bluuebunny/crossref_metadata_2025 huggingface dataset:
MET alterations as resistance mechanisms of dabrafenib-trametinib in BRAF p.V600E mutated non-small cell lung cancer patient
Authors: Pluchino Monica , Testi Irene , Minari Roberta , Dodi Alessandra , Airò Giulia , Mazzaschi Giulia , Verzè Michela , Adorni Alessia , Gnetti Letizia , Azzoni Cinzia , Lagrasta Costanza Anna Maria , Pecci Federica , Tiseo Marcello
Published: August 2024

The combination of BRAF and MEK inhibitors demonstrated significant clinical benefit in patients with BRAF-mutant non-small cell lung cancer (NSCLC). However, the molecular mechanisms of acquired resistance to BRAF and MEK inhibition in NSCLC are still unknown. Herein, we report a case of a 76-year-old man with a history of smoking who was diagnosed with BRAF V600E-mutant lung adenocarcinoma (PD-L1 > 50%) and subsequently candidate to first-line therapy with pembrolizumab. After 18 months since the start of immunotherapy, computed tomography scan showed disease progression and a second-line therapy with dabrafenib and trametinib was initiated. Seven months later, due to a suspect disease progression, a left supraclavicular lymphadenectomy was performed and next-generation sequencing analysis revealed the appearance of MET exon 14 skipping mutation, while fluorescence in situ hybridization analysis showed MET amplification. The patient is still on BRAF and MEK inhibitor treatment. Our case highlights the relevance of performing tumor tissue rebiopsy at the time of progression during treatment with BRAF/MEK inhibition with the aim of identifying putative mechanisms of resistance.
Strengthening the Chain: A Continuing Medical Education Program for Test Results Follow-up
Authors: Normand Élisabeth , Ramsey Hannah , Mimeault Richard , Lemay Karen , Heroux Diane , McDougall Allan
Published: August 2024

Introduction:

The Canadian Medical Protective Association (CMPA)'s Commitment to Change in Test-Results Follow-Up (CTC-TRFU) program aims to provide physicians with resources to enhance their test results follow-up systems for improved patient safety. Framed around the Transtheoretical Model, the program involves a 6-month multimodal educational intervention involving individual and group coaching sessions, action planning, and reflection surveys.

Methods:

This study evaluates the CTC-TRFU program's impact by analyzing survey responses and course documents, focusing on three main outcomes: physicians' perceived barriers and challenges, changes in their confidence and commitment, and implemented practice changes with perceived impact on patient safety. Participants were Canadian physicians who enrolled through the CMPA's open-access registration, with a particular emphasis on those facing challenges in test result follow-up.

Results:

One hundred two physicians have enrolled in the program. Of these physicians, 34 (33.3%) have successfully completed the program and 28 (27.5%) are actively enrolled. Among the 34 physicians who successfully completed the program, an overwhelming majority of 97.1% (n = 33) expressed their belief that the improvements made to their test follow-up system significantly enhance patient safety within their practice. We observed a significant increase in confidence in the robustness of the physician's follow-up system from program registration to completion (P < .001). Physicians reported catching specific missed test results (55.9%, n = 19), including various laboratory reports and diagnostic imaging like abnormal mammograms or missing MRI/CT results.

Discussion:

Physicians who participated in the CTC-TRFU program reported meaningful practice changes, which we believe underscores the value of comprehensive, longitudinal continuing patient safety CPD initiatives. These findings indicate the potential for future studies to explore the long-term impact of similar programs and their scalability.
The Impact of Hydrogen Sulfide in the Paraventricular Nucleus on the MAPK Pathway in High Salt–Induced Hypertension
Authors: Liang Yan-Feng , You Qing-Xin , Chen Shu-Yue , Ni Lei , Meng Xiang-Lian , Gao Jian-Xiang , Ren Yong-Bo , Song Han-Jun , Su Jia-Lu , Teng Yang , Gu Qing-Yun , Lv Chao , Yuan Bo-Yang , Wang Xuan , Zheng Yong-Tai , Zhang Dong-Dong
Published: August 2024

The hypothalamic paraventricular nucleus (PVN) plays a central role in regulating cardiovascular activity and blood pressure. We administered hydroxylamine hydrochloride (HA), a cystathionine-β-synthase inhibitor, into the PVN to suppress endogenous hydrogen sulfide and investigate its effects on the mitogen-activated protein kinase (MAPK) pathway in high salt (HS)–induced hypertension. We randomly divided 40 male Dahl salt-sensitive rats into 4 groups: the normal salt (NS) + PVN vehicle group, the NS + PVN HA group, the HS + PVN vehicle group, and the HS + PVN HA group, with 10 rats in each group. The rats in the NS groups were fed a NS diet containing 0.3% NaCl, while the HS groups were fed a HS diet containing 8% NaCl. The mean arterial pressure was calculated after noninvasive measurement using an automatic sphygmomanometer to occlude the tail cuff once a week. HA or vehicle was infused into the bilateral PVN using Alzet osmotic mini pumps for 6 weeks after the hypertension model was successfully established. We measured the levels of H2S in the PVN and plasma norepinephrine using enzyme linked immunosorbent assay. In addition, we assessed the parameters of the MAPK pathway, inflammation, and oxidative stress through western blotting, immunohistochemical analysis, or real-time polymerase chain reaction. In this study, we discovered that decreased levels of endogenous hydrogen sulfide in the PVN contributed to the onset of HS-induced hypertension. This was linked to the activation of the MAPK signaling pathway, proinflammatory cytokines, and oxidative stress in the PVN, as well as the activation of the sympathetic nervous system.
The Buccal Mask: Safe Positive Airway Pressure Delivery for Patients with a Paramedian Forehead Flap
Authors: Nassar Aref , Sleilati Fadi
Published: August 2024

