forest edges, where humans, mosquitoes, and wildlife interact, may serve as a nexus for zoonotic arbovirus exchange. Although often treated as uniform interfaces, the landscape context of edge habitats can greatly impact ecological interactions. Here, we investigated how the landscape context of forest edges shapes mosquito community structure in an Amazon rainforest reserve near the city of Manaus, Brazil, using hand-nets to sample mosquitoes at three distinct forest edge types. Sampling sites were situated at edges bordering urban land cover, rural land cover, and natural treefall gaps, while sites in continuous forest served as controls. Community composition differed substantially among edge types, with rural edges supporting the highest species diversity. Rural edges also provided suitable habitat for forest specialists, including key sylvatic vectors, of whichHaemagogus janthinomyswas the most abundant species sampled overall. Our findings emphasize the importance of landscape context in assessing pathogen emergence risk at forest edges.
UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair
Authors: Mu Yunxiang , Chen Zaowen , Plummer Joshua B. , Zelazowska Monika A. , Dong Qiwen , Krug Laurie T. , McBride Kevin M.
Published: May 2024

Mammalian Uracil DNA glycosylase (UNG) removes uracils and initiates high-fidelity base excision repair to maintain genomic stability. During B cell development, activation-induced cytidine deaminase (AID) creates uracils that UNG processes in an error-prone fashion to accomplish immunoglobulin (Ig) somatic hypermutation (SHM) or class switch recombination (CSR). The mechanism that governs high-fidelity versus mutagenic uracil repair is not understood. The B cell tropic gammaherpesvirus (GHV) encodes a functional homolog of UNG that can process AID induced genomic uracils. GHVUNG does not support hypermutation, suggesting intrinsic properties of UNG influence repair outcome. Noting the structural divergence between the UNGs, we define the RPA interacting motif as the determinant of mutation outcome. UNG or RPA mutants unable to interact with each other, only support high-fidelity repair. In B cells, transversions at the Ig variable region are abated while CSR is supported. Thus UNG-RPA governs the generation of mutations and has implications for locus specific mutagenesis in B cells and deamination associated mutational signatures in cancer.
Comparing approaches to quantify urbanization on a multicontinental scale
Authors: Murray-Stoker David , Santangelo James S , Szulkin Marta , Johnson Marc
Published: May 2024

Urbanization is an increasingly prevalent driver of environmental, ecological, and evolutionary change in both terrestrial and aquatic systems, and it is important that our sampling designs accurately capture this urban environmental change. Common approaches to sampling urban environments include: urban-nonurban transects, which sample along urbanization gradients; random points, which sample locations at random within an area of interest; and systematic points, which sample locations based on a regularly-spaced grid from a predetermined starting point within the area of interest. Presently, we lack a comparative analysis of the efficacy of these different sampling designs in capturing variation in urban environments. Here, we compare the environmental variation captured by transect- and point-based sampling designs in 136 cities across six continents. We quantified and compared a common set of environmental variables for each sampling design, with variables capturing landcover, climate, and socioeconomic facets of urban environments. Mean landcover and socioeconomic metrics consistently differed among sampling designs, in contrast to climate variables that primarily varied among cities. Additionally, changes in environmental variables with distance from the city centre depended on the sampling design, with this distance-by-sampling design interaction present in 27%-51% of cities, depending on the environmental variable. This implies that the rate of environmental change along urban-nonurban gradients frequently depends on the sampling design used. We also examined potential causes of deviations between transect- and point-based sampling designs and identified human population density and city area as common predictors of deviations between transect- and point-sampling designs. Our results show that sampling design can dictate how the urban environment is characterized, with sampling design as important - or more important - as the selected environmental variable. We further developed R code so researchers can implement these methods as they develop and validate sampling designs in novel or unstudied urban environments.
Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing
Authors: Mietzsch Mario , Nelson Austin R. , Hsi Jane , Zachary Jon , Potts Lindsay , Chipman Paul , Ghanem Mohammad , Khandekar Neeta , Alexander Ian E. , Logan Grant J. , Huiskonen Juha T. , McKenna Robert
Published: May 2024

