bluuebunny/crossref_metadata_2025 huggingface dataset:
An Organizational Commitment to Diversity, Equity, Inclusion, and Justice
Authors: Moreno Janette V. , Marshall David R. , Girard Anita , Mitchell Nicole M. B. , Minissian Margo B. , Coleman Bernice
Published: December 2023

Cedars-Sinai is a sixth continuous Magnet organization in Southern California that embodies inclusive leadership in support of diversity, equity, inclusion, and justice (DEIJ) principles. The organization adheres to a strategic model prioritizing staff sense of belonging, empowerment, engagement, curiosity, and creativity. Employing inclusive leadership, we have implemented strong programs of professional development and continuous learning, innovation, and research. This leadership and these programs have fostered a culture of inquiry, support evidence-driven practice, quality improvement, and staff engagement. Our organization is committed to creating a caring and healing environment that promotes performance. We believe in practicing loving-kindness toward ourselves and others as a core value. Executive leadership support has been a key element in our successful implementation of DEIJ strategies, including employee resource groups, Shared Leadership Councils, transition to practice programs, health equity research, and innovative solutions. These strategies have been shown to yield a significant return on investment.
Evaluating Skill-Mix Models of Care
Authors: Cermak Carly A. , Bruno Frances , Jeffs Lianne
Published: December 2023

OBJECTIVE

To synthesize the literature on measures and outcomes for skill-mix models of care.

BACKGROUND

To address the human health resource crisis, changes to skill mix within models of care are being implemented emphasizing the need to synthesize evaluation methods for skill-mix models in the future.

METHODS

A scoping review of the literature using a rigorous search strategy and selection process was completed to identify articles that examined skill-mix models in an effort to identify related concepts.

RESULTS

Ten studies examined skill-mix models. Areas of measurement in assessing the impact of skill-mix models included patient outcomes, patient satisfaction, nurse satisfaction, cost, and nurse perceptions of role changes, model effectiveness, and quality of care. Studies examining nurse satisfaction, patient satisfaction, and/or cost generally reported improvements upon skill-mix model implementation. Studies examining patient outcomes related to skill mix were inconsistent.

CONCLUSIONS

Factors for consideration upon implementation of a skill-mix change include education of role clarity, the number of unregulated staff who require supervision, and professional practice support.
Fetal Type Morphologies Suggest the Presence of DICER1 Hotspot Mutations in Non–small Cell Lung Cancer
Authors: Chong Anne-Laure , Thorner Paul , Ellis Michelle , Swensen Jeff , Benlimame Naciba , Fiset Pierre-Olivier , Gatalica Zoran , Evans Mark G. , Foulkes William D.
Published: December 2023

Germline and somatic pathogenic variants (PVs) in DICER1, encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic entities. The lung tumors pleuropulmonary blastoma, pulmonary blastoma (PB), and well-differentiated fetal lung adenocarcinoma (WDFLAC) are all known to harbor DICER1 biallelic variants (loss of function and/or somatic hotspot missense mutations), and all share pathologic features reminiscent of the immature lung. However, the role of DICER1 PVs in non–small cell lung cancer (NSCLC) is relatively unknown. Here, we aimed to establish the spectrum of lung pathologies associated with DICER1 hotspot PVs and to compare the mutational landscape of DICER1-mutated NSCLC with and without hotspots. We queried DNA sequencing data from 12,146 NSCLCs featuring somatic DICER1 variants. 235 (1.9%) cases harboring ≥ 1 DICER1 PV were found and 9/235 (3.8%) were DICER1 hotspot-positive cases. Histologic review of DICER1 hotspot-positive cases showed that all but one tumor were classified as within the histologic spectrum of PB/WDFLAC, whereas all the DICER1 non-hotspot double variants were classified as lung adenocarcinomas, not otherwise specified. Comparison between the mutational landscape of DICER1 hotspot-positive and hotspot-negative cases revealed a higher frequency of CTNNB1 mutations in the hotspot-positive cases (5/9 vs. 2/225; P<0.00001). We conclude that DICER1 somatic hotspots are not implicated in the most common forms of NSCLC but rather select for morphologic features of lung tumor types such as PB and WDFLAC. As a corollary, cases showing this tumor morphology should undergo testing for DICER1 variants, and if positive, genetic counseling should be considered.
Colloid Pattern of Salivary Mucinous Adenocarcinomas With Recurrent BRAF V600E Mutations
Authors: Zhang Ye , Zhou Zheng , Liu Xiaoxiao , Zhu Lijing , Cui Yajuan , Li Tie-jun , Zhou Chuan-Xiang
Published: December 2023

The relationship between various patterns of mucin-producing salivary adenocarcinomas, including invasive salivary adenocarcinomas with mucinous differentiation, such as colloid and papillary carcinomas, remains unclear. Herein, we aimed to describe the clinicopathologic characteristics, immunophenotypes, molecular underpinnings, and clinical behavior of salivary mucinous adenocarcinomas (MA) to clarify their classification. We described a broad series of colloid and papillary patterns of MAs, indicating that papillary pattern presented papillary cystic proliferation of mucinous columnar cells as salivary intraductal papillary mucinous neoplasms with recurrent AKT1 E17K mutations, whereas colloid adenocarcinomas containing large mucinous pools or lakes around the malignant epithelial nests or islands harbored BRAF V600E mutations with worse prognosis. Typical morphologic structures, CK7(+), CK20(–), CDX2(–), p63(–), p40(–), MAML2 fluorescence in situ hybridization (–), AR(–), TTF-1(–), S100(–), mammaglobin(–), or S100/mammaglobin(+) with ETV6 fluorescence in situ hybridization (–) immunophenotype, and recurrent AKT1 E17K or BRAF V600E mutations may be defined. To our knowledge, this small series represents the first genetic study on a typical colloid pattern of MA, and our study with the spectrum documentation for MA in clinicopathologic characteristics, histologic and immunophenotypes, molecular features, and clinical behavior will allow for a better understanding of these rare but distinctive tumors.
Microneedling Radiofrequency Enhances Poly-L-Lactic Acid Penetration That Effectively Improves Facial Skin Laxity without Lipolysis
Authors: Wu Xianglei , Cen Qingqing , Wang Xue , Xiong Ping , Wu Xiujuan , Lin Xiaoxi
Published: December 2023

Background:

Microneedle fractional radiofrequency (MFR) is commonly used for skin laxity treatment, and poly-L-lactic acid (PLLA) can stimulate collagen synthesis in the body. However, the synergy of their combination for skin rejuvenation has not been proven. The authors aimed to evaluate the combined efficacy of PLLA and MRF and the potential mechanism underlying skin laxity.

Methods:

This prospective, randomized study included C57BL/6 mice treated with MFR, MFR plus PLLA, and carbon dioxide laser plus PLLA and 32 patients who underwent split-face treatments with MFR or MFR plus PLLA twice every 2 months. The Global Aesthetic Improvement Scale, Facial Laxity Rating scale of the whole face, the Echelle d’Evaluation Clinique des Cicatrices d’Acne grading scale of acne scars, and VISIA parameters on both treated sides were evaluated. Dermatologic changes were measured by ultrasonography in the submental space, and adverse events were documented.

Results:

PLLA was delivered by channels produced by MFR but not carbon dioxide laser in the mouse model. Thirty patients were treated with split-face MFR plus PLLA or MFR, revealing an improvement in VISIA wrinkle percentile (0.020) compared with the age-matched controls (0.000). The thickness of the dermis increased, whereas the fat layer did not change significantly. No adverse effects were observed.

Conclusions:

PLLA can be delivered through microchannels produced by MFR. PLLA enhances the efficacy of MFR for skin laxity without lipolysis.
Surgical Outcomes of Vertical Rectus Abdominis Myocutaneous Flap Pelvic Reconstruction
Authors: Asaad Malke , Mitchell David , Slovacek Cedar , Hassan Abbas M. , Rajesh Aashish , Liu Jun , Kapur Sahil , Baumann Donald , Butler Charles E.
Published: December 2023

Background:

The vertical rectus abdominis myocutaneous (VRAM) flap has emerged as the workhorse flap for perineal and pelvic reconstruction. The authors aimed to evaluate outcomes of the VRAM flap over a 20-year period and the role of mesh abdominal wall reinforcement following VRAM flap–based reconstruction.

Methods:

The authors conducted a retrospective review of all consecutive patients who underwent pelvic reconstruction with a VRAM flap between January of 2001 and March of 2021. Our primary outcome measure included recipient and donor surgical-site occurrences (SSOs).

Results:

The authors identified a total of 546 patients (55% women) with a mean age of 58 years and mean body mass index of 27 kg/m2. Mesh was used at the time of VRAM reconstruction to reinforce the abdominal donor site in 36% of patients. Recipient SSOs occurred in 38% of patients, and donor SSOs occurred in 17% of patients. Hernia was identified in 9.9% of patients, and bulge developed in 6.4% of patients. The Cox proportional hazards regression model for hernia occurrence identified age, body mass index, tobacco use (hazard ratio, 2.03; 95% CI, 1.02 to 4.04), and use as an extended VRAM flap (hazard ratio, 2.13; 95% CI, 1.04 to 4.36). The use of mesh or component separation were not independent protective factors for hernia occurrence.

Conclusions:

The pedicled VRAM flap is versatile and is our preferred flap for reconstruction of pelvic and perineal defects. The use of mesh/component separation to allow for fascial closure was not shown to reduce donor-site hernia occurrence.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Community engagement tools in HIV/STI prevention research
Authors: Li Chunyan , Zhao Peipei , Tan Rayner K.J. , Wu Dan
Published: December 2023

Purpose of review

Community engagement is key to the success of sustainable public health interventions. This review highlights recent published studies that describe the use of community-engaged methods in sexually transmitted infection (STI) prevention research.

Recent findings

We organized the findings using a socio-ecological model. At the individual level, communities were engaged through participation in formative research, short-term consultations and community advisory board participation, as well as co-creation activities. At the interpersonal level, studies reviewed described peer-led interventions that leverage the influence and guidance of peers, patient-led interventions in the form of patient navigation and notification, as well as those that mobilize social networks and the power of social relationships to promote health. At the organizational and community level, multisectoral, multifacility collaborations between community, government, and academic stakeholders were highlighted. At the policy and population level, communities were engaged through community dialogues to disseminate research findings, as well as in developing strategic frameworks and clinical guidelines. Digital tools have also been leveraged for effective community engagement.

Communities have an effective role to play in STI prevention and can be engaged at multiple levels. Future efforts may consider the use of community engagement tools highlighted in this review, including digital technologies that have the potential to reach more diverse end-users.
Skin and soft tissue infections in solid organ transplants
Authors: Peghin Maddalena , Graziano Elena , Grossi Paolo Antonio
Published: December 2023

Purpose of review

Skin and soft tissue infections (SSTI) in solid organ transplant (SOT) recipients may be a great challenge for clinicians caring for SOT due to the involvement of both common and opportunistic pathogens associated with a blunted immune response. The purpose of this review is to outline current literature and describe open issues on the management of SSTI in this special population.

Recent findings

Clinical presentation in SOT recipients can manifest as isolated skin lesions after primary inoculation or be the sign of a disseminated infection. Tissue samples for microscopy and histopathology are crucial to making an accurate diagnosis given the nonspecific and heterogeneous appearance of skin lesions. Multidisciplinary teams are required for a comprehensive diagnosis and management.

SSTI are frequent contributors to morbidity and mortality in SOT. Specific research focused on the clinical presentation, risk factors and management in this special population is needed.
177Lu-DOTATATE in the Treatment of Recurrent Pheochromocytoma With Multiple Metastases
Authors: Su Dan , Zhang Yu , Li Zhuoyuan , Yang Hongyu , Chen Yue
Published: December 2023

The treatment of metastatic pheochromocytoma is challenging. We report a case of a woman with recurrent pheochromocytoma with multiple metastases who achieved excellent response after 4 cycles of 177Lu-DOTATATE therapy. She did not experience any observable adverse effects. Her disease was still stable 6 months after the fourth cycle of treatment.
“It’s Incapacitated me in so Many Ways”
Authors: Keny Christina , Dillon Ellis C. , Russell Marcia M. , Colley Alexis , Yank Veronica , Tang Victoria
Published: December 2023

Objective:

This qualitative study aimed to explore the challenges faced by older adults regarding the postoperative symptom experience following major elective surgery.

Background:

Although extensively studied in oncology settings, the impact of postoperative symptom burden remains largely underexplored in elective major surgery among older adults.

Methods:

We employed convenience sampling to recruit adults aged ≥65 years undergoing major elective surgery at the University of California, San Francisco. Semi-structured interviews regarding the surgical experience were conducted at one and three months postoperatively. An inductive qualitative approach was used to identify emerging themes. Symptoms revealed by participants during interviews were also captured.

Results:

Nineteen participants completed a one-month postoperative interview, and seventeen additionally completed a three-month interview. Three themes emerged: 1) postoperative symptoms significantly impacted valued life activities and psychosocial well-being, 2) participants felt “caught off guard” by the intensity and duration of postoperative symptoms, and 3) participants expressed the need for additional support, resources, and education on symptom management. The most frequently mentioned symptoms were postoperative pain (n=12, 63.1%), gastrointestinal discomfort (n=8, 42.1%), and anxiety/stress (n=8, 42.1%) at one-month post-surgery, compared to pain and depression (both n=6, 35.3%) at three months.

Conclusions:

Study participants were surprised by the negative impact of postoperative symptoms on their psychosocial well-being and ability to engage in valued life activities. Symptom burden is an important patient-reported outcome that should be assessed postoperatively. Interventions to minimize postoperative symptom burden in older adults could optimize quality of life and participation in meaningful activities during surgical recovery.
A Systematic Review of Literatures: To Identify Non-Cancer Drugs Repurposed for Lung Cancer
Authors: Samadder Saikat
Published: December 2023

Aim

The aim of this study is to identify literature suggesting drug repurposing based on various medicines found to possess enhanced efficacy against lung cancer in humans based on pre-clinical and retrospective analysis. Often pre-clinical and retrospective study findings may deviate from the results of randomized prospective clinical studies, this study intends to identify the efficacious new drugs against lung cancer in placebo-controlled studies.

Methods

A systematic review of literature was performed in PubMed database on 30thAugust 2023 without any fixed timeline with terms related to ‘drug repurposing’ and ‘Lung cancer’. Post screening of literature, the names of non-chemo drugs identified were further searched inclinicaltrials.govadditionally NCT# was searched in google scholar, in-case the trial results were not available in respective source to validate the study findings.

Results

In PubMed 513 articles were found, 9% articles mentioned about drugs with potential efficacy against lung cancer in humans. In these 45 articles 61 non-chemo drugs were identified from specific 293 clinical studies. Among these 30 studies for 23 drugs were in advanced clinical stage and 9 non-chemo medicines were identified to have positive results in randomized controlled clinical trials, rest of the drugs failed to attend designated clinical efficacy till-date. Anti-alcoholism, anti-bacterial, anti-emetics, cox-2 inhibitors, and HMG-CoA reductase inhibitor are the drugs that could potentially effective against advanced non-small cell lung cancer.

Conclusion

Applying the advanced search methodology to identify drugs repurposed or approved for targeted disease. All these 9 non-chemo were screened under randomized trial and currently only one drug disulfiram was found to enhance survival and response, reduced disease progression, in advanced NSCLC originally indicated for anti-alcoholism.
Identification of clinically-relevant genetic alterations in uveal melanoma using RNA sequencing
Authors: Nell R.J. , Versluis M. , Cats D. , Mei H. , Verdijk R.M. , Kroes W.G.M. , Luyten G.P.M. , Jager M.J. , van der Velden P.A.
Published: December 2023

Introduction

Uveal melanoma is a lethal intraocular tumour, in which the presence of certain genetic alterations correlates with the risk of metastatic dissemination and patient survival. RNA data is typically used to transcriptionally characterise tumours and their micro-environment. In this study, we tested the detectability of all key genetic alterations in uveal melanoma from RNA sequencing data.

Methods

Cohort-wide gene expression profiling was used to classify tumours at the transcriptional level. In individual samples, copy number alterations affecting chromosomes 3 and 8q were analysed by measuring expressed allelic imbalances of heterozygous common single nucleotide polymorphisms. Mutations inGNAQ, GNA11, CYSLTR2, PLCB4, BAP1, SF3B1andEIF1AXwere identified by screening of hotspot regions and by evaluating their transcriptional effects. All findings were cross-validated with DNA-derived data in a training cohort of 80 primary uveal melanomas studied by The Cancer Genome Atlas (TCGA) initiative, and in five prospectively analysed cases from our institution.

Results

Unsupervised gene expression profiling strongly correlated to the presence of chromosome 3 alterations, but was not reliable in identifying other (clinically-)relevant genetic alterations. However, the presence of both chromosome 3 and 8q copy number alterations could be successfully inferred from expressed allelic imbalances in most tumours. The majority of mutations were adequately recognised at the RNA level by their nucleotide changes (all genes), alternative splicing around the mutant position (BAP1) and transcriptome-wide aberrant splice junction usage (SF3B1). Notably, in the TCGA cohort we detected previously unreported mutations inBAP1(n=3) andEIF1AX(n=5), that were missed by the original DNA sequencing. In our prospective cohort, all mutations and copy number alterations were successfully identified at the RNA level by combining the described approaches.

Conclusion

In addition to providing gene expression levels and profiles, RNA from uveal melanomas presents insights into the expressed tumour genotype and its phenotypic consequences. Such complete analysis of transcriptional data may augment or even substitute current DNA-based approaches, and has potential applicability in both research and clinical practice.
Genomic Profiling and Spatial SEIR Modeling of COVID-19 Transmission in Western New York
Authors: Bard Jonathan E , Jiang Na , Emerson Jamaal , Bartz Madeleine , Lamb Natalie A. , Marzullo Brandon J. , Pohlman Alyssa , Boccolucci Amanda , Nowak Norma J. , Yergeau Donald A. , Crooks Andrew T. , Surtees Jennifer A.
Published: December 2023

The COVID-19 pandemic has prompted an unprecedented global effort to understand and mitigate the spread of the SARS-CoV-2 virus. In this study, we present a comprehensive analysis of COVID-19 in Western New York, integrating individual patient-level genomic sequencing data with a spatially informed agent-based disease Susceptible-Exposed-Infectious-Removed (SEIR) computational model. The integration of genomic and spatial data enables a multi-faceted exploration of the factors influencing the transmission patterns of COVID-19, including population density, movement dynamics, and genetic variations in the viral genomes replicating in New York State (NYS). Our findings shed light on local dynamics of the pandemic, revealing potential hotspots of transmission. Additionally, the genomic analysis provides insights into the genetic heterogeneity of SARS-CoV-2 within a single lineage at a region-specific level. This interdisciplinary approach, bridging genomics and spatial modeling, contributes to a more holistic understanding of COVID-19 dynamics. The results of this study have implications for future public health strategies, guiding targeted interventions and resource allocation to effectively control the spread of similar viruses in the Western New York region.
Lupus Nephritis Subtype Classification with only Slide Level labels
Authors: Sharma Amit , Chauhan Ekansh , Uppin Megha S , Rajasekhar Liza , Jawahar C V , Vinod P K
Published: December 2023

Lupus Nephritis classification has historically relied on labor-intensive and meticulous glomerular-level labeling of renal structures in whole slide images (WSIs). However, this approach presents a formidable challenge due to its tedious and resource-intensive nature, limiting its scalability and practicality in clinical settings. In response to this challenge, our work introduces a novel methodology that utilizes only slide-level labels, eliminating the need for granular glomerular-level labeling. A comprehensive multi-stained lupus nephritis digital histopathology WSI dataset was created from the Indian population, which is the largest of its kind.LupusNet, a deep learning MIL-based model, was developed for the sub-type classification of LN. The results underscore its effectiveness, achieving an AUC score of 91.0%, an F1-score of 77.3%, and an accuracy of 81.1% on our dataset in distinguishing membranous and diffused classes of LN.
DeePNAP: A deep learning method to predict protein-nucleic acids binding affinity from sequence
Authors: Pandey Uddeshya , Behara Sasi M. , Sharma Siddhant , Patil Rachit S. , Nambiar Souparnika , Koner Debasish , Bhukya Hussain
Published: December 2023

Predicting the protein-nucleic acid (PNA) binding affinity solely from their sequences is of paramount importance for the experimental design and analysis of PNA interactions (PNAIs). A large number of currently developed models for binding affinity prediction are limited to specific PNAIs, while also relying on both sequence and structural information of the PNA complexes for both train/test and also as inputs. As PNA complex structures available are scarce, this significantly limits the diversity and generalizability due to a small training dataset. Additionally, a majority of the tools predict a single parameter such as binding affinity or free energy changes upon mutations, rendering a model less versatile for usage. Hence, we propose DeePNAP, a machine learning-based model trained on a vast and heterogeneous dataset with 14,401 entries (from both eukaryotes and prokaryotes) of ProNAB database, consisting of wild-type and mutant PNA complex binding parameters. Our model precisely predicts the binding affinity and free energy changes due to the mutation(s) of PNAIs exclusively from the sequences. While other similar tools extract features from both sequence and structure information, DeePNAP employs sequence-based features to yield high correlation coefficients between the predicted and experimental values with low root mean squared errors for PNA complexes in predicting theKDand ΔΔG implying the generalizability of DeePNAP. Additionally, we have also developed a web interface hosting DeePNAP that can serve as a powerful tool to rapidly predict binding affinities for a myriad of PNAIs with high precision toward developing a deeper understanding of their implications in various biological systems. Web interface:http://14.139.174.41:8080/
Adaptive algorithms for shaping behavior
Authors: Tong William L. , Iyer Anisha , Murthy Venkatesh N. , Reddy Gautam
Published: December 2023

Dogs and laboratory mice are commonly trained to perform complex tasks by guiding them through a curriculum of simpler tasks (‘shaping’). What are the principles behind effective shaping strategies? Here, we propose a machine learning framework for shaping animal behavior, where an autonomous teacher agent decides its student’s task based on the student’s transcript of successes and failures on previously assigned tasks. Using autonomous teachers that plan a curriculum in a common sequence learning task, we show that near-optimal shaping algorithms adaptively alternate between simpler and harder tasks to carefully balance reinforcement and extinction. Based on this intuition, we derive an adaptive shaping heuristic with minimal parameters, which we show is near-optimal on the sequence learning task and robustly trains deep reinforcement learning agents on navigation tasks that involve sparse, delayed rewards. Extensions to continuous curricula are explored. Our work provides a starting point towards a general computational framework for shaping animal behavior.
Towards A Wireless Image Sensor for Real-Time Fluorescence Microscopy in Cancer Therapy
Authors: Rabbani Rozhan , Najafiaghdam Hossein , Roschelle Micah , Papageorgiou Efthymios Philip , Zhao Biqi Rebekah , Ghanbari Mohammad Meraj , Muller Rikky , Stojanovic Vladimir , Anwar Mekhail
Published: December 2023

We present a mm-sized, ultrasonically powered lensless CMOS image sensor as a progress towards wireless fluorescence microscopy. Access to biological information within the tissue has the potential to provide insights guiding diagnosis and treatment across numerous medical conditions including cancer therapy. This information, in conjunction with current clinical imaging techniques that have limitations in obtaining images continuously and lack wireless compatibility, can improve continual detection of multicell clusters deep within tissue. The proposed platform incorporates a 2.4×4.7 mm2integrated circuit (IC) fabricated in TSMC 0.18 μm, a micro laser diode (μLD), a single piezoceramic and off-chip storage capacitors. The IC consists of a 36×40 array of capacitive trans-impedance amplifier-based pixels, wireless power management and communication via ultrasound and a laser driver all controlled by a Finite State Machine. The piezoceramic harvests energy from the acoustic waves at a depth of 2 cm to power up the IC and transfer 11.5 kbits/frame via backscattering. DuringCharge-Up, the off-chip capacitor stores charge to later supply a high-power 78 mW μLD duringImaging. Proof of concept of the imaging front end is shown by imaging distributions of CD8 T-cells, an indicator of the immune response to cancer,ex vivo, in the lymph nodes of a functional immune system (BL6 mice) against colorectal cancer consistent with the results of a fluorescence microscope. The overall system performance is verified by detecting 140 μm features on a USAF resolution target with 32 ms exposure time and 389 ms ultrasound backscattering.
Comparative single-cell transcriptomic analysis reveals putative differentiation drivers and potential origin of vertebrate retina
Authors: Zeng Xin , Gyoja Fuki , Cui Yang , Loza Matin , Kusakabe Takehiro G , Nakai Kenta
Published: December 2023

Despite known single-cell expression profiles in vertebrate retinas, understanding of their developmental and evolutionary expression patterns among homologous cell classes remains limited. We examined and compared approximately 240,000 retinal cells from four species and found significant similarities among homologous cell classes, indicating inherent regulatory patterns. To understand these shared patterns, we constructed gene regulatory networks for each developmental stage for three of these species. We identified 690 regulons governed by 530 regulators across three species, along with 10 common cell class-specific regulators and 16 preserved regulons. RNA velocity analysis pinpointed conserved putative driver genes and regulators to retinal cell differentiation in both mouse and zebrafish. Investigation of the origins of retinal cells by examining conserved expression patterns between vertebrate retinal cells and invertebrate Ciona intestinalis photoreceptor-related cells implied functional similarities in light transduction mechanisms. Our findings offer insights into the evolutionarily conserved regulatory frameworks and differentiation drivers of vertebrate retinal cells.
Neutron capture enhances dose and reduces cancer cell viability in and out of beam during helium and carbon ion therapy
Authors: Howell Nicholas , Middleton Ryan J. , Sierro Frederic , Wyatt Naomi A. , Chacon Andrew , Fraser Benjamin H. , Bambery Keith , Livio Elle , Dobie Christopher , Bevitt Joseph J. , Davies Justin , Dosseto Anthony , Franklin Daniel R. , Garbe Ulf , Guatelli Susanna , Hirayama Ryoichi , Matsufuji Naruhiro , Mohammadi Akram , Mutimer Karl , Rendina Louis M. , Rosenfeld Anatoly B. , Safavi-Naeini Mitra
Published: December 2023

Purpose

Neutron Capture Enhanced Particle Therapy (NCEPT) is a proposed augmentation of charged particle therapy which exploits thermal neutrons generated internally, within the treatment volume via nuclear fragmentation, to deliver a biochemically targeted radiation dose to cancer cells. This work is the first experimental demonstration of NCEPT, performed using both carbon and helium ion beams with two different targeted neutron capture agents (NCAs).

Materials and Methods

Human glioblastoma cells (T98G) were irradiated by carbon and helium ion beams in the presence of NCAs, [10B]-BPA and [157Gd]-DOTA-TPP. Cells were positioned within a PMMA phantom either laterally adjacent to, or within, a 100×100×60 mm spread out Bragg peak (SOBP). The impact of NCAs and location relative to the SOBP on the cells was measured by cell growth and survival assays in six independent experiments. Neutron fluence within the phantom was characterised by quantifying the neutron activation of gold foil.

Results

Cells placed inside the treatment volume reached 10% survival by 2 Gy of C or 2-3 Gy of He in the presence of NCAs compared to 5 Gy of C and 7 Gy of He with no NCA. Cells placed adjacent to the treatment volume showed a dose-dependent decrease in cell growth when treated with NCAs, reaching 10% survival by 6 Gy of C or He (to the treatment volume), compared to a no detectable effect on cells without NCA. The mean thermal neutron fluence at the centre of the SOBP was approximately 2.2×109n/cm2/Gy(RBE) for the carbon beam and 5.8×109n/cm2/Gy(RBE) for the helium beam and gradually decreased in all directions.

Conclusions

The addition of NCAs to cancer cells during C and He beam irradiation has a measurable impact on cell survival and growthin-vitro. Through the capture of internally generated neutrons, NCEPT introduces the concept of a biochemically targeted radiation dose to charged particle therapy. NCEPT enables the established pharmaceuticals and concepts of neutron capture therapy to be applied to a wider range of deeply situated and diffuse tumours, by targeting this dose to micro-infiltrates and cells outside of defined treatment regions. These results also demonstrate the potential for NCEPT to provide an increased dose to tumour tissue within the treatment volume, with a reduction in radiation doses to off target tissue.
Temperament in early childhood is associated with gut microbiota composition and diversity
Authors: Ueda Eriko , Matsunaga Michiko , Fujihara Hideaki , Kajiwara Takamasa , Takeda Aya K. , Watanabe Satoshi , Hagihara Keisuke , Myowa Masako
Published: December 2023

Temperament is a key predictor of human mental health, and cognitive and emotional development. While human fear behavior is reportedly associated with gut microbiome in infancy, infant gut microbiota changes dramatically during the first five years, when the diversity and composition of gut microbiome are established. This period is crucial for developing human executive functioning, including emotion regulation. Therefore, this study investigated the relationship between temperament and gut microbiota in 284 preschool children aged 3–4 years. Child temperament was assessed by maternal reports of the Children’s Behavior Questionnaire. Gut microbiota (alpha/beta diversity and genera abundance) was evaluated using 16S rRNA sequencing of stool samples. A high abundance of anti-inflammatory bacteria (e.g., Faecalibacterium) and low abundance of inflammatory bacteria (e.g., Eggerthella, Flavonifractor) were associated with higher positive emotionality and reward-seeking (i.e., Surgency/Extraversion, β =0.15, p = 0.013), and lower negative emotionality and behavioral inhibition (i.e., Negative Affectivity, β = -0.17, p = 0.004). Additionally, gut microbiota diversity was associated with a more active approach and exploration (i.e., Impulsivity, a specific aspect of Surgency/Extraversion, β = 0.16, p = 0.008). This study provides insight into the biological mechanisms of temperament and takes important steps toward identifying predictive markers of psychological/emotional risk.
Fibroblast Growth Factor-induced lens fiber cell elongation is driven by the stepwise activity of Rho and Rac
Authors: Sugiyama Yuki , Reed Daniel A. , Herrmann David , Lovicu Frank J. , Robinson Michael L. , Timpson Paul , Masai Ichiro
Published: December 2023

The spheroidal shape of the eye lens is critical for precise light focusing onto the retina. This shape is determined by concentrically aligned, convexly elongated lens fiber cells along the anterior and posterior axis of the lens. Upon differentiation at the lens equator, the fiber cells increase in height as their apical and basal tips migrate towards the anterior and posterior poles, respectively. The forces driving this elongation and migration remain unclear. We found that membrane protrusions or lamellipodia are observed only in the maturing fibers undergoing cell curve conversion, indicating lamellipodium is not the primary driver of earlier fiber migration. We demonstrated that elevated levels of fibroblast growth factor (FGF) suppressed the extension of Rac-dependent protrusions, suggesting changes in the activity of FGF controling Rac activity, switching to lamellipodium-driven migration. Inhibitors of ROCK, myosin, and actin reduced the height of both early and later fibers, indicating elongation of these fibers relies on actomyosin contractility. Consistently, active RhoA was detected throughout these fibers. Given that FGF promotes fiber elongation, we propose it to do so through regulation of Rho activity.

Summary statement

FGF differentially regulates Rho- and Rac-activity at the lens equator to promote lens fiber cell elongation and migration.
Real-world effectiveness of sotrovimab for the treatment of SARS-CoV-2 infection during Omicron BA.2 and BA.5 subvariant predominance: a systematic literature review
Authors: Drysdale Myriam , Berktas Mehmet , Gibbons Daniel C. , Rolland Catherine , Lavoie Louis , Lloyd Emily J.
Published: December 2023

Background

Emerging SARS-CoV-2 variants have impacted the in vitro activity of sotrovimab, with variable fold changes in neutralization potency reported for Omicron BA.2 and subsequent variants. We performed a systematic literature review (SLR) to evaluate clinical outcomes associated with sotrovimab use during Omicron BA.2 and BA.5 predominance.

Methods

Electronic databases were searched for observational studies published in peer-reviewed journals, preprint articles and conference abstracts from January 1, 2022–February 27, 2023.

Results

The 14 studies identified were heterogeneous in terms of study design, population, endpoints and definitions, and comprised >1.7 million high-risk patients with COVID-19, of whom approximately 41,000 received sotrovimab (range n=20– 5979 during BA.2 and n=76–1383 during BA.5 predominance). Studies were from the US, UK, Italy, Denmark, France, Qatar, and Japan. Four studies compared the effectiveness of sotrovimab with untreated or no monoclonal antibody treatment controls, two compared sotrovimab with other treatments, and three single-arm studies compared outcomes during BA.2 and/or BA.5 versus BA.1. The remaining five studies descriptively reported rates of clinical outcomes in patients treated with sotrovimab. Rates of COVID-19-related hospitalization or mortality among sotrovimab-treated patients were consistently low (0.95% to 4.0% during BA.2; 0.5% to 2.0% during BA.5). All-cause hospitalization or mortality was also low (1.7% to 2.0% during BA.2; 3.4% during combined BA.2 and BA.5 periods). During BA.2, a lower risk of all-cause hospitalization or mortality was reported across studies with sotrovimab versus untreated cohorts. Compared with other treatments, sotrovimab was associated with a lower (molnupiravir) or similar (nirmatrelvir/ritonavir) risk of COVID-19-related hospitalization or mortality during BA.2 and BA.5. There was no significant difference in outcomes between the BA.1, BA.2 and BA.5 periods.

Conclusions

The studies included in this SLR suggest continued effectiveness of sotrovimab in preventing severe clinical outcomes during BA.2 and BA.5 predominance, both against an active/untreated comparator and compared with BA.1 predominance.
Epidemiological overlaps in COVID-19 and malaria within healthcare and community settings of Southern Ghana
Authors: Amegatcher Gloria , Acquah Maame E. , Tetteh Deborah , Obeng Rachael , Debrah Ethel , Quist Bridget , Acquah-Jackson Priscilla , Boateng Kyerewaa A. , Twieku Gideon , Armoo Samuel , Awandare Gordon A. , Mosi Lydia , Narh Charles A.
Published: December 2023

Background

COVID-19 disruptions in Africa in 2020-2022 contributed to reductions in malaria control activities including antimalarial surveillance programs. This study investigated the malaria burden and distribution on the background of active transmission of SARS-CoV-2 in Southern Ghana. Specifically, it aimed to identify epidemiological factors that can maximise programmatic control for both diseases, utilising community health education and medical screening (CHEMS).

Methods

Between October-December 2022, prospective cross-sectional surveys, with CHEMS were conducted in Greater Accra and Central regions, where 994 participants enrolled either at a hospital or community setting provided demographic and clinical data including history of clinical malaria infection and antimalarial treatment in the past two weeks. Of this study population, 953 provided nasal/throat swabs for COVID-19 RT-PCR testing, with a subset of 136 participants also providing finger-prick blood for malaria RDT testing.

Results

The study population comprised of 73.6% adults, with 54.6% COVID-19 vaccination rate. Overall, 18.1% of participants had a history of clinical malaria, which was associated (adjusted odds ratio > 1.50, P-value ≤ 0.022) with COVID-19 symptoms and positivity, study area and hospital setting, suggestive of overlaps in the epidemiological risk for malaria. On a background of widespread SARS-CoV-2 infections (12-37%), malaria parasitaemia was detected in 6%, with 2% being co-infections. Among the malaria positives, 9.5% had a history of antimalarial treatment, which suggested that their infections were recrudescent parasitaemia.

Conclusion

The overlaps in the epidemiological risk for malaria and COVID-19 indicate that innovative surveillance programs, with community engagement are needed to maximise control interventions including treatment of asymptomatic malaria infections.
CRISPR-based multiplex detection of human papillomaviruses for one-pot point-of-care diagnostics
Authors: Ghouneimy Ahmed , Ali Zahir , Aman Rashid , Jiang Wenjun , Aouida Mustapha , Mahfouz Magdy
Published: December 2023

The World Health Organization’s global initiative toward eliminating high-risk Human Papillomavirus (hrHPV)-related cancers recommends DNA testing over visual inspection in all settings for primary cancer screening and HPV eradication by 2100. However, multiple hrHPV types cause different types of cancers, and there is a pressing need for a, easy-to-use, multiplex point-of-care diagnostic platform for detecting different hrHPV types. Recently, CRISPR-Cas systems have been repurposed for point-of-care detection. Here, we established aCRISPR-Cas multiplexeddiagnostic assay (CRISPRD) to detect cervical cancer-causing hrHPVs in one reaction (one-pot assay). We harnessed the compatibility of thermostable AapCas12b, TccCas13a, and HheCas13a nucleases with isothermal amplification and successfully detected HPV16 and HPV18, along with an internal control in a single-pot assay with a limit of detection of 10 copies and 100% specificity. This platform offers a rapid and practical solution for multiplex detection of hrHPVs, facilitating large-scale hrHPV point-of-care screening, guiding effective treatment and policy development, and supporting global health initiatives. Furthermore, the CRISPRD platform’s programmability enables it to be adapted for simultaneously detecting hrHPVs-causing cancer, strengthening the scope of early diagnosis of HPV in the fight against infectious disease.
Beyond defense: Glucosinolate structural diversity shapes recruitment of a metabolic network of leaf-associated bacteria
Authors: Unger Kerstin , Raza Ali K. , Mayer Teresa , Reichelt Michael , Stuttmann Johannes , Hielscher Annika , Wittstock Ute , Gershenzon Jonathan , Agler Matthew T.
Published: December 2023

Leaf bacteria are critical for plant health, but little is known about how plant traits control their recruitment. Aliphatic glucosinolates (GLSs) are secondary metabolites present in leaves of Brassicaceae plants in genotypically-defined mixtures. Upon damage, they are broken down to products that deter herbivory and inhibit pathogens. Using twoA. thalianagenotypes with different aliphatic GLS profiles, we find that structural variants differentially affect commensal leaf bacteria: In the model genotype Col-0, GLS breakdown products (mostly from 4-methylsulfinylbutyl-glucosinolate) are potentially highly toxic to bacteria but have no effect on natural leaf colonization. In contrast, in anA. thalianagenotype from a wild population, GLS (mostly allyl-GLS) enriches Burkholderiales bacteria, an effect also detected in nature. Indeed,in-vitroas a carbon source, intact allyl-GLS specifically enriches a Burkholderiales-containing community in which Burkholderiales depend on other bacteria but in turn increase community growth rates. Metabolism of different GLSs is linked to breakdown product detoxification, helping explain GLS structural control of community recruitment.
Revisiting the Kuleshov effect with authentic films: A behavioral and fMRI study
Authors: Cao Zhengcao , Wang Yashu , Wu Liangyu , Xie Yapei , Shi Zhichen , Zhong Yiren , Wang Yiwen
Published: December 2023

As a fundamental film theory, montage theory posits that film editing significantly influences the viewer’s perception. The Kuleshov effect, a central concept in montage theory, proposes that the emotional interpretation of neutral facial expressions is influenced by the accompanying emotional scene in a face-scene-face sequence. However, concerns persist regarding the validity of previous studies, often employing inauthentic film materials like static images, leaving the question of its existence in authentic films unanswered. This study addresses these concerns by utilizing authentic films in two experiments. In Experiment 1, multiple film clips were captured under the guidance of a professional film director and seamlessly integrated into authentic film sequences. A total of 59 participants viewed these face-scene-face film sequences and were tasked with rating the valence of neutral faces. The findings revealed that the interpretation of emotion in neutral faces is significantly influenced by the accompanying fearful or happy scene, eliciting perceptions of negative or positive emotion from the neutral face. These results affirm the existence of the Kuleshov effect within authentic film sequences. In Experiment 2, 31 participants engaged in a similar task under functional magnetic resonance imaging (fMRI). The results revealed neural correlates supporting the existence of the Kuleshov effect at a neural level. These correlates include the cuneus, precuneus, hippocampus, parahippocampal gyrus, post cingulate gyrus, orbitofrontal cortex, fusiform gyrus, and insula. These findings also underscore the contextual framing inherent in the Kuleshov effect. By seamlessly integrating film theory and cognitive neuroscience experiments, this comprehensive study provides robust evidence supporting the existence of the Kuleshov effect. It significantly enhances our understanding of film editing and its profound impact on viewers’ perception.
VDAC1 selective molecules promote patients’-derived cancer organoids death through mitochondrial-dependent metabolic interference
Authors: Conti Nibali Stefano , De Siervi Silvia , Luchinat Enrico , Magrì Andrea , Brocca Lorenza , Mantovani Stefania , Oliviero Barbara , Mondelli Mario U. , De Pinto Vito , Turato Cristian , Arrigoni Cristina , Lolicato Marco
Published: December 2023

In the continuous pursuit of advanced cancer therapeutics, our research unveils the potential to selectively target Voltage-Dependent Anion-selective Channel isoform 1 (VDAC1), a pivotal component in cellular metabolism and apoptosis. VDAC1’s role in metabolic rewiring and its subsequent prominence in many cancer types offer a unique intervention point. The incorporation of a systematic,in silicotoin vitromethodology identified novel VA (VDAC-Antagonist) molecules with the capability to selectively bind to VDAC1, displaying a substantial specificity towards cancer cells while sparing healthy ones.

This research first led to the revelation of a specialized VDAC1 pocket, which accommodates the binding of these VA molecules, thereby instigating a selective displacement of NADH. The coenzyme is a critical metabolic substrate, and its displacement ensues in notable mitochondrial distress and a reduction in cell proliferation, specifically in cancer cells. Furthermore, meticulous analysis using organoids derived from intrahepatic cholangiocarcinoma patients (iCCA) demonstrated a dose-dependent reduction in cell viability upon treatment with VA molecules, correlating with the findings from commercial cell lines.

Interestingly, VA molecules significantly reduced cell viability and demonstrated a lower impact on healthy cells than conventional treatments like gemcitabine. This differential impact is possibly due to the elevated expression of VDAC1 in various cancer cell lines, rendering them more susceptible to metabolic disruptions induced by VA molecules.

This endeavor uncovers a multifaceted approach to cancer treatment, involving meticulous targeting of metabolic gatekeepers like VDAC1 using novel entities, thereby paving the way for developing more selective and refined cancer therapeutics. The identified VA molecules, albeit in the nascent stages, represent promising candidates for further optimization and development, potentially revolutionizing treatment modalities in cancer therapy through precise metabolic interventions.