bluuebunny/crossref_metadata_2025 huggingface dataset:
Does controlled, gradually increased venous pressure exposure (dangling) of the lower extremity after free flap reconstructions reduce partial flap loss? A multicenter randomized controlled trial
Authors: Krijgh David D. , List Emile B. , Qiu Shan S. , Schols Rutger M. , Mureau Marc A.M. , Luijsterburg Antonius J.M. , Tempelman T.M.T. , van der Beek E.S.J. , Coert J. Henk , Teunis Teun , Maarse Wiesje ,   Dangle Research Group (Laurentien .S.E. van Egdom M.D Ph.D.; Arda. Goceroglu M.D., Ph.D; Nadine.S. Hillberg, M.D., Ph.D; Jop. Beugels, M.D., Ph.D)
Published: December 2024

Introduction:

Controlled, gradually increased venous pressure exposure of lower extremity free flaps (dangling) is common, based on the assumption that this reduces (partial) flap loss. Dangling protocols potentially increase length of hospital stay and resource utilization. We investigated whether: (1) the proportion of partial flap loss 6 weeks after lower extremity free flap reconstruction is non-inferior after uncontrolled exposure compared to gradually increased venous pressure exposure; (2) there is a difference in length of hospital stay and major or minor adverse events 3 months after surgery.

Materials and Methods:

For this multicenter randomized controlled trial patients who underwent lower extremity free flap reconstruction were included. Seven days after surgery 39 were randomized to dangling and 36 mobilized without limitations. Partial flap loss was assessed 6 weeks after surgery (primary outcome), length of stay, and major and minor adverse events 3 months after surgery. An absolute increase of 12% partial flap loss was considered inferior.

Results:

Uncontrolled exposure was non-inferior to controlled, gradually increased venous pressure exposure (absolute risk difference: 2.4%, 95% CI -10%-15%, partial flap loss dangling: 5.1% (n=2) vs. non-dangling: 2.8% (n=1)). There was no difference in length of stay and major or minor complications.

Conclusion:

Seven days after surgery, dangling the lower extremity after free flap reconstruction seems unnecessary. Surgeons and patients can consider forgoing a formal dangling protocol at that time. Future research is warranted to assess whether forgoing dangling is also safe earlier after free tissue transfer possibly reducing length of hospital stay and resource utilization.
Outcomes of all-dorsal augmented intercarpal ligament reconstruction (ADAIR)
Authors: Colwell Jennifer L. , Florczynski Matthew M. , Riggs Jeanne M. , Kim Hyungjin M. , Burns Patricia B. , Chung Kevin C.
Published: December 2024

Background:

Scapholunate (SL) and lunotriquetral (LT) ligament injuries are frequently undiagnosed and can lead to progressive loss of wrist function and chronic pain. Many surgical reconstruction options exist, but outcomes are suboptimal and no superior approach has been established.

Methods:

Consecutive candidates for SL and/or LT ligament reconstruction utilizing an all-dorsal augmented intercarpal ligament reconstruction (ADAIR) were evaluated in this prospective case series. The Michigan Hand Questionnaire (MHQ), Patient-Rated Wrist Evaluation (PRWE), range of motion, and grip and pinch strength were administered preoperatively and at postoperative visits up to 12 months.

Results:

Twenty-two patients (24 wrists) were included in the study, with 17 wrists followed to 6 months and 15 wrists to 12 months postoperatively. In the operated extremity, overall MHQ scores improved over 12 months by a mean of 17.2 points (p < 0.001). All MHQ domain scores except aesthetic and work domains showed significant improvement. Overall PRWE scores improved by 24.1 points by 12 months (p < 0.001). At 12 months, all clinical outcomes, including grip and pinch strength, wrist range of motion, and radiographic measurements were improved or similar to baseline.

Conclusions:

ADAIR demonstrated encouraging short-term patient-reported and functional outcomes, comparable to other intercarpal reconstructions despite its relative technical simplicity. ADAIR is a promising technique for improving outcomes in these challenging surgical cases.
Increasing the Accessibility and Relevance of Implementation Science for Front-Line Implementers
Authors: Golub Sarit A. , Wolfer Carly , Chastain Cody A.
Published: December 2024

Background:

Implementation science has been heralded as a critical strategy for ending the HIV epidemic, and the United States has made a tremendous financial investment in implementation research. However, several dynamics in its development and organization may alienate front-line implementers and recapitulate some of the same missteps that have stymied past translational work.

Setting:

Increasing the accessibility and relevance of HIV implementation science for front-line implementers (eg, health department and health systems directors, clinic administrators, program managers, clinicians, and other providers) is critical.

Methods:

We review current challenges to the meaningful inclusion of front-line implementers in implementation science research, and consider specific changes to language, frameworks, and methods that would maximize the accessibility and relevance of the field.

Results:

Our analysis suggests the need for greater attention to implementation strategies most relevant to front-line implementers, that is, those focused on intervention recipients. We propose a novel, multilayer framework for conceptualizing the strategies necessary to achieve HIV implementation outcomes by organizations, providers, and recipients. There is a compelling rationale to adopt incentive structures that prioritize research questions most important for practice.

Conclusions:

Maximizing the impact of implementation science on ending the HIV epidemic goals requires (1) expanding the focus of implementation science to include more recipient-focused implementation strategies, (2) developing and applying frameworks that better reflect the experience and needs of front-line implementers, (3) using language most relevant and applicable to practice, and (4) prioritizing actionable research questions that directly address the needs and concerns of those doing implementation work.
Feasibility of Periauricular Incision for Parotidectomy: A Retrospective Study
Authors: Köroğlu Erdem
Published: December 2024

Backgrounds:

Various incisions are used in parotid surgery, yet they often result in visible scarring on the neck and potential deformities. This study aimed to assess the efficacy and feasibility of utilizing a periauricular approach for excising parotid tumors irrespective of their location and size.

Methods:

This retrospective study involved 46 consecutive patients with parotid lesions, who underwent minimally invasive excision through a periauricular incision performed by a single surgeon between January 2022 and January 2024. Basic demographic data were recorded. Parameters such as the need for incision extension, total volume of drainage, length of hospital stay, postoperative complications, and final pathological diagnosis were also documented.

Results:

The main trunk of the facial nerve was successfully identified in all patients, and the tumors were excised without requiring incision extension. Warthin tumor was the most common pathology (n=20, 43%). Three patients (6.5%) had malignant tumors. The inferior portion of the superficial lobe was the most frequent tumor location (n=18, 39%), with 11% of patients having deep lobe parotid tumors. Median operation time was 114 min (range, 90–170), tumor size was 2.8 cm (range, 1–6.5 cm), and drainage volume was 45 mL (range, 10–80). Postoperative complications occurred in 7 patients, with sialocele formation being the most common (n=5, 11%). No serious complications like permanent facial paralysis or skin necrosis were observed.

Conclusion:

The periauricular approach is feasible for parotid tumors across all levels of the parotid gland. Its cosmetic advantage lies in the smaller scar size that does not extend into the neck.
USP33 promotes caerulein-induced apoptotic, oxidative and inflammatory injuries in acute pancreatitis by deubiquitinating TRAF3
Authors: Guo Jian , Qu Huiheng , Cui Peng , Xue Yu
Published: December 2024

Background: Tumor necrosis factor receptor associated factor 3 (TRAF3) and deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) have been identified to play important roles in inflammatory diseases, including acute pancreatitis (AP). Here, we aimed to explore whether USP33 affected AP progression by affecting TRAF3 expression through deubiquitination.

Methods: Caerulein-treated HPDE6-C7 cells were used to mimic AP conditions in vitro. Levels of mRNAs and proteins were examined by qRT-PCR and Western blot. Cell proliferation and apoptosis were evaluated using CCK-8 assay, EdU assay and flow cytometry. Cell oxidative stress was assessed by detecting the production of superoxide dismutase and malonaldehyde. ELISA analysis detected IL-6 and TNF-α levels. Macrophage M1 polarization was evaluated by flow cytometry. Cellular ubiquitination analyzed the ubiquitination effect on TRAF3. Protein interaction between USP33 and TRAF3 was identified by immunofluorescence staining.

Results: Caerulein dose-dependently induced apoptosis, oxidative stress, and inflammatory response in HPDE6-C7 cells and promoted macrophage M1 polarization to enhance inflammation (P < 0.05). TRAF3 was highly expressed in AP patients (3.5±1.10 vs. 1.0 ±0.74, P < 0.05) and caerulein-induced HPDE6-C7 cells (3.3 ±0.34 vs. 1.0 ±0.10, P < 0.05). Knockdown of TRAF3 protected HPDE6-C7 cells from caerulein-induced apoptotic, oxidative and inflammatory injuries. Mechanistically, USP33 interacted with TRAF3 and induced TRAF3 deubiquitination to up-regulate its expression (P < 0.05). Further analyses showed that USP33 knockdown reversed caerulein-induced apoptosis, oxidative stress and inflammation in HPDE6-C7 cells by TRAF3 (P < 0.05). Moreover, USP33-TRAF3 activated the NF-κB pathway (P < 0.05).

Conclusion: USP33 promoted caerulein-induced apoptosis, oxidative stress and inflammation in pancreatic ductal cells by deubiquitinating TRAF3, indicating a novel insight into the pathogenesis of AP.
Low dose oral ketamine treatment on post-traumatic stress disorder (PTSD) (OKTOP): An open-label pilot study
Authors: Quigley Bonnie L. , Can Adem T. , Dutton Megan , Gallay Cyrana C. , Forsyth Grace , Jones Monique , Randall Fiona , Wilson Trish , Lagopoulos Jim , Hermens Daniel F.
Published: December 2024

Ketamine is being actively investigated as a rapid-acting treatment for many conditions with a stress-related psychopathology, including post-traumatic stress disorder (PTSD). The majority of studies regarding ketamine treatment for PTSD to date (including open-label and randomised control trials) have focused on intravenous (IV) ketamine administration. This administration route has limitations that can be overcome with oral ketamine. As such, this study undertook the first open-label low dose Oral Ketamine Trial on PTSD (OKTOP) to determine the safety and feasibility of sub-anaesthetic ketamine for PTSD symptom reduction. Participants with PTSD (n = 22 adults, aged 22-77 years, 55% female, 82% with comorbid depression) followed a weekly treatment course of low dose oral ketamine (titrated from 0.5 mg/kg to a maximum of 3.0 mg/kg) for six weeks. The primary outcome measure was the PTSD Checklist (PCL-5), with secondary measures including scales for depression, anxiety, stress, suicidality, sleep, and wellbeing. Mean PCL-5 scores were significantly reduced from a pre-ketamine baseline score of 40 to a post-ketamine score of 17 and remained at a reduced score (21) at follow-up, 1-month post-treatment. This reduction resulted in a response rate (defined as a ≥50% reduction in PCL-5 score from baseline) of 73% post-ketamine and 59% at follow-up. This response rate is comparable with IV ketamine trials for PTSD and suggests oral ketamine administration is a feasible and tolerable treatment for PTSD.
A Phase II/III, Randomized, double-blind, placebo-controlled trial to evaluate Immunogenicity and Safety of the Gam-COVID-Vac combined vector vaccine in the prophylactic Treatment for SARS-CoV-2 infection in the United Arab Emirates
Authors: Al Hammadi Ahmed AK. , Alzaabi Amna H. , Choker Haneen B. , Ibrahim Ahmed A. , Ishaq Asma Bin , Mahboub Ahmed E. , Al Dhaheri Reem S. , Alzaabi Mohamed N. , Collyns Timothy A. , ElGhazali Gehad , Weber Stefan , al-Ramadi Basel K.
Published: December 2024

Background

Different platforms were used to develop vaccines against SARS-CoV-2 which were instrumental in bringing an end to the pandemic. Nevertheless, long term efficacy and safety profiles of the various vaccine types is still being investigated. The current trial aimed to assess the safety and immunogenicity of the Gam-COVID-Vac combined vector vaccine against SARS-CoV-2-induced coronavirus infection up to 6 months post vaccination.

Methods

In this randomized, double-blind, placebo-controlled trial, study participants ≥18 years of age with no prior SARS-COV-2 infection or vaccination were randomized (3:1) to receive the heterologous recombinant human adenovirus-vectored vaccines serotypes 26 and 5 or placebo. Immunogenicity was determined based on quantitative IgG antibodies (Abs) to viral S and N proteins, virus-neutralizing Abs (VNA), seroconversion rates, and S protein-specific CD4 and CD8 T cell responses.

Results

A total of 990 participants were randomized to the vaccine (n=74) and placebo (n=246) groups. Overall incidence of Adverse events (AEs) was 1844 (81.5%) in the vaccine and 501 in placebo (82.1%) groups, the majority being in the mild/moderate categories. Two doses of vaccine induced VNA in 100% of participants on Day 42, with geometric mean ratio (GMR) reaching maximum at 120 days with average 24.14 (p<0.001). Vaccine group showed a very significant GMR for quantitative IgG to S protein. Difference in seroconversion rates was also significant with 90.0%, 83.7% and 78.9% on days 42, 120 and 180 (p<0.001 at all three points). A significant rise in the median of S protein-specific CD4+and CD8+T-lymphocytes with a robust IFN-γ response was evident after 28 days compared to baseline. Long-term follow-up demonstrated persistent and significant CD8+T cell and IFN-γ responses at 120 days (p=0.049 and 0.039, respectively) compared to placebo group.

Conclusion

Gam-COVID-Vac vaccine showed a good safety profile and induced strong and durable humoral and cellular immune responses. The viral-specific CD8+T cell response appears to be more durable following vaccination than CD4+T cell counterpart. Importantly, there was no evidence of any severe or persistent AEs in vaccinees suggestive of long COVID syndrome, emphasizing the safety of this heterologous prime-boost vaccine.
Assessing Bias in Gene Expression Omnibus (GEO) Datasets
Authors: Gondal Mahnoor N.
Published: December 2024

The Gene Expression Omnibus (GEO) is a widely used repository for gene expression data, but its datasets may be subject to biases in terms of diversity, equity, and inclusion. This study aims to assess DEI-related biases in GEO datasets specifically focusing on gender and ethnicity representation. We curated a subset of GEO datasets by applying filters for organism type, sample size, and DEI-related metadata (gender and ethnicity). Following rigorous data extraction and cleaning, we analyzed 211 datasets, evaluating gender balance and ethnicity/race distribution using quantitative metrics. For gender representation, we calculated a gender ratio for each dataset, with a ratio closer to 1 indicating balanced representation. Ethnicity/race representation was assessed using Chi-square goodness-of-fit tests to identify disparities in ethnic distribution. We ranked datasets based on these DEI criteria to identify those with the highest and lowest bias. Our findings revealed that while many datasets displayed balanced gender ratios, significant bias in ethnicity representation was observed, with a predominance of White and African American participants. Additionally, we observed some variation in DEI metrics for datasets published before and after 2015, suggesting a shift in gender recruitment practices. These results highlight the need for more inclusive data collection and reporting in genomic research. We emphasize the importance of incorporating DEI criteria into data curation and encourage future efforts to standardize DEI data reporting across repositories to mitigate bias and improve the generalizability of genomic research.
Dona Flor and her two husbands: Discovery of novel HDAC6/AKT2 inhibitors for myeloid cancer treatment
Authors: Waitman Karoline B. , Martin Holli-Joi , Carlos Jorge A. E. G. , Braga Rodolpho C. , Souza Vinícius A. M. , Melo-Filho Cleber C. , Hilscher Sebastian , Toledo Mônica F. Z. J. , Tavares Maurício T. , Costa-Lotufo Letícia V. , Machado-Neto João A. , Schutkowski Mike , Sippl Wolfgang , Kronenberger Thales , Alves Vinicius M. , Parise-Filho Roberto , Muratov Eugene N.
Published: December 2024

Hematological cancer treatment with hybrid kinase/HDAC inhibitors is a novel strategy to overcome the challenge of acquired resistance to drugs. We collected IC50datasets from the ChEMBL database for 13 cancer cell lines (72 h cytotoxicity, measured by MTT), known inhibitors for 38 kinases, and 10 HDACs isoforms, that we identified by target fishing and literature review. The data was subjected to rigorous biological and chemical curation leaving the final datasets ranging from 76 to 8173 compounds depending on the target. We generated Random Forest classification models, whereby 14 showed greater than 80% predictability after 5-fold external cross-validation. We screened 30 hybrid kinase/HDAC inhibitor analogs through each of these models. Fragment-contribution maps were constructed to aid the understanding of SARs and the optimization of these compounds as selective kinase/HDAC inhibitors for cancer treatment. Among the predicted compounds, 9 representative hybrids were synthesized and subjected to biological evaluation to validate the models. We observed high hit rates after biological testing for the following models: K562 (62.5%), MV4-11 (75.0%), MM1S (100%), NB-4 (62.5%), U937 (75.0), and HDAC6 (86.0%). This aided the identification of6band6kas potent anticancer inhibitors with IC50of 0.2-0.8 µM in three cancer cell lines, linked to HDAC6 inhibition below 2 nM, and blockade of AKT2 phosphorylation at 2 μM, validating the ability of our models to predict novel drug candidates.

Graphical Abstract

Highlights

Novel kinase/HDAC inhibitors for cancer treatment were found using machine learning

61 QSAR models for hematological cancers and its targets were built and validated

K562, MV4-11, MM1S, NB-4, U937, and HDAC6 models had hit rates above 62.5% in tests

6band6kpresented potent IC50of 0.2-0.8 µM in three cancer cell lines

6band6kinhibited HDAC6 below 2 nM, and blockade of AKT2 phosphorylation at 2 μM
Cannabidiol promotes apoptosis and downregulation of oncogenic factors
Authors: Greenwood Ashley , Yamamoto Tomomi M. , Joshi Molishree , Hutchison Kent , Bitler Benjamin G.
Published: December 2024

Patients with high-grade serous carcinoma of tubo-ovarian origin (HGSC) often experience significant side effects related to their disease and treatments, such as pain, discomfort, nausea, and vomiting. Over the last two decades, the use of cannabinoids (CBD) to manage pain and anxiety has become more mainstream. However, there is limited data on how CBD interacts with HGSC tumor cells or whether CBD impacts the effect of chemotherapy.

Prior preclinical data has suggested the antitumor benefits of cannabinoids; however, the mechanism and data in ovarian cancer are limited. The objectives of this proposed research are to define the endocannabinoid system milieu in ovarian cancer, determine if CBD influences the growth of ovarian cancer cells, measure the cell viability when cannabinoids such as CBD are combined with standard-of-care therapies, and identify potential molecular pathways in which cannabinoids have a therapeutic effect. We conducted publicly available database searches, in vitro proliferation and apoptotic assays, functional protein signaling via reverse phase protein array analysis of CBD-treated cells using 2D cultured cells, and immunohistological analysis of ex vivo cultured patient-derived tumor slices treated with CBD.

Our data suggests that CBD is unlikely to affect the growth of cancer cells at physiologic doses but promotes apoptosis and can have growth inhibitory effects at higher concentrations. The inhibitory effects seen at high dose concentrations are likely from the upregulation of apoptotic pathways and inhibition of oncogenic pathways. Overall, physiologic CBD levels have minimal impact on cancer cell growth or chemotherapy efficacy.
Predicting Tissue of Origin from Bulk Tumor Gene Expression using a Pre-trained Transformer Model
Authors: Mellors Ted , Spitmann Mehran
Published: December 2024

Identifying the tissue of origin for cancers is essential for enhancing diagnostic precision, selecting effective treatments, and guiding clinical decision-making. In this study, we developed a predictive model to classify the tissue of origin across various cancer types. Using a dataset with 10,300 samples from 32 unique tissue types, the model achieved an overall accuracy of 88% in distinguishing among all 32 classes, with an average accuracy of 99.2% within each class. When tested on metastatic skin tumors, it reached an accuracy of 87%, underscoring its potential in addressing challenging metastatic cases. These results demonstrate the model’s reliability in oncology applications, offering a promising tool for improving diagnostic accuracy and supporting personalized cancer treatment strategies.
Microvascular pulsatility of the ageing brain and confounding effects of anaesthesia
Authors: Skøtt Mia Viuf , Melnikova Elizaveta , Gutiérrez Eugenio , Matchkov Vladimir , Østergaard Leif , Postnov Dmitry D
Published: December 2024

Microvascular pulsatility in the brain is crucial for sustaining the delicate balance between the brain’s metabolic demands and blood supply, as it affects nutrient exchange, waste removal and blood-brain barrier permeability. Abnormal pulsatility, associated with ageing or vascular risk factors, may impair the clearance of metabolic waste or contribute to conditions such as cerebral small vessel disease, ultimately leading to dementia and increasing the risk of stroke. In the present study, we introduce a new approach for robust full-field characterization of microvascular pulsatility and apply it to study cerebral perfusion and pulsatility across nearly the entire lifespan of awake and anaesthetized C57BL/6 mice. Our findings in awake animals reveal remarkably stable perfusion and pulsatility from 18 to 81 weeks, with pulsatility starting to change only in the final weeks of observation. In contrast, measurements taken under anaesthesia display a range of age-dependent and age-independent changes. We show that isoflurane affects the perfusion in an age-dependent manner, and both isoflurane and ketamine-xylazine, despite their distinct mechanisms, double the perfusion pulsatility and affect vascular diameter pulsatility in a complex manner, highlighting a previously overlooked detrimental effect of anaesthesia on assessing brain function.
Uncovering the Structural and Functional Implications of Uncharacterized NSPs and Variations in the Molecular Toolkit Across Mammalian and Non-Mammalian Arteriviruses
Authors: Siuli Rakesh , Behera Kshitij , Krishnan Arunkumar
Published: December 2024

Despite considerable scrutiny of mammalian arterivirus genomes, their genomic architecture remains incomplete, with several unannotated non-structural proteins (NSPs) and the puzzling absence of methyltransferase (MTase) domains. Additionally, the host range of arteriviruses has expanded to include seven newly sequenced genomes from non-mammalian hosts, which remain largely unannotated and await detailed comparisons alongside mammalian isolates. Utilizing comparative genomics approaches and comprehensive sequence-structure analysis, we provide enhanced genomic architecture and annotations for arterivirus genomes. We identify the previously unannotated C-terminal domain of NSP3 as a winged helix-turn-helix domain and classified NSP7 as a new small β-barrel domain, both likely involved in interactions with viral RNA. NSP12 is identified as a derived variant of the N7-MTase-like Rossmann fold domain, showing structural alignment with N7-MTases in Nidovirales, yet it likely lacks enzymatic functionality due to the erosion of catalytic residues, indicating a unique role-specific to mammalian arteriviruses. In contrast, non-mammalian arteriviruses sporadically retain a 2ʹ O-MTase and an exonuclease domain, which are typically absent in mammalian arteriviruses, highlighting contrasting evolutionary trends and variations in their molecular armory. Similar lineage-specific paterns are observed in the diversification of papain-like proteases and structural proteins. Overall, the study extends our knowledge of arterivirus genomic diversity and evolution.
Sparse dimensionality reduction for analyzing single-cell-resolved interactions
Authors: Brunn Niklas , Hackenberg Maren , Vogel Tanja , Binder Harald
Published: December 2024

Several approaches have been proposed to reconstruct interactions between groups of cells or individual cells from single-cell transcriptomics data, leveraging prior information about known ligand-receptor interactions. To enhance downstream analyses, we present an end-to-end dimensionality reduction workflow, specifically tailored for single-cell cell-cell interaction data. In particular, we demonstrate that sparse dimensionality reduction can pinpoint specific ligand-receptor interactions in relation to clusters of cell pairs. For sparse dimensionality reduction, we focus on the Boosting Autoencoder approach (BAE). Overall, we provide a comprehensive workflow, including result visualization, that simplifies the analysis of interaction patterns in cell pairs. This is supported by a Jupyter notebook that can readily be adapted to different datasets.

Availability and implementation

https://github.com/NiklasBrunn/Sparse-dimension-reduction

Contact

niklas.brunn@uniklinik-freiburg.de

Supplementary material

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Circular RNA - circCLIP2 is predominantly expressed in GSC niche and enhances glioblastoma aggressiveness via EMT and ECM signaling
Authors: Misiorek Julia , Zarębska Żaneta , Kuczyński Konrad , Latowska-Łysiak Julia , Grabowska Adriana , Głodowicz Paweł , Sajek Marcin Piotr , Karlik Anna , Wronka Dorota , Barciszewska Anna Maria , Przybył Łukasz , Rolle Katarzyna
Published: December 2024

Glioblastoma (GBM) is the most common and malignant type of brain tumor in adults and no effective therapies exist to combat this disease. Surgical resection, radio- and temozolomide-based-chemotherapy are insufficient mainly due to inter- and intra-tumoral heterogeneity of GBM tumors, therefore personalized approaches are required. Additionally, diverse tumor microenvironment with a leading role of glioblastoma stem cells (GSCs) in hypoxic core underlie the aggressiveness and recurrence of GBM. However, the molecules and pathways which directly promote tumor aggressiveness together with the driving process of epithelial-to-mesenchymal transition (EMT) and the components of extracellular matrix (ECM), remain only partially covered with prior studies focused mainly on coding oncogenes and tumor suppressor genes. Over the past years, a special attention has been paid to non-coding, circular RNAs (circRNAs) differentially expressed in various cancers, including GBM. Despite high abundance and stability, the exact biological roles of most individual circRNAs have not been fully revealed, so far. Besides anti-cancer targets, circRNAs have been considered as essential biomarkers and stratifying criterion of malignancy. Thus, studies on functions of differentially expressed circRNAs in GBM are an emerging field to be explored. In herein study, the biological role of circRNA CLIP2 (circCLIP2) was found highly overexpressed in primary tumor tissues. Upon the knock-down of circCLIP2 in 2D and 3Din vitromodels, functional tests performed clearly indicate a significant contribution of circCLIP2 to aggressive potential of GBM as showed by decreased rates of proliferation, migration and invasion. Additional studies indicated predominant expression of circCLIP2 in GSC fractions additionally elevated by hypoxic conditions. The increased rates of proliferation and migration as well as molecular analyses were also confirmed inin vivosettings where xenograft model was applied. The expression of EMT markerSnail2and ECM-degrading enzyme metalloproteinase 9 (MMP9) were significantly downregulated in the tumors formed from circCLIP2 silenced cells. Taken together, these results indicate a strong contribution of circCLIP2 in the aggressive phenotype of GBM which is due to a modulation of GSC proliferative potential as well as migration and invasion via EMT together with the modulator of ECM composition.
Transcutaneous afferent patterned stimulation reduces essential tremor symptoms through modulation of neural activity in the ventral intermediate nucleus of the thalamus
Authors: Luu Cuong P. , Ranum Jordan , Youn Youngwon , Perrault Jennifer L. , Krause Bryan , Banks Matthew , Buyan-Dent Laura , Ludwig Kip A. , Lake Wendell B. , Suminski Aaron J.
Published: December 2024

Essential tremor (ET), the most common movement disorder in adults, presents with involuntary shaking of the arms during postural hold and kinetic tasks linked to dysfunction in the cerebello-thalamo-cortical (CTC) network. Recently, transcutaneous afferent patterned stimulation (TAPS), applied through a wrist-worn device, has emerged as a non-invasive therapy for medication refractory ET. However, its mechanism remains unclear. We hypothesize that TAPS reduces tremor through modulation of the VIM thalamus in the CTC network. Employing refractory ET patients seeking VIM deep brain stimulation (DBS), we quantified clinical tremor improvement following TAPS treatment in a pre-operative setting, followed by intra-operative, microelectrode recording of the contralateral thalamus with concurrent TAPS treatment on and off. After one preoperative session, TAPS significantly reduces upper limb tremor, with asymmetric effect favoring the treated limb and greatest improvement tending to kinetic tremor. The magnitude of TAPS-related tremor reduction demonstrates a positive correlation with the modulation of alpha and beta band LFPs in the VIM. TAPS also modulated spiking activity in the VIM, though it was uncorrelated with the degree of tremor reduction. Of note, TAPS related modulation of LFPs and spiking activity was greatest near the optimal placement location for DBS lead in treating ET. In sum, TAPS likely reduces tremor in ET by modulating the VIM and connected nodes in the cerebello-thalamo-cortical pathway.
Characterising the 2023 chikungunya outbreak in Paraguay and the potential impact of a vaccine campaign
Authors: Pérez-Estigarribia Pastor E , Ribeiro dos Santos Gabriel , Cauchemez Simon , Vazquez Cynthia , Ibarrola-Vannucci Ana Karina , Sequera Guillermo , Villalba Shirley , José Ortega María , Luis Di Fabio Jose , Scarponi Danny , Mukandavire Christinah , Deol Arminder , Cabello Águeda , Vargas Elsi , Fernández Cyntia , León Liz , Salje Henrik
Published: December 2024

There now exists a licensed chikungunya vaccine, however, it remains unclear if it could be deployed during outbreaks to reduce the health burden. We used an epidemic in Paraguay as a case study. We conducted a seroprevalence study and used models to reconstruct epidemic transmission dynamics, providing a framework to assess the theoretical impact of a vaccine had it been available. We estimated 33.0% (95% CI: 30.1-36.0) of the population became infected during the outbreak, 6.3% (95%CI: 5.8-6.9) of which were detected by the surveillance system, with a mean infection fatality ratio of 0.013 % (95%CI: 0.012-0.014). A disease-blocking vaccine with 75% efficacy deployed in 40% of > 12-year-olds over a three-month period would have prevented 34,200 (95% CI: 30,900-38,000) cases, representing 23% of cases, and 73 (95%CI: 66-81) deaths. If the vaccine also leads to infection blocking, 88% of cases would have been averted. These findings suggest the vaccine is an important new tool to control outbreaks.
Jumping plant-lice of the tribe Paurocephalini (Hemiptera: Psylloidea: Liviidae) in Brazil
Authors: Serbina Liliya š. , Malenovský Igor , Queiroz Dalva L. , Burckhardt Daniel
Published: December 2024

Abstract

The predominantly tropical tribe Paurocephalini of jumping plant-lice currently consists of seven genera and 94 described species worldwide, of which the generaKlyveriaBurckhardtet al. andMelanasteraSerbinaet al. have been recorded from Brazil with two and one species, respectively. Here we review the taxonomy of the Brazilian species based on material collected from extensive fieldwork carried out in 15 states over the last decade. One species ofKlyveriaand 59 species ofMelanasteraare newly described, bringing the number of extantKlyveriaspp. to three (both in Brazil and worldwide) and that of extantMelanasteraspp. to 69 (60 in Brazil, 67 in the Neotropical region and one each in the Afrotropical and Oriental regions). The new species are described and illustrated, and identification keys for the Brazilian species are provided for adults and last instar immatures. The most diagnostically important structures are the distal segment of the aedeagus and the paramere, the forewing (shape, venation, surface spinules and colour pattern) and the female terminalia in the adults, and the chaetotaxy, tarsal arolium and shape of the additional pore fields on the caudal plate in the last instar immatures. The species descriptions are complemented by mitochondrial DNA barcodes (COIandcytB) and information on host plants.Klyveriaspp. are restricted toLuehea(Malvaceae), while in Brazil 28Melanasteraspp. develop or are likely to develop on Melastomataceae, 18 spp. on Annonaceae, four spp. each on Asteraceae and Myristicaceae, and one species on Cannabaceae. Only three of the 63 species of Paurocephalini reported here from Brazil, are also known from other countries: two from Paraguay and one from Trinidad. Probably many more species ofMelanasteraare yet to be discovered and described. Priority in fieldwork should be given to areas that are at high risk of destruction or degradation by human activities, such as the Amazon rainforest, the Atlantic Forest and the Cerrado.
Balancing Locality and Reconstruction in Protein Structure Tokenizer
Authors: Zhang Jiayou , Meynard-Piganeau Barthelemy , Gong James , Cheng Xingyi , Luo Yingtao , Ly Hugo , Song Le , Xing Eric
Published: December 2024

The structure of a protein is crucial to its biological function. With the expansion of available protein structures, such as those in the AlphaFold Protein Structure Database (AFDB), there is an increasing need for efficient methods to index, search, and generate these structures. Additionally, there is a growing interest in integrating structural information with models from other modalities, such as protein sequence language models. We present a novel VQ-VAE-based protein structure tokenizer, AIDO.StructureTokenizer (AIDO.St), which is a pretrained module for protein structures in an AI-driven Digital Organism [1]. AIDO.StructureTokenizer is a 300M parameter model consisting of an equivariant encoder to discretize input structures into tokens, and an invariant decoder to reconstruct the inputs from these tokens. In addition to evaluating structure reconstruction ability, we also compared our model to Foldseek, ProToken, and ESM3 in terms of protein structure retrieval ability. Through our experiments, we discovered an intriguing trade-off between the encoder’s locality and retrieval ability and the decoder’s reconstruction ability. Our results also demonstrate that a better balance between retrieval and reconstruction enables a better alignment between the structure tokens and a protein sequence language model, resulting in better structure prediction accuracy. Models and code are available through ModelGenerator inhttps://github.com/genbio-ai/AIDOand onHugging Face.
SynapseNet: Deep Learning for Automatic Synapse Reconstruction
Authors: Muth Sarah , Moschref Frederieke , Freckmann Luca , Mutschall Sophia , Hojas-Garcia-Plaza Ines , Bahr Julius N. , Petrovic Arsen , Thao Do Thanh , Schwarze Valentin , Archit Anwai , Weyand Kirsten , Michanski Susann , Maus Lydia , Imig Cordelia , Brose Nils , Wichmann Carolin , Fernandez-Busnadiego Ruben , Moser Tobias , Rizzoli Silvio O. , Cooper Benjamin H. , Pape Constantin
Published: December 2024

Electron microscopy is an important technique for the study of synaptic morphology and its relation to synaptic function. The data analysis for this task requires the segmentation of the relevant synaptic structures, such as synaptic vesicles, active zones, mitochondria, presynaptic densities, synaptic ribbons, and synaptic compartments. Previous studies were predominantly based on manual segmentation, which is very time-consuming and prevented the systematic analysis of large datasets. Here, we introduce SynapseNet, a tool for the automatic segmentation and analysis of synapses in electron micrographs. It can reliably segment synaptic vesicles and other synaptic structures in a wide range of electron microscopy approaches, thanks to a large annotated dataset, which we assembled, and domain adaptation functionality we developed. We demonstrated its capability for (semi-)automatic biological analysis in two applications and made it available as an easy-to-use tool to enable novel data-driven insights into synapse organization and function.
Draft genome and transcriptomic sequence data of three invasive insect species
Authors: Lombaert Eric , Klopp Christophe , Blin Aurélie , Annonay Gwenolah , Iampietro Carole , Lluch Jérôme , Sallaberry Marine , Valière Sophie , Poloni Riccardo , Joron Mathieu , Deleury Emeline
Published: December 2024

Cydalima perspectalis(the box tree moth),Leptoglossus occidentalis(the western conifer seed bug), andTecia solanivora(the Guatemalan tuber moth) are three economically harmful invasive insect species. This study presents their genomic and transcriptomic sequences, generated through whole-genome sequencing, RNA-seq transcriptomic data, and Hi-C sequencing. The resulting genome assemblies exhibit good quality, providing valuable insights into these species. The genome size are 469.1 Mb forC. perspectalis, 1.77 Gb forL. occidentalis, and 601.7 Mb forT. solanivora. These datasets are available in the NCBI Sequence Read Archive (BioProject PRJNA1140410) and serve as essential resources for population genomics studies and the development of effective pest management strategies, addressing significant gaps in the understanding of invasive insect species.
Essential genes encoded by the mating-type locus of the human fungal pathogenCryptococcus neoformans
Authors: Bian Zhuyun , Xu Ziyan , Peer Anushka , Choi Yeseul , Priest Shelby J. , Akritidou Konstantina , Dasgupta Ananya , Dahlmann Tim A. , Kück Ulrich , Nowrousian Minou , Sachs Matthew S. , Sun Sheng , Heitman Joseph
Published: December 2024

Fungal sexual reproduction is controlled by the mating-type (MAT) locus. In contrast to a majority of species in the phylum Basidiomycota that have tetrapolar mating-type systems, the opportunistic human pathogenCryptococcus neoformansemploys a bipolar mating-type system, with two mating types (aand α) determined by a singleMATlocus that is unusually large (∼120 kb) and contains more than 20 genes. While severalMATgenes are associated with mating and sexual development, others control conserved cellular processes (e.g. cargo transport and protein synthesis), of which five (MYO2,PRT1,RPL22,RPL39, andRPO41) have been hypothesized to be essential. In this study, through genetic analysis involving sporulation of heterozygous diploid deletion mutants, as well as in some cases construction and analyses of conditional expression alleles of these genes, we confirmed that with the exception ofMYO2, both alleles of the other fourMATgenes are indeed essential for cell viability. We further showed that whileMYO2is not essential, its function is critical for infectious spore production, faithful cytokinesis, adaptation for growth at high temperature, and pathogenicityin vivo. Our results demonstrate the presence of essential genes in theMATlocus that are divergent between cells of opposite mating types. We discuss possible mechanisms to maintain functional alleles of these essential genes in a rapidly-evolving genomic region in the context of fungal sexual reproduction and mating-type evolution.

IMPORTANCE

Sexual reproduction is essential for long-term evolutionary success. Fungal cell type identity is governed by theMATlocus, which is typically rapidly evolving and highly divergent between different mating types. In this study, we show that theaand α alleles of four genes encoded in theMATlocus of the opportunistic human fungal pathogenC. neoformansare essential. We demonstrate that a fifth gene,MYO2, which had been predicted to be essential, is in fact dispensable for cell viability. However, a functionalMYO2allele is important for cytokinesis and fungal pathogenicity. Our study highlights the need for careful genetic analyses in determining essential genes, which is complementary to high-throughput approaches. Additionally, the presence of essential genes in theMATlocus ofC. neoformansprovides insights into the function, maintenance, and evolution of these fast-evolving genomic regions.
IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma
Authors: Karakousi Triantafyllia , Cristaldi Vanessa , Lopes de Oliveira Maria Luiza , Medeiros Geraldo Luiz Henrique , González-Robles Tania J. , da Silva Gabrielle , Breazeale Alec P. , Encarnacion-Rosado Joel , Pozniak Joanna , Kimmelman Alec C. , Ruggles Kelly V. , Chris Marine J. , Chandel Navdeep S. , Lund Amanda W.
Published: December 2024

Lymphatic vessels play a crucial role in activating anti-tumor immune surveillance but also contribute to metastasis and systemic tumor progression. Whether distinct lymphatic phenotypes exist that govern the switch between immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential. We find that in mice and humans, intratumoral lymphatic vessel density negatively correlates with productive cytotoxic immune responses and identify IFNγ as an intrinsic inhibitor of lymphangiogenesis. Specific deletion of theIfngr1in lymphatic endothelial cells (LECs) greatly expanded the intratumoral lymphatic network and drove the emergence of a tip-like endothelial state, promoting lymph node metastasis but not dendritic cell migration. IFNγ inhibits oxidative phosphorylation, which is required for proliferation and acquisition of the pathologic transcriptional state. Our data indicate that IFNγ induces a phenotypic switch in tumor-associated lymphatic vessels to reinforce canonical immune surveillance and block metastasis.
CellSexID: Sex-Based Computational Tracking of Cellular Origins in Chimeric Models
Authors: Tai Huilin , Li Qian , Wang Jingtao , Tan Jiahui , Lang Ryann , Petrof Basil J. , Ding Jun
Published: December 2024

Cell tracking in chimeric models is essential yet challenging, particularly in developmental biology, regenerative medicine, and transplantation studies. Existing methods, such as fluorescent labeling and genetic barcoding, are technically demanding, costly, and often impractical for dynamic, heterogeneous tissues. To address these limitations, we propose a computational framework that leverages sex as a surrogate marker for cell tracking. Our approach uses a machine learning model trained on single-cell transcriptomic data to predict cell sex with high accuracy, enabling clear distinction between donor (male) and recipient (female) cells in sex-mismatched chimeric models. The model identifies specific genes critical for sex prediction and has been validated using public datasets and experimental flow sorting, confirming the biological relevance of the identified cell populations. Applied to skeletal muscle macrophages, our method revealed distinct transcriptional profiles associated with cellular origins. This pipeline offers a robust, cost-effective solution for cell tracking in chimeric models, advancing research in regenerative medicine and immunology by providing precise insights into cellular origins and therapeutic outcomes.
NJGPT: A Large Language Model-Driven, User-Friendly Solution for Phylogenetic Tree Construction
Authors: Wang Zhixuan , Huang Haoyuan , Li Teng , Rodrigo Allen
Published: December 2024

Motivation

Phylogenetic reconstruction plays an integral part in much of the research in evolutionary biology. Currently, a newly minted phylogeneticist must choose amongst a relatively large array of phylogenetic software, each often with its own analytical routines, inputs and outputs. Our overarching aim is to construct a user-friendly pipeline with the most recent generative AI tool, ChatGPT-4 (at the time of writing) released by OpenAI, that is able to understand queries written in natural language, to build a phylogenetic tree using sequence data. By doing this, we demonstrate how generative AI may be used in phylogenetics, as a proof-of-concept. We also demonstrate the steps needed, presently, to ensure that ChatGPT can build phylogenetic trees accurately.

Results

We present NJGPT, a phylogenetic tool built using ChatGPT, a Large Language Model (LLM) Generative Pre-trained Transformer (GPT),which employs the Neighbor-Joining method to construct phylogenetic trees. NJGPT simplifies phylogenetic tree construction by allowing users to generate and visualize trees using natural language queries. It supports multiple sequence file formats, matrix calculation models, and gap-deletion methods. To evaluate the performance of NJGPT, we compared output and runtimes with the widely-used phylogenetic software, MEGA. Our results show that NJGPT produces identical trees over a range of sequence lengths and simple models of evolution. However, NJGPT faces visualization issues with datasets over 50 taxa and operational failures with larger datasets due to token limits. NJGPT runtimes were also substantially slower than MEGA; however, NJGPT’s user-friendly interface makes it ideal for beginners.

Availability

This plugin is available for free athttps://chatgpt.com/g/g-1OzP3Qviw-njgpt, the source code is available on GitHub (https://github.com/ZWan622/NJGPT1.0.git) and is implemented using Python

Contact

zwan622@aucklanduni.ac.nz

Supplementary information

Supplementary data are available atBioinformaticsonline.