Monoclonal antibodies (mAbs) are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids used as gene therapy delivery vectors. This study structurally characterizes the interactions of 21 human-derived antibodies from patients treated with the AAV9 vector, Zolgensma®, utilizing high-resolution cryo-electron microscopy. The majority of the bound antibodies do not conform to the icosahedral symmetry of the capsid, thus requiring localized reconstructions. These complex structures provide unprecedented details of the mAbs binding interfaces, with some antibodies inducing structural perturbations of the capsid upon binding. Key surface capsid amino acid residues were identified facilitating the design of capsid variants with an antibody escape phenotype, with the potential to expand the patient cohort treatable with AAV9 vectors to include those that were previously excluded due to their pre-existing neutralizing antibodies, and possibly also to those requiring redosing.
Non-invasive evidence for rhythmic interactions between the human brain, spinal cord, and muscle
Authors: Spedden Meaghan E. , O’Neill George C. , Timms Ryan C. , West Timothy O. , Mellor Stephanie , Tierney Tim M. , Alexander Nicholas A. , Seymour Robert , Farmer Simon F. , Bestmann Sven , Barnes Gareth R.
Published: May 2024

Voluntary human movement relies on interactions between the spinal cord, brain, and sensory afferents. The integrative function of the spinal cord has proven particularly difficult to study directly and non-invasively in humans due to challenges in measuring spinal cord activity. Investigations of sensorimotor integration often rely on cortico-muscular coupling, which can capture interactions between the brain and muscle, but cannot reveal how the spinal cord mediates this communication. Here, we introduce a system for direct, non-invasive imaging of concurrent brain and cervical spinal cord activity in humans using optically-pumped magnetometers (OPMs). We used this system to study endogenous interactions between the brain, spinal cord, and muscle involved in sensorimotor control during simple maintained contraction. Participants (n=3) performed a hand contraction with real-time visual feedback while we recorded brain and spinal cord activity using OPMs and muscle activity using EMG. We first identify the part of the spinal cord exhibiting a peak in estimated current flow in the cervical region during contraction. We then demonstrate that rhythmic activity in the spinal cord exhibits significant coupling with both brain and muscle activity in the 5-35 Hz frequency range. These findings evidence the possibility of concurrent spatio-temporal imaging along the entire neuro-axis.
Single-Cell Transcriptomic Analysis of Kaposi Sarcoma
Authors: Rauch D. A. , Ramos P. Valiño , Khanfar M. , Harding J. , Joseph A. , Griffith O , Griffith M , Ratner L.
Published: May 2024

Kaposi Sarcoma (KS) is a complex tumor caused by KS-associated herpesvirus 8 (KSHV). Histological analysis reveals a mixture of “spindle cells”, vascular-like spaces, extravasated erythrocytes, and immune cells. In order to elucidate the infected and uninfected cell types in KS tumors, we examined skin and blood samples from twelve subjects by single cell RNA sequence analyses. Two populations of KSHV-infected cells were identified, one of which represented a proliferative fraction of lymphatic endothelial cells, and the second represented an angiogenic population of vascular endothelial tip cells. Both infected clusters contained cells expressing lytic and latent KSHV genes. Novel cellular biomarkers were identified in the KSHV infected cells, including the sodium channel SCN9A. The number of KSHV positive tumor cells was found to be in the 6% range in HIV-associated KS, correlated inversely with tumor-infiltrating immune cells, and was reduced in biopsies from HIV-negative individuals. T-cell receptor clones were expanded in KS tumors and blood, although in differing magnitudes. Changes in cellular composition in KS tumors were identified in subjects treated with antiretroviral therapy alone, or immunotherapy. These studies demonstrate the feasibility of single cell analyses to identify prognostic and predictive biomarkers.

Author Summary

Kaposi sarcoma (KS) is a malignancy caused by the KS-associated herpesvirus (KSHV) that causes skin lesions, and may also be found in lymph nodes, lungs, gastrointestinal tract, and other organs in immunosuppressed individuals more commonly than immunocompetent subjects. The current study examined gene expression in single cells from the tumor and blood of these subjects, and identified the characteristics of the complex mixtures of cells in the tumor. This method also identified differences in KSHV gene expression in different cell types and associated cellular genes expressed in KSHV infected cells. In addition, changes in the cellular composition could be elucidated with therapeutic interventions.