The paramedian forehead flap is commonly performed for the reconstruction of complex nasal defects. It typically requires two separate procedures: flap elevation and inset, and then, 2–3 weeks later, pedicle division. In patients with obesity hypoventilation syndrome, the use of positive airway pressure is often mandatory, especially in the postoperative period. However, the face mask used for positive airway pressure has to apply pressure over the bridge of the nose and may compromise the vascularity of a paramedian forehead flap. We report a case where a buccal mask was used successfully in the postoperative period in a patient who needed positive airway pressure after nasal reconstruction with a paramedian forehead flap.
Examining School Nurses' Knowledge and Confidence Related to Their Intention to Screen for and Report Child Sexual Abuse: A Descriptive Cross-Sectional Study
Authors: Ackers Suzanne M. , Colbert Alison M. , Sekula L. Kathleen , Fraley Hannah E.
Published: August 2024

Background

Child sexual abuse (CSA) is a preventable national public health problem that results in adverse health consequences. Research suggests youth experiencing CSA are often of school age. Screening for early detection of health issues is integral to school nurse (SN) practice. Still, there is little evidence that routine screening when CSA is suspected is occurring in schools, despite recommendations that it should be. Lack of confidence and knowledge related to screening and reporting for CSA contribute to a SN's missed opportunity for early intervention.

Purpose

The aim of this study was to describe SNs' knowledge and self-efficacy associated with screening for and reporting suspected CSA in school settings.

Methods

A descriptive cross-sectional survey design was employed. The Child Abuse Report Intention Scale was sent to over 2,000 members of the National Association of School Nurses.

Results

Among SN respondents (N = 123), the main findings showed almost half reported being concerned a youth was experiencing CSA but may have missed identifying it. Self-efficacy and professional responsibility were predictors of SNs' intention to screen as well as knowledge about obvious and serious signs of abuse were predictors of SNs' intention to report in this sample.

Implications

An educational partnership between forensic nurse examiners and SNs can facilitate improving SNs' knowledge about nonspecific physical and behavioral indicators of abuse that are not overtly obvious. The development of a screening tool specific for use by SNs can empower their confidence to screen by providing a resource for them to use as a guide when they are uncertain about the evidence.
The Synergy of Cadaver-Based and Virtual Education: Comparing Learning Outcomes in a Physician Assistant Clinical Anatomy Course
Authors: Lufler Rebecca S. , Saini Harleen , Cardamone Carie , Marchant Jeffrey K.
Published: August 2024

Introduction

During the COVID-19 pandemic, nearly all educational content at Tufts University School of Medicine was transformed to virtual formats, including anatomy dissection labs. This study compares face-to-face cadaveric to virtual anatomy instruction and quantifies the utility of cadaver-based laboratory.

Methods

In 2019, Physician Assistant students completed traditional Clinical Anatomy I and Clinical Anatomy II courses with content delivered via face-to-face lectures, cadaveric-based anatomy laboratories, and case-based workshops. In 2020, students took a traditional Clinical Anatomy I course and a virtual Clinical Anatomy II course (hybrid curriculum). Virtual anatomy course content was delivered via Zoom-based lectures, anatomy laboratories using virtual 3D anatomical models and cadaveric dissection images, and Zoom case-based workshops. In Fall 2020, the traditional and hybrid cohorts were asked to complete surveys to evaluate the utility of the pedagogical approaches used during their respective courses. Examinations were compared to evaluate the impact of pedagogical approaches on learning.

Results

Students who experienced the virtual format scored significantly higher on the extremities examination and final grade (P = .006; P = .03) than did students with the traditional experience. Thirty-one hybrid (63% response rate) and 31 traditional students (62% response rate) completed their surveys. The traditional cohort agreed/strongly agreed their cadaver-based laboratory experience contributed to the development of their professionalism (82.1%). Most (71%) of the hybrid students agree/strongly agree that a cadaveric laboratory experience will lead to longer retention of anatomy and give them an appreciation of anatomical variation (93.1%), but 68% also felt some structures visualized with virtual tools would not be possible in a cadaver.

Discussion

Cadaver-based laboratories play an important role and are valued by students for anatomy learning, professional development, and understanding anatomical variation. Our data indicate that adding virtual components to cadaver-based laboratories offers a synergistic learning experience.
Thoracic endovascular aortic repair with unibody single-branched stent-graft for type B aortic dissection: a real-world multicenter study
Authors: Li Xiaoye , Zhou Qing , Li Cunren , Wan Zhengdong , Zhang Hao , Cai Nan , Zhang Lei , Song Chao , Lu Qingsheng
Published: August 2024

Objective:

To evaluate the outcome of TEVAR for TBAD and revascularization of LSA with Castor single-branched stent-graft.

Summary background data:

One-stage thoracic endovascular aortic repair (TEVAR) and revascularization of left subclavian artery (LSA) of type B aortic dissection (TBAD) with off-the-shelf stent-graft is limited.

Methods:

A multicenter study consisting of consecutive patients from four different centers in China treated with Castor single-branched stent-graft for TBAD was conducted. Rate of technical success, mortality, complications, and reinterventions were evaluated.

Results:

Between September 2018 and April 2022, 180 consecutive patients with TBAD received TEVAR with Castor single-branched stent-graft. Technical success was achieved in all patients. The mean oversize ratio at the proximal landing zone was 4.9±3.8% (median, 3.7; IQR, 2.0–6.9%). Five patients died within the first 30 days after the operation or during hospitalization. Early reintervention was performed in one case. The median follow-up was 18.0 months (IQR, 13–24 months). Five patients died during follow-up, including three cases of respiratory failure, one case of immune thrombocytopenia purpura, and one case of a cerebral hemorrhage. Three patients had reintervention. In total, three cases of stroke were recorded, which were all within 30 days after the operation. Image data at 1 year presented complete thrombosis in 97.1% cases for the false lumen covered by the stent-graft.

Conclusions:

TEVAR with Castor device for treatment of TBAD and revascularization of LSA is a feasible and safe technique. The deployment procedure is safe, easy, and accurate. Castor devices meets the hemodynamical and biomechanical requirement of elastic aorta and could restore the physiological blood flow pattern of LSA.
Novel interventions on the tricuspid valve: how to consider the pulmonary circulation?
Authors: Wensel Roland , Opitz Christian
Published: August 2024

Purpose of review

This review addresses treatment options for moderate to severe tricuspid valve regurgitation and the importance of right ventricular function and the pulmonary circulation.

Recent findings

Several interventional treatment options for severe tricuspid regurgitation have been developed including transcatheter edge-to-edge repair, annuloplasty and valve replacement. So far, transcatheter edge-to-edge repair is most frequently used with procedural success rates of more than 95% and improvements in functional and quality of life parameters for up to 2 years. Right ventricular function as well as pulmonary artery pressure and resistance levels are important outcome predictors. Mean pulmonary artery pressure more than 30 mmHg, transpulmonary gradient more than 17 mmHg and right ventricular to pulmonary artery coupling ratio less than 0.406 indicate poor outcome.

Despite the remarkable safety of interventional treatment of severe tricuspid regurgitation right ventricular dysfunction and abnormal pulmonary hemodynamics are important determinants of procedural success and clinical outcome.

Complete hemodynamic work-up should be an integral part of prerepair assessment although validated data predicting outcome are limited.
Accuracy of respiratory event indices downloaded from positive airway pressure devices: can they be relied upon when making treatment decisions?
Authors: Richter Matthias , Schroeder Maik , Nilius Georg
Published: August 2024

Purpose of review

The gold standard for diagnosis and treatment of obstructive sleep apnea (OSA) is attended overnight polysomnography (PSG) in a sleep laboratory. Alternative diagnostic techniques are urgently needed for both diagnosis and treatment control when initiating positive airway pressure (PAP) in the home setting. Current PAP devices compute data such as residual AHI (apnea–hypopnea index) using their proprietary algorithms to provide an automatic event detection (AED). It was suggested that these should be labeled AHIFLOW.

Recent findings

The current study situation shows an acceptable agreement with the tendency of mildly overestimating the AHI by the PAP devices. But, the literature is still limited in terms of accuracy, especially when considering the lack of standardization and different detection algorithms.

A validation of PAP devices regarding the agreement of AHIFLOW compared to AHIPSG is extremely important, given that the device analysis is exclusively based on the measured flow. There are considerable concerns about assessing the PAP effectiveness in higher risk groups based on the AED function alone. Given these reservations, the use of PAP event detection can be an important addition to the diagnostic spectrum and, in combination with telemonitoring, offers promising potential.
Quality of life in people with chronic kidney disease: focusing on modifiable risk factors
Authors: Fraser Simon D.S. , Phillips Thomas
Published: August 2024

Purpose of review

With ageing populations and rising prevalence of key risk factors, the prevalence of many long-term conditions including chronic kidney disease (CKD) is increasing globally. Health-related quality of life (HRQoL) is important to people living with CKD but not all HRQoL determinants are modifiable. This review summarizes recently identified potentially modifiable factors affecting HRQoL for people with CKD and recent trials incorporating HRQoL as an outcome.

Recent findings

Considering a broad definition of ‘potentially modifiable’, many factors have been associated with HRQoL in recent observational studies. These include mental health conditions, symptoms, medications, health behaviours, weight-related issues, poor social support, lower education, limited literacy and directly CKD- related factors such as anaemia. Some potentially modifiable factors have been tested in CKD trials, though often with HRQoL as a secondary outcome, so may be underpowered for HRQoL. Interventions with evidence of effect on HRQoL include physical activity, education, some nutritional interventions and medications targeting CKD-related anaemia.

Clinicians should consider the range of potentially modifiable factors influencing HRQoL as part of a holistic approach to CKD care. High-quality, adequately-powered trials, with HRQoL as a primary outcome, with interventions focusing on the other potentially modifiable factors identified are needed.
Plant-based diets for kidney disease prevention and treatment
Authors: Kim Hyunju , Rebholz Casey M.
Published: August 2024

Purpose of review

Plant-based diets are associated with a lower risk of hypertension, diabetes, cardiovascular disease, and mortality. Using the most recent evidence, we critically appraised the role of plant-based diets in primary and secondary prevention of chronic kidney disease (CKD) with a focus on key nutritional factors (dietary acid load, phosphorus, potassium, sodium, and fiber).

Recent findings

In healthy individuals, observational studies found that greater intake of plant protein and higher adherence to plant-based diets (overall, healthful, and provegetarian) was associated with a lower risk of CKD. In those with CKD, plant-based diets were associated with a lower risk of mortality, improved kidney function, and favorable metabolic profiles (fibroblast growth factor-23, uremic toxins, insulin sensitivity, inflammatory biomarkers). Only few studies reported nutrient content of plant-based diets. These studies found that plant-based diets had lower dietary acid load, lower or no significant difference in phosphorus and sodium, and higher potassium and fiber. One study reported that vegetarian diets were associated with severe vitamin D deficiency compared to nonvegetarian diets.

Plant-based diets provide several benefits for prevention and management of CKD, with little risk for individuals with CKD. Incorporation of vitamin D rich foods in plant-based diets may be helpful.
Role of textural and radiomic analysis parameters in predicting histopathological parameters of the tumor in breast cancer patients
Authors: Kote Rutuja , Ravina Mudalsha , Goyal Harish , Mohanty Debajyoti , Gupta Rakesh , Shukla Arvind Kumar , Reddy Moulish , Prasanth Pratheek N.
Published: August 2024

Introduction

Texture and radiomic analysis characterizes the tumor’s phenotype and evaluates its microenvironment in quantitative terms. This study aims to investigate the role of textural and radiomic analysis parameters in predicting histopathological factors in breast cancer patients.

Materials and methods

Two hundred and twelve primary breast cancer patients underwent 18F-FDG PET/computed tomography for staging. The images were processed in a commercially available textural analysis software. ROI was drawn over the primary tumor with a 40% threshold and was processed further to derive textural and radiomic parameters. These parameters were then compared with histopathological factors of tumor. Receiver-operating characteristic analysis was performed with a P-value <0.05 for statistical significance. The significant parameters were subsequently utilized in various machine learning models to assess their predictive accuracy.

Results

A retrospective study of 212 primary breast cancer patients was done. Among all the significant parameters, SUVmin, SUVmean, SUVstd, SUVmax, discretized HISTO_Entropy, and gray level co-occurrence matrix_Contrast were found to be significantly associated with ductal carcinoma type. Four parameters (SUVmin, SUVmean, SUVstd, and SUVmax) were significant in differentiating the luminal subtypes of the tumor. Five parameters (SUVmin, SUVmean, SUVstd, SUVmax, and SUV kurtosis) were significant in predicting the grade of the tumor. These parameters showcased robust capabilities in predicting multiple histopathological parameters when tested using machine learning algorithms.

Conclusion

Though textural analysis could not predict hormonal receptor status, lymphovascular invasion status, perineural invasion status, microcalcification status of tumor, and all the molecular subtypes of the tumor, it could predict the tumor’s histologic type, triple-negative subtype, and score of the tumor noninvasively.
Mechanical circulatory support devices in adults with congenital heart disease
Authors: Garba Deen L. , Joseph Susan , Cedars Ari
Published: August 2024

Purpose of review

Mechanical circulatory support is used frequently as a method of stabilizing patients with end stage heart failure who are unable to safely await allograft availability. While this technology has been fundamentally important in supporting patients with normal cardiac anatomy, it is still used infrequently in adult patients with congenital heart disease and end-stage heart failure. Here, we review the data on mechanical circulatory support technology in this small but growing population of patients with chronic heart disease prone to the development of circulatory failure.

Recent findings

Mechanical circulatory support (MCS) has been increasingly employed in adults with congenital heart disease (ACHD) as a bridge to transplant. The new United Network for Organ Sharing listing system favoring temporary MCS use with a higher listing status offers another tool to stabilize ACHD patients and potentially shorten wait times. Both temporary and Durable MCS could help improve transplant candidacy and posttransplant outcomes in select groups of ACHD patients.

Durable and temporary MCS have the potential to significantly improve access to transplant and overall transplant outcomes in ACHD patients.
Acceptance of the Respiratory Syncytial Virus Vaccine in Pregnant Individuals
Authors: Tucker Tonya , Garvey Zoe , O'Sullivan David , Loza Alexandra
Published: August 2024

The respiratory syncytial virus (RSV) vaccine was officially offered to pregnant individuals in 2023–2024, with the purpose of providing immunity to infants and young children. We performed a retrospective review to determine the rate of offering the RSV vaccine and acceptance of the vaccine among patients between 32 0/7 and 36 6/7 weeks of gestation. A prospective survey was administered to examine barriers to RSV vaccination. We identified 206 patients, including 111 (53.8%) who were offered the vaccine and 95 (46.1%) who were not offered the vaccine. Of those who were offered the vaccine, 62 (55.9%) accepted and 49 (44.1%) declined. Individuals who declined had significantly higher rates of declining other vaccines in pregnancy (P<.001). More than half of those who declined the RSV vaccine reported both accepting the RSV antibody for their newborn and plans of accepting the vaccine in subsequent pregnancies.
Estimating the Effect of Disclosure of Patient Safety Incidents in Diagnosis-Related Patient Safety Incidents: A Cross-sectional Study Using Hypothetical Cases
Authors: Mahmudah Noor Afif , Im Dasom , Ock Minsu
Published: August 2024

Background

Disclosure of patient safety incidents (DPSIs) is a strategic measure to reduce the problems of patient safety incidents (PSIs). However, there are currently limited studies on the effects of DPSIs on resolving diagnosis-related PSIs. Therefore, this study aimed to estimate the effects of DPSIs using hypothetical cases, particularly in diagnosis-related PSIs.

Methods

A survey using 2 hypothetical cases of diagnosis-related PSIs was conducted in 5 districts of Ulsan Metropolitan City, Korea, from March 18 to 21, 2021. The survey used a multistage stratified quota sampling method to recruit participants. Multiple logistic regression and linear regression analyses were performed to determine the effectiveness of DPSIs in hypothetical cases. The outcomes were the judgment of a situation as a medical error, willingness to revisit and recommend the hypothetical physician, intention to file a medical lawsuit and commence criminal proceedings against the physicians, trust score of the involved physicians, and expected amount of compensation.

Results

In total, 620 respondents, recruited based on age, sex, and region, completed the survey. The mean age was 47.6 (standard deviation, ±15.1) years. Multiple logistic regression showed that DPSIs significantly decreased the judgment of a situation as a medical error (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.24–0.79), intention to file a lawsuit (OR, 0.53; 95% CI, 0.42–0.66), and commence criminal proceedings (OR, 0.43; 95% CI, 0.34–0.55). It also increased the willingness to revisit (OR, 3.28; 95% CI, 2.37–4.55) and recommend the physician (OR, 8.21; 95% CI, 4.05–16.66). Meanwhile, the multiple linear regression demonstrated that DPSIs had a significantly positive association with the trust score of the physician (unstandardized coefficient, 1.22; 95% CI, 1.03–1.41) and a significantly negative association with the expected amount of compensation (unstandardized coefficient, −0.18; 95% CI, −0.29 to −0.06).

Conclusions

DPSIs reduces the possibility of judging the hypothetical case as a medical error, increases the willingness to revisit and recommend the physician involved in the case, and decreases the intent to file a lawsuit and commence a criminal proceeding. Although this study implemented hypothetical cases, the results are expected to serve as empirical evidence to apply DPSIs extensively in the clinical field.
Places for reasoning
Authors: Gastelum-Vargas Melina , Chemero Anthony , Raja Vicente
Published: August 2024

In this article, we explore behaviour settings that enable reasoning and the diversity of constraints that not only limit but also make these behaviour settings possible. We focus specifically on reasoning and surveying how behaviour settings allow for the generation of norms of action that are nevertheless differentiated by geographies and sociocultural systems. These geographies and sociocultural systems involve diverse trajectories for reasoning even within similar behaviour settings. We will touch on places for reasoning like Twitter, social movements, traditional knowledge and laboratories set up for experimentation on our reasoning abilities. We will show how these places and the behaviour settings that emerge in them can be studied in terms of the complexity of the interactions between their participants and in terms of enabling constraints.

This article is part of the theme issue ‘People, places, things, and communities: expanding behaviour settings theory in the twenty-first century’.
A Tough Biointerface in Human Knee Empowered by Dynamic Phase-transforming Minerals in Collagenous Matrix
Authors: Li Wenyue , Wang Xiaozhao , Mao Renwei , Li Dong , Meng Hongxu , Zhang Ru , Fang Jinghua , Kang Zhengzhong , Wu Boxuan , Ma Weiwei , Yao Xudong , Xie Chang , Li Rui , Wang Jin , Chen Xiao , Pan Xihao , Chen Weiqiu , Duan Wangping , Gao Huajian , Ouyang Hongwei
Published: August 2024

Joining heterogeneous materials in engineered structures remains a daunting challenge because of stress concentration, often resulting in unexpected failures1,2. Studying the structures in organisms that evolved for centuries provides valuable insights that can be instrumental in addressing this mechanical challenge3–5. The human meniscus root-bone interface is a remarkable example known for its exceptional fatigue resistance, toughness and interfacial adhesion properties throughout its lifespan6–8. We studied the multiscale graded mineralization structure designs within the 30-micron soft-hard interface at the root-bone junction and examined its toughening mechanisms. This graded interface with interdigitated structures and exponential modulus increase exhibits a phase transition from amorphous calcium phosphate (ACP) to gradually matured hydroxyapatite (HAP) crystals, mediated by location-specific distributed biomolecules. In coordination with collagen fibril deformation and reorientation, ACP particles debond with collagen and slide to new positions which enable frictional energy dissipation, and HAP particles arrest cracks. The mineral in transforming phases work synergistically to provide interfacial toughening. The presented biointerface model exemplifies human musculoskeletal system’s adaptations to mechanical requirements, offering a blueprint for developing tough interfaces in broad applications.
Scalable imaging-free spatial genomics through computational reconstruction
Authors: Hu Chenlei , Borji Mehdi , Marrero Giovanni J. , Kumar Vipin , Weir Jackson A. , Kammula Sachin V. , Macosko Evan Z. , Chen Fei
Published: August 2024

Tissue organization arises from the coordinated molecular programs of cells. Spatial genomics maps cells and their molecular programs within the spatial context of tissues. However, current methods measure spatial information through imaging or direct registration, which often require specialized equipment and are limited in scale. Here, we developed an imaging-free spatial transcriptomics method that uses molecular diffusion patterns to computationally reconstruct spatial data. To do so, we utilize a simple experimental protocol on two dimensional barcode arrays to establish an interaction network between barcodes via molecular diffusion. Sequencing these interactions generates a high dimensional matrix of interactions between different spatial barcodes. Then, we perform dimensionality reduction to regenerate a two-dimensional manifold, which represents the spatial locations of the barcode arrays. Surprisingly, we found that the UMAP algorithm, with minimal modifications can faithfully successfully reconstruct the arrays. We demonstrated that this method is compatible with capture array based spatial transcriptomics/genomics methods, Slide-seq and Slide-tags, with high fidelity. We systematically explore the fidelity of the reconstruction through comparisons with experimentally derived ground truth data, and demonstrate that reconstruction generates high quality spatial genomics data. We also scaled this technique to reconstruct high-resolution spatial information over areas up to 1.2 centimeters. This computational reconstruction method effectively converts spatial genomics measurements to molecular biology, enabling spatial transcriptomics with high accessibility, and scalability.
Spatial sampling of deep neural network features improves encoding models of foveal and peripheral visual processing in humans
Authors: Mueller Niklas , Scholte H.Steven , Groen Iris Isabelle Anna
Published: August 2024

Deep Neural Networks (DNNs) are increasingly being used to build encoding models to predict neural data recorded during visual stimulation. Their ability to process natural images makes them a prime candidate for studying the neural profile underlying real-world visual perception. However, there are still prominent discrepancies in how DNNs and humans process visual information. One discrepancy lies in the spatial sampling of visual input: while DNNs uniformly sample from their input at every spatial location, the human visual system samples differentially from central and peripheral regions. Here, we implement multiple spatial sampling strategies on feature maps of DNNs into encoding models that predict human EEG responses to a novel stimulus set consisting of large, high-quality natural scene images. By applying differential spatial sampling of DNN feature maps, we reveal distinct temporal profiles for encoding of peripheral vs. central information in EEG signals. Moreover, we show that a differential spatial sampling derived from the density of retinal ganglion cells yields the best performing encoding model when using DNN feature maps. We experimentally confirm this pattern by separately stimulating peripheral and central visual field regions, and demonstrate that the distinct temporal profiles for central and peripheral information are only revealed when using large-field stimuli. Together, these results show that aligning the spatial sampling of humans and DNN encoding models can improve predictions of neural data. The distinct temporal profiles for encoding of peripheral vs. central information support a global-to-local processing hierarchy of real-world vision.
Temporal and spatial population genetic variation in Chilean jack mackerel,Trachurus murphyi
Authors: Canales-Aguirre CB , Ferrada-Fuentes S , Galleguillos R
Published: August 2024

TheTrachurus murphyihave been studied for population genetic structure for decades, identifying only one large population across the South Pacific Ocean. Although all these studies have extensively examined the spatial genetic pattern, there remains a gap in understanding the potential role of temporality. Our study aims to elucidate temporal and spatial genetic patterns inT. murphyipopulations in the South Pacific Ocean, examining genetic composition across seasons, including feeding and spawning seasons, where the latter was not previously investigated. Using 10 microsatellite loci, our study confirms a consistent and stable population genetic pattern inT. murphyiacross its geographic distribution, observed over multiple years and seasons. Furthermore, we identify potential genetic markers for monitoring variability in the species.
In-silico heart model phantom to validate cardiac strain imaging
Authors: Mukherjee Tanmay , Usman Muhammad , Mehdi Rana Raza , Mendiola Emilio , Ohayon Jacques , Lindquist Diana , Shah Dipan , Sadayappan Sakthivel , Pettigrew Roderic , Avazmohammadi Reza
Published: August 2024

The quantification of cardiac strains as structural indices of cardiac function has a growing prevalence in clinical diagnosis. However, the highly heterogeneous four-dimensional (4D) cardiac motion challenges accurate “regional” strain quantification and leads to sizable differences in the estimated strains depending on the imaging modality and post-processing algorithm, limiting the translational potential of strains as incremental biomarkers of cardiac dysfunction. There remains a crucial need for a feasible benchmark that successfully replicates complex 4D cardiac kinematics to determine the reliability of strain calculation algorithms. In this study, we propose an in-silico heart phantom derived from finite element (FE) simulations to validate the quantification of 4D regional strains. First, as a proof-of-concept exercise, we created synthetic magnetic resonance (MR) images for a hollow thick-walled cylinder under pure torsion with an exact solution and demonstrated that “ground-truth” values can be recovered for the twist angle, which is also a key kinematic index in the heart. Next, we used mouse-specific FE simulations of cardiac kinematics to synthesize dynamic MR images by sampling various sectional planes of the left ventricle (LV). Strains were calculated using our recently developed non-rigid image registration (NRIR) framework in both problems. Moreover, we studied the effects of image quality on distorting regional strain calculations by conducting in-silico experiments for various LV configurations. Our studies offer a rigorous and feasible tool to standardize regional strain calculations to improve their clinical impact as incremental biomarkers.
Comparative Analysis of Housing Temperature Impact on Heart Failure with Preserved Ejection Fraction in J vs N Strain C57BL/6 Mice
Authors: Chaudhary Rajesh , Suhan Tahra K. , Wu Chao , Alzamrooni Afnan , Abdel-Latif Ahmed
Published: August 2024

Introduction

Heart failure studies are conducted in preclinical animal models with different genotypic strains, 7-times higher metabolic rate, 5 to 6 times higher heart rate, and are housed in a cold-stressed environment of 23°C, unlike humans. These differences severely affect how animals respond to interventions, particularly those that lead to the development of metabolic syndrome, such as the two-hit model of diet-induced obesity (DIO) and Nμ-nitro-L-arginine methyl ester (L-NAME) administration. A two-hit model of diet-induced obesity (DIO) and L-NAME administration has been proposed to induce heart failure with preserved ejection fraction (HFpEF) and mimic the hallmarks of metabolic syndrome and inflammation-induced heart failure in humans [1]. However, studies have reported conflicting results using this model. In this study, we examined the influence of mouse strain and environmental temperature on the development of metabolic syndrome and HFpEF using a two-hit model.

Methods

Eight-week-old, C57BL/6 mice (n=30) from the J and N strains were randomized to receive a high-fat diet (HFD) plus L-NAME versus a regular chow diet; and were randomized to be housed at a regular temperature of 23 °C versus a thermoneutral temperature of 30 °C. Glucose tolerance test (GTT, 2g/kg body weight), blood pressure via tail cuff, and echocardiography were conducted at baseline and, then at 5 and 15 weeks. Metabolic phenotyping was conducted at week 15 by using the Promethion Sable System.

Results

Our study revealed the significant effects of housing temperature and strain on the development of metabolic syndrome and HFpEF following the initiation of HFD +L-NAME over 5 and 15 weeks. At 5 weeks, both strains showed thermoneutral housing-induced attenuation of the effects of HFD + L-NAME on blood pressure and glucose tolerance, with the J strain exhibiting reduced diastolic dysfunction. By week 15, thermoneutral housing decreased energy expenditure (EE) and fat oxidation in both strains, while specifically reducing the respiratory exchange ratio (RER)_and glucose oxidation in J strain. Ejection fraction increased in both strains compared with the Chow group, except for J strain at 23 °C. Notably, physical activity levels remained constant across the groups, suggesting that the observed metabolic changes were not activity related. These findings highlight the complex physiological adaptations of these strains to different housing temperatures.

Conclusions

Thermoneutral housing conditions elicited strain-specific metabolic and cardiac effects in mice, with the J strain showing more pronounced responses. These findings highlight the critical influence of ambient temperature on experimental outcomes in rodent models, emphasizing the need to consider housing conditions when interpreting the results of metabolic and cardiovascular research.
Micro to macro scale anatomical analysis of the human hippocampal arteries with synchrotron Hierarchical Phase-Contrast Tomography
Authors: Bellier A. , Tafforeau P. , Bouziane A. , Angelloz-Nicoud T. , Lee P.D. , Walsh C.
Published: August 2024

Purpose

To date, no non-invasive imaging modality has been employed to profile the structural intricacies of the hippocampal arterial microvasculature in humans. We hypothesised that synchrotron-based imaging of the human hippocampus would enable precise characterisation of the arterial microvasculature.

Methods

Two preserved human brains from, a 69-year-old female and a 63-year-old male body donors were imaged using hierarchical phase-contrast tomography (HiP-CT) with synchrotron radiation at multiple voxel resolutions from 25.08 μm down to 2.45 μm. Subsequent manual and semi-automatic artery segmentation were performed followed by morphometric analyses. These data were compared to published data from alternative methodologies.

Results

HiP-CT made it possible to segment in context the arterial architecture of the human hippocampus. Our analysis identified anterior, medial and posterior hippocampal arteries arising from the P2 segment of the posterior cerebral artery on the image slices. We mapped arterial branches with external diameters greater than 50 μm in the hippocampal region. We visualised vascular asymmetry and quantified arterial structures with diameters as small as 7 μm.

Conclusions

Through the application of HiP-CT, we have provided the first imaging visualisation and quantification of the arterial system of the human hippocampus at high resolution in the context of whole brain imaging. Our results bridge the gap between anatomical and histological scales.
Defining the cardiac fibroblast secretome in the healthy and infarcted mouse heart
Authors: Bahr Jasmin , Poschmann Gereon , Jungmann Andreas , Busch Martin , Ding Zhaoping , Zalfen Ria , Steinhausen Julia , Wachtmeister Thorsten , Rickert Daniel , Lautwein Tobias , Alter Christina , Amrute Junedh M. , Lavine Kory J. , Köhrer Karl , Most Patrick , Stühler Kai , Hesse Julia , Schrader Jürgen
Published: August 2024

Cardiac fibroblasts (CF) are key players after myocardial infarction (MI), but their signaling is only incompletely understood. Here we report a first secretome atlas of CF in control (cCF) and post-MI hearts (miCF), combining a rapid cell isolation technique with SILAC and click chemistry. In CF, numerous paracrine factors involved in immune homeostasis were identified. Comparing secretome, transcriptome (SLAMseq), and cellular proteome disclosed protein turnover. In miCF at day 5 post-MI, significantly upregulated proteins included SLIT2, FN1, and CRLF1 in mouse and human samples. Comparing the miCF secretome at day 3 and 5 post-MI showed the dynamic nature of protein secretion. Specific in-vivo labeling of miCF proteins via biotin ligase TurboID using the POSTN promotor mirrored the in-vitro data. In summary, we have identified numerous paracrine factors specifically secreted from CF in mice and humans. This secretome atlas may lead to new biomarkers and/or therapeutic targets for the activated CF.
VUStruct: a compute pipeline for high throughput and personalized structural biology
Authors: Moth Christopher W. , Sheehan Jonathan H. , Mamun Abdullah Al , Sivley R. Michael , Gulsevin Alican , Rinker David , Capra John A. , Meiler Jens
Published: August 2024

Effective diagnosis and treatment of rare genetic disorders requires the interpretation of a patient’s genetic variants of unknown significance (VUSs). Today, clinical decision-making is primarily guided by gene-phenotype association databases and DNA-based scoring methods. Our web-accessible variant analysis pipeline, VUStruct, supplements these established approaches by deeply analyzing the downstream molecular impact of variation in context of 3D protein structure. VUStruct’s growing impact is fueled by the co-proliferation of protein 3D structural models, gene sequencing, compute power, and artificial intelligence.

Contextualizing VUSs in protein 3D structural models also illuminates longitudinal genomics studies and biochemical bench research focused on VUS, and we created VUStruct for clinicians and researchers alike. We now introduce VUStruct to the broad scientific community as a mature, web-facing, extensible, High Performance Computing (HPC) software pipeline.

VUStruct maps missense variants onto automatically selected protein structures and launches a broad range of analyses. These include energy-based assessments of protein folding and stability, pathogenicity prediction through spatial clustering analysis, and machine learning (ML) predictors of binding surface disruptions and nearby post-translational modification sites. The pipeline also considers the entire input set of VUS and identifies genes potentially involved in digenic disease.

VUStruct’s utility in clinical rare disease genome interpretation has been demonstrated through its analysis of over 175 Undiagnosed Disease Network (UDN) Patient cases. VUStruct-leveraged hypotheses have often informed clinicians in their consideration of additional patient testing, and we report here details from two cases where VUStruct was key to their solution. We also note successes with academic research collaborators, for whom VUStruct has informed research directions in both computational genomics and wet lab studies.
Local lateral connectivity is sufficient for replicating cortex-like topographical organization in deep neural networks
Authors: Qian Xinyu , Dehghani Amir Ozhan , Farahani Asa Borzabadi , Bashivan Pouya
Published: August 2024

Across the primate cortex, neurons that perform similar functions tend to be spatially grouped together. This biological principle extends to many other species as well, reflecting a common way of organizing sensory processing across diverse forms of life. In the visual cortex, this biological principle manifests itself as a modular organization of neuronal clusters, each tuned to a specific visual property. The tendency toward short connections is widely believed to explain the existence of such an organization in the brains of many animals. However, the neural mechanisms underlying this phenomenon remain unclear. Here, we use artificial deep neural network models to demonstrate that a topographical organization akin to that in the primary, intermediate, and high-level human visual cortex emerges when units in these models are locally laterally connected and their weight parameters are tuned by top-down credit assignment. The emergence of modular organization without explicit topography-inducing learning rules or objective functions challenges their necessity and suggests that local lateral connectivity alone may suffice for the formation of topographic organization across the cortex. Furthermore, the incorporation of lateral connections in deep convolutional networks enhances their robustness to subtle alterations in visual inputs, such as those designed to deceive the model (i.e. adversarial examples), indicating an additional role for these connections in learning robust representations.
Engineered Protein-G variants for plug-and-play applications
Authors: Slezak Tomasz , O’Leary Kelly M. , Li Jinyang , Rohaim Ahmed , Davydova Elena K. , Kossiakoff Anthony A.
Published: August 2024

We have developed a portfolio of antibody-based modules that can be prefabricated as standalone units and snapped together in plug-and-play fashion to create uniquely powerful multifunctional assemblies. The basic building blocks are derived from multiple pairs of native and modified Fab scaffolds and protein G (PG) variants engineered by phage display to introduce high pair-wise specificity. The variety of possible Fab-PG pairings provides a highly orthogonal system that can be exploited to perform challenging cell biology operations in a straightforward manner. The simplest manifestation allows multiplexed antigen detection using PG variants fused to fluorescently labeled SNAP-tags. Moreover, Fabs can be readily attached to a PG-Fc dimer module which acts as the core unit to produce plug-and-play IgG-like assemblies, and the utility can be further expanded to produce bispecific analogs using the “knobs into holes” strategy. These core PG-Fc dimer modules can be made and stored in bulk to produce off-the-shelf customized IgG entities in minutes, not days or weeks by just adding a Fab with the desired antigen specificity. In another application, the bispecific modalities form the building block for fabricating potent Bispecific T-cell Engagers (BiTEs), demonstrating their efficacy in cancer cell-killing assays. Additionally, the system can be adapted to include commercial antibodies as building blocks, greatly increasing the target space. Crystal structure analysis reveals that a few strategically positioned interactions engender the specificity between the Fab-PG variant pairs, requiring minimal changes to match the scaffolds for different possible combinations. This plug-and-play platform offers a user-friendly and versatile approach to enhance the functionality of antibody-based reagents in cell biology research.