bluuebunny/crossref_metadata_2025 huggingface dataset:
SARS-CoV-2 cross-sectional serosurvey across three HIV-1 therapeutic clinical trials in Africa
Authors: Papot Emmanuelle , Tovar-Sanchez Tamara , Woods Joana , Thaurignac Guillaume , Eriobu Nnakelu , Borok Margaret , Kaplan Richard , Avihingsanon Anchalee , Azwa Iskandar , Grinsztejng Beatriz , Kumarasamy Nagalingeswaran , Sokhela Simiso , Mpoudi-Etame Mireille , Arriaga Maria , Jacoby Simone , Matthews Gail V. , Losso Marcelo H. , Khoo Saye , Calmy Alexandra , Kouanfack Charles , Ayouba Ahidjo , Petoumenos Kathy , Venter W.D. Francois , Delaporte Eric , Polizzotto Mark N. ,   COHIVE study group∗
Published: November 2024

Objective:

Data on the impact of coronavirus disease 2019 (COVID-19) in people with HIV (PWH) are lacking in resource-constrained settings. We utilized existing randomized clinical trials (RCTs) on antiretroviral therapies (ART) in HIV-1 infection to conduct a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurvey, between January and March 2021, while characterizing participants’ features.

Design:

Cross-sectional serosurvey.

Methods:

Demographic characteristics, medical history and a serum sample were collected from consenting PWH. Samples were analyzed centrally for immunoglobulin G antibodies to recombinant nucleocapsid and spike proteins derived from SARS-CoV-2 using a Luminex based assay.

Results:

The 549 participants recruited in 9 sites across Africa had a median age of 40 years (interquartile range, IQR [34–45]); 63.0% (346) were female. All were on ART; 81.8% (449) had an HIV-1 viral load <50 copies/ml, with CD4+ cell count median at 478/mm3 (IQR [320–677]). None had received vaccination against SARS-CoV-2. Forty participants (7.3%) had a prior SARS-CoV-2 PCR testing, of whom 10 were positive (1.8%). Crude SARS-CoV-2 seroprevalence was 36.2% (95% confidence interval (CI) [32.2–40.4]). In the explorative multivariable analysis, comparison of the characteristics of PWH with a positive SARS-CoV-2 serology with those with a negative or indeterminate serology: PWH with a body mass index (BMI) ≥30 kg/m2 were more likely to have a positive serology than those with a BMI <25 (adjusted odds ratio (aOR) = 2.39 [1.48–3.86], P < 0.001); and PWH living in Cameroon were less likely to have a positive serology.

Conclusion:

This study demonstrates a substantial seroprevalence level of SARS-CoV-2 in PWH in the first quarter of 2021, with a marked disparity with the number of COVID-19 PCR tests reported positive.
Assessing Whether Providing Regular, Free HIV Self-Testing Kits Reduces the Time to HIV Diagnosis: An Internet-Based, Randomized Controlled Trial in Men Who Have Sex With Men
Authors: Dunn David T. , McCabe Leanne , Ward Denise , Phillips Andrew N. , Lampe Fiona C. , Burns Fiona , Delpech Valerie , Weatherburn Peter , Witzel T. Charles , Pebody Roger , Kirwan Peter , Khawam Jameel , Croxford Sara , Brady Michael , Fenton Kevin A. , Trevelion Roy , Collaco-Moraes Yolanda , McCormack Sheena , Rodger Alison J.
Published: November 2024

Background:

The risk of onward HIV transmission is strongly influenced by the interval between HIV infection and its diagnosis. The SELPHI trial examined whether this interval could be reduced by offering free HIV self-testing kits to men who have sex with men (MSM).

Setting:

Internet-based RCT of MSM aged ≥16 years, resident in England/Wales, recruited through sexual and social networking sites.

Methods:

The second-stage randomization of SELPHI was open to participants who used an initial free HIV self-test kit, were HIV seronegative, and reported recent condomless anal sex. They were randomized to receive a free HIV self-test kit every 3 months (repeat testing [RT] group) versus no such offer (nRT group). The primary outcome was time from randomization to a confirmed HIV diagnosis, determined from linkage to national HIV surveillance databases. The key secondary outcome was the frequency of HIV testing regardless of test modality.

Results:

In total, 2308 eligible participants (1161 RT, 1147 nRT) were randomized between April 2017 and June 2018, and followed for 15–27 months. The proportion of participants reporting an HIV test in the previous 3 months was much higher in the RT group (86%) than in the nRT group (39%). Overall, 16 (9 RT, 7 nRT) confirmed HIV diagnoses were observed (0.35/100 person-years), with no difference between the groups (hazard ratio = 1.27 [95% CI: 0.47 to 3.41], P = 0.63).

Conclusions:

Providing regular free self-testing kits to sexually active MSM was highly acceptable and markedly increased HIV testing. However, in this low incidence cohort, it did not result in a demonstrably more rapid diagnosis of incident infections.
Clinical and Imaging Pulmonary Manifestations in IgG4-Related Disease
Authors: Gallo Jesica Romina , Froullet Cristian , Varizat Alejandro , Calvo Romina Andrea , Pisoni Cecilia , Cosatti Micaela , Bertoli Ana , Paira Sergio
Published: November 2024

Objectives

The aims of this study were to describe the frequency of pleuropulmonary computed tomography (CT) findings in patients with IgG4-related disease (IgG4-RD) and to compare clinical and laboratory characteristics between patients with and without pleuropulmonary involvement in chest CT.

Methods

This is a study conducted within the IgG4-RD study group of the Argentine Society of Rheumatology (GESAR IgG4) cohort of patients with IgG4-RD. Member centers of the group were requested to submit pulmonary CT scans of the patients. Lung lesions were classified into 4 subtypes: (1) nodules, (2) ground-glass opacity, (3) interstitial-alveolar involvement, and (4) bronchovascular involvement. The presence of pleural involvement and mediastinal adenopathy was also assessed.

Results

We examined data from 28 patients, with 17 (61%) showing pulmonary involvement. The subtypes of pulmonary involvement, in order of frequency, were as follows: type 4 (n = 17, 100%), type 3 (n = 10, 59%), type 2 (n = 6, 36%), and type 1 (n = 5, 29%). Pleural lesions were observed in 2 (12%) cases, and mediastinal adenopathies were found in 4 (23%) cases. No demographic, clinical, or laboratory differences were noted between patients with and without pulmonary involvement, except for serum levels of IgG4, which were higher among patients without pulmonary involvement (339.0 [293.1–1592.1 mg/dL] vs 2869 [1156.3–4037.4 mg/dL]; p = 0.022).

Conclusions

In this case series, the predominant subtype of pulmonary involvement was septal thickening and increased bronchovascular tissue. Patients with and without pleuropulmonary involvement exhibited similar clinical and laboratory manifestations, except for serum IgG4, which was higher in patients without pleuropulmonary involvement.
Anti-RA33 Antibodies Are Present in Patients With Lyme Disease
Authors: Miller John B. , Yang Ting , Rebman Alison W. , Cappelli Laura , Bingham Clifton O. , Villegas de Flores Marcia Daniela , Darrah Erika , Aucott John N.
Published: November 2024

Background/Objective

To determine if anti-RA33 antibodies, which can be seen in early forms of inflammatory arthritis, are present in patients with Lyme arthritis (LA).

Methods

Anti-RA33 antibodies were tested using a commercially available assay in patients with LA (n = 47) and compared with patients with erythema migrans who returned to health (EM RTH, n = 20) and those with post-treatment Lyme disease (PTLD) (n = 50), characterized by noninflammatory arthralgia, as an observational comparative study utilizing Lyme-exposed patients from various original cohorts.

Results

We found that anti-RA33 was present in higher proportions of patients with LA (23.4% vs. 0%, p = 0.001) and PTLD (12.0% vs. 0%, p = 0.040) than healthy controls. There was also a trend toward a higher percentage of anti-RA33 positivity in patients with EM RTH versus controls (10.0% vs. 0%, p = 0.080). There were no statistically significant differences among groups of patients with LA, PTLD, and EM RTH (p ≥ 0.567). There was also no difference in the proportion of patients with antibiotic-responsive LA compared with those with persistent synovitis after antibiotics, termed post-infectious LA, and there were no differences in clinical manifestations, musculoskeletal ultrasound evaluation (synovial hypertrophy, power Doppler, tendinopathy), or patient-reported outcomes based on anti-RA33 status.

Conclusions

This is the first study to identify anti-RA33 antibodies in patients with LA, though these antibodies did not identify a unique clinical subset of patients in this cohort. Unexpectedly, we found anti-RA33 antibodies at similar levels in patients with PTLD and EM RTH; further study is needed to determine the relevance of this finding.
First Successful In-Human Application of 225Ac-DOTA-LM3 Mono-PRRT for the Treatment of an Otherwise Therapy-Resistant Neuroendocrine Tumor (NET G3)
Authors: Speicher Tilman , Burgard Caroline , Bastian Moritz , Rosar Florian , Bartholomä Mark , Maus Stephan , Ezziddin Samer
Published: November 2024

We present a case of a 60-year-old woman diagnosed with metastasized small bowl NET G3 with high hepatic tumor burden and highly glucometabolic (FDG-avid) disease. In the postchemotherapy setting with progressive disease, the patient underwent PRRT with 177Lu-DOTA-octreotate and 225Ac-DOTA-octreotate initially resulting in stable disease. In a novel approach, 225Ac-DOTA-LM3 (somatostatin receptor antagonist) was administered, leading to a favorable treatment response in the 18F-FDG PET/CT scan. This interesting image illustrates the promising antitumor potential of alpha-sst2 antagonist PRRT with 225Ac-DOTA-LM3, and to the best of our knowledge, it is the first documented evidence of superiority over standard alpha-PRRT from intraindividual comparison.
HER2-Targeted Affibody Molecule 99mTc-ABH2 for Imaging HER2 Expression in Breast Cancer
Authors: Jin Xiaona , Zhang Yuwei , Cao Xi , Wang Peipei , Ren Chao , Cai Jiong , Wang Xuefei , Jing Hongli , Sun Qiang , Li Fang
Published: November 2024

Purpose

Accuracy in in vivo assessment of human epidermal growth factor receptor type 2 (HER2) status is crucial for predicting the response to HER2-targeted therapies in breast cancer. This study assessed the safety, feasibility, and diagnostic accuracy of 99mTc-ABH2, a reengineered affibody molecule with radionuclide labeling, for HER2 expression in breast cancer using SPECT/CT imaging, compared with 18F-FDG PET/CT.

Patients and Methods

Thirty-six patients suspected of primary breast cancer were enrolled in this prospective, single-center study from March to July in 2023. Each participant underwent SPECT/CT imaging with 99mTc-ABH2 SPECT/CT and 18F-FDG PET/CT. The imaging results were validated against immunohistochemistry and fluorescence in situ hybridization, employing visual scores and quantitative values for analysis.

Results

Optimal imaging contrast was observed around 2 hours postinjection of 99mTc-ABH2. Among the evaluated 27 patients with immunohistochemistry and fluorescence in situ hybridization findings, the 99mTc-ABH2 SPECT/CT visual evaluation displayed a sensitivity of 71.4%, specificity of 72.2%, and accuracy of 71.9%. Using an SUVmax cutoff of 2.32, the sensitivity, specificity, and accuracy for detecting HER2 status were 92.86%, 72.22%, and 81.25%, respectively. Notably, 99mTc-ABH2 precisely identified all immunohistochemistry (3+) tumors and showed increased uptake in bone and lymph node metastases. Meanwhile, 18F-FDG PET/CT showed no significant difference in uptake between HER2 (2+/3+) and HER2 (0/1+) tumors (P = 0.81).

Conclusions

This study validated 99mTc-ABH2 SPECT/CT as a promising diagnostic tool for precise HER2 assessment. The robust sensitivity for immunohistochemistry (3+) tumors and the visualization of metastases highlight its diagnostic significance, potentially impacting patient outcomes positively.
A Case Report
Authors: Al Sawafi Fatema Mohd , Hasan Olfat Kamel , Bonert Michael , Haider Ehsan , Shayegan Bobby
Published: November 2024

Prostate-specific membrane antigen (PSMA) PET/CT scan has significantly improved the detection and staging of prostate cancer. We report a rare case of a 72-year-old man with a history of Gleason score 7 (3 + 4) prostate adenocarcinoma, status post radical prostatectomy, referred for restaging PSMA PET/CT scan due to rising PSA (0.12 μg/L). The scan revealed a PSMA-avid lesion in the retroperitoneum, later confirmed via further investigations and histopathological analysis to be a retroperitoneal hemangioma. This case emphasizes the challenges in interpreting PSMA PET/CT scan in prostate cancer and highlights the significance of thorough consideration in forming a comprehensive differential diagnosis.
Head-to-Head Comparison of 68Ga-FAPI-04 and 68Ga-DOTA-TATE PET/CT in Recurrent Medullary Thyroid Cancer
Authors: Isik Emine Goknur , Has Simsek Duygu , Gul Nurdan , Erturk Sukru Mehmet , Buyukkaya Fikret , Soyluk Selcukbiricik Ozlem , Iscan Ahmet Yalin , Özkan Zeynep Gözde , Sanli Yasemin , Mudun Ayse , Kuyumcu Serkan
Published: November 2024

Purpose

We aimed to compare the diagnostic performance of 68Ga-FAPI-04 (FAPI) in comparison to 68Ga-DOTATATE (SSTR) PET/CT for patients presenting with recurrent medullary thyroid carcinoma (MTC).

Patients and Methods

Sixteen MTC patients with elevated calcitonin levels (>150 pg/mL) underwent FAPI and SSTR PET/CT. Two nuclear medicine physicians evaluated all images, categorizing lesions into locoregional metastases, mediastinal lymph nodes (LNs), liver, and bone metastases. SUVmax and tumor-to-background ratio were recorded. PET modalities were compared using the McNemar test. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FAPI and SSTR PET were calculated.

Results

The cohort comprised 16 patients (50% female; mean age 50 ± 17 years). Median calcitonin and CEA levels were 6234 pg/mL and 17.3 ng/mL, respectively. In patient-based analysis, SSTR exhibited higher diagnostic sensitivity compared with FAPI (88% vs 81%), resulting a statistically significant difference (P = 0.004). Mean SUVmax and tumor-to-background ratio values were 10.3 and 5.35 for FAPI, and 9.7 and 11.9 for SSTR PET, respectively. In lesion-based analyses, FAPI demonstrated higher accuracy than SSTR for cervical LNs (91.9% vs 50%), mediastinal LNs (94.9% vs 54.4%), and liver metastases (57.4% vs 7.3%), respectively. Notably, 31% of patients (n = 5) with FAP-expressing liver lesions showed no uptake on SSTR imaging. MRI confirmed liver metastases in 3 of these patients; however, 2 FAP-expressing lesions were confirmed as hemangiomas. False-positive findings of DOTA primarily included reactive LNs and bone hemangiomas.

Conclusions

FAPI PET presents promising outcomes in detecting metastases in recurrent MTC patients. Although its diagnostic performance matches SSTR on a per-patient basis, FAPI PET exhibits superior sensitivity and accuracy in lesion-based analyses, notably for liver and bone metastases.
Efficacy and Safety of 177Lu-DOTA-IBA in Tumor Bone Metastasis Treatment
Authors: Xu Tingting , Wang Yudi , Liu Guangfu , Li Hongmei , Qu Gengcuo , Zhang Xiaoling , Wang Wei , Xing Naiguo , Hua Qingchu , Chen Yue
Published: November 2024

Purpose

The aim of this study was to evaluate the efficacy and safety of 177Lu-DOTA-IBA for pain palliation in participants with bone metastases and confirm its potential for treating bone metastasis.

Patients and Methods

Overall, 69 participants with bone metastases were included. 68Ga-DOTA-IBA PET/CT was performed within 1 week before treatment. Vital signs, blood markers, electrocardiogram, Karnofsky Performance Status (KPS), and pain scores were evaluated within 7 days before treatment. Postadministration of 177Lu-DOTA-IBA, participants’ vital signs and general conditions were monitored. Follow-up evaluations of KPS, pain scores, and blood biomarkers were performed within 8 weeks. 68Ga-DOTA-IBA PET/CT was repeated to evaluate imaging responses at 8 weeks. Imaging responses were defined as complete response, partial response, stable disease, and disease progression. Subsequent treatments were administered based on participants’ agreement and clinical conditions.

Results

Sixty-nine participants received at least 1 dose of 177Lu-DOTA-IBA treatment; 22 received 38 reinjected doses, totaling 107 treatments. The median injection dose of 177Lu-DOTA-IBA was 1110 MBq. The pain remission rates after first treatment, retreatment, and total treatment were 82.5%, 72.4%, and 79.3%, respectively. The improvement rates in KPS for first treatment, retreatment, and total treatment were 81.3%, 60.6%, and 74.2%, respectively. The total incidence of the pain flare reaction (temporary aggravation of pain intensity after treatment) was 16.8%. Comparative analysis of 68Ga-DOTA-IBA PET/CT showed a 27.1% rate of partial response imaging response. The total incidence of adverse hematological events was 15%.

Conclusions

177Lu-DOTA-IBA is a promising bone-seeking radiopharmaceutical with a considerable pain relief rate and safety. It also can benefit some participants with bone metastases in imaging response.
Uncovering Hidden Metastases at Unusual Site
Authors: Mahdi Raza Abbas , Saraswat Dhananjaya , Aggarwal Piyush , Sood Ashwani , Kumar Munish , Mittal Bhagwant Rai
Published: November 2024

Prostate cancer frequently metastasizes to bones; however, the detection of metastases can be challenging in rare locations. We present the case of a 76-year-old man with metastatic castration-resistant prostate cancer with lymph nodal and skeletal metastases who underwent 177Lu–prostate-specific membrane antigen (PSMA) therapy. Initial 18F-PSMA PET/CT scan acquired until the midthigh failed to identify metastases in the foot, but posttherapy 177Lu-PSMA scan revealed the presence of metastases in the navicular and cuboid bones of the right foot, which is a very rare finding. This case highlights the limitations of standard PSMA PET/CT acquisition protocol and incremental value of whole-body posttherapy scan.
Single-dock Robotic Bilateral Transversus Abdominis Release: Technique Description and Preliminary Outcomes
Authors: Estrada Arturo , Rodriguez-Quintero Jorge Humberto , Arias-Espinosa Luis , Sreeramoju Prashanth , Cheema Fareed , Pereira Xavier , Malcher Flavio
Published: November 2024

Background:

Posterior component separation with transversus abdominis release (TAR) is a valuable adjunct to address incisional hernia defects. Currently, bilateral docking is a standard technique for robotic TAR. The aim of this study is to describe our technique for extended totally extraperitoneal (eTEP) repair with bilateral TAR through a bottom single-dock robotic approach for hernias at the level of the umbilicus or higher.

Materials and Methods:

We retrospectively reviewed a case series of patients who underwent robotic eTEP repair with bilateral TAR using a single bottom docking between November 2021 and November 2023. A comprehensive description of our patient selection, surgical technique, and short-term clinical outcomes is reported.

Results:

Ten patients with incisional hernias were included. Their median age was 55 years (IQR: 49.5 to 61.25), 70% were male, the median BMI was 27.25 kg/m (IQR: 22.95 to 33.53), and ASA class was ≥2 in 80%. Median hernia width was 10 cm (IQR: 6.75 to 12.25) and length 11 cm (IQR: 9.25 to 16.25). The median operative time was 178.5 minutes (IQR: 153.75 to 222), and the length of stay was 1 day (IQR: 0.75 to 1.75). At a median follow-up of 5 months (IQR: 2.6 to 9.7), 20% of patients developed a surgical site occurrence requiring procedural intervention.

Conclusion:

Bilateral TAR using a single bottom dock is a feasible and safe adjunct to robotic eTEP ventral hernia repair in appropriately selected patients.
Protein profile of the Escherichia coli strain, BW25113, exposed to two novel iron-halide compounds: Fe(Hampy)2Cl4 and Fe(Hampy)2Br4.
Authors: Abedin Nusrat , Wagner Sarah , Khalkar Yukta Sanjay , Johnson Zulekha , Egbowon Biola F. , Hargreaves Alan J. , Fitzpatrick Anthony J. , Miles Amanda K. , Dafhnis-Calas Felix
Published: November 2024

The mortality rate and economic burden of infections caused by antimicrobial resistant pathogens are increasingly higher. This frustrating scenario emphasizes the urgent need for developing new antimicrobial drugs. We have previously addressed this problem by studying the antimicrobial activity of two novel iron-halide complexes, Fe(Hampy)2Cl4 (iron-tetrachloride) and Fe(Hampy)2Br4 (iron-tetrabromide). Both compounds showed bactericidal and antibiofilm activities against bacteria with an antimicrobial resistance phenotype. Herein, we used a proteomics approach to investigate the protein-expression profile  of bacterial cells previously exposed to both iron-halide complexes. For this study, the Escherichia coli strain, BW25113, was used as a model to facilitate the rapid identification of deregulated proteins. Heat map analysis of the common deregulated proteins highlighted that both complexes caused downregulation of proteins associated with key metabolic pathways, biofilm formation, cell-envelope biogenesis, and iron ion binding. In addition, network study suggested that the most influential proteins of the tetrachloride activity were those involved in TCA cycle, oxidative phosphorylation, iron ion homeostasis and carbon/secondary metabolism. This protein-protein interaction analysis also hinted that the main drivers of the tetrabromide activity were proteins involved in translation, ribosomal biogenesis, and cell motility. The above results strongly suggested how the presence of different halide ligands could be used to generate compounds with potentially different molecular mechanisms. Importantly, the findings of this study can also be used as a reference to compare with the protein profile of a bacteria exposed to future variants of the iron-halide complexes.
Characterizing the Solution Space of Migration Histories of Metastatic Cancers with MACH2
Authors: Roddur Mrinmoy S. , Ramavarapu Vikram , Bunkum Abigail , Huebner Ariana , Mineyev Roman , McGranahan Nicholas , Zaccaria Simone , El-Kebir Mohammed
Published: November 2024

Understanding the migration history of cancer cells is essential for advancing metastasis research and developing therapies. Existing migration history inference methods often rely on parsimony criteria such as minimizing migrations, comigrations, and seeding locations. Importantly, existing methods either yield a single optimal solution or are probabilistic algorithms without guarantees on optimality nor comprehensiveness of the returned solution space. As such, current methods are unable to capture the full extent of uncertainty inherent to the data. To address these limitations, we introduce MACH2, a method that systematically enumerates all plausible migration histories by exactly solving the ParsimoniousMigrationHistory withTreeRefinement(PMH-TR). In addition to the migration and comigration criteria, MACH2 employs a novel parsimony criterion that minimizes the number of clones unobserved in their inferred location of origin. MACH2 allows one to specify both the order and the set of criteria to include during optimization, allowing users to adapt the model to specific analysis needs. MACH2 also includes a summary graph to identify high-confidence migrations. Finally, we introduce MACH2-viz, an interactive webtool for visualizing and exploring MACH2 solution spaces. Using simulated tumors with known ground truth, we show that MACH2, especially the version that prioritizes the new unobserved clone criterion, outperforms existing methods. On real data, MACH2 detects extensive uncertainty in non-small cell lung, ovarian, and prostate cancers, and infers migration histories consistent with orthogonal experimental data.
Barley resistance and susceptibility to fungal cell entry involve the interplay of ROP signaling with phosphatidylinositol-monophosphates
Authors: Weiß Lukas Sebastian , Bartram Christoph , Bradai Mariem , Heilmann Mareike , Mergner Julia , Kuster Bernhard , Hensel Götz , Kumlehn Jochen , Engelhardt Stefan , Heilmann Ingo , Hückelhoven Ralph
Published: November 2024

Rho-of-plant small GTPases (ROPs) are regulators of plant polar growth and of plant- pathogen interactions. The barley ROP, RACB, is involved in susceptibility towards infection by the barley powdery mildew fungusBlumeria hordei(Bh), but little is known about the cellular pathways that connect RACB-signaling to disease susceptibility. Here we identify novel RACB interaction partners of plant or fungal origin by untargeted co-immunoprecipitation of constitutively active (CA) RACB tagged by green-fluorescent protein fromBh-infected barley epidermal layers expressing and subsequent analysis by liquid chromatography-coupled mass spectrometry. Three of immunoprecipitated proteins, a plant phosphoinositide phosphatase, a plant phosphoinositide phospholipase and a putativeBh-effector protein are involved in the barley-Bh-pathosystem and mediate disease resistance or susceptibility, respectively. RACB and its plant interactors bind to overlapping anionic phospholipid speciesin vitro, and in case of RACB, this lipid-interaction is mediated by its carboxy-terminal polybasic region (PBR). Fluorescent markers for anionic phospholipids show altered subcellular distribution in barley cells duringBh-attack. Phosphatidylinositol 4-phosphate and phosphatidylserine show a distinct enrichment at the haustorial neck region, suggesting a connection to subcellular targeting of RACB at this site. The interplay of ROPs with anionic phospholipids and phospholipid–metabolizing enzymes may, thus, enable the subcellular enrichment of components pivotal for success or failure of fungal penetration.
Brain-Cognitive Gaps in relation to Dopamine and Health-related Factors: Insights from AI-Driven Functional Connectome Predictions
Authors: Esmaeili Morteza , Bjørkeli Erin Beate , Pedersen Robin , Falahati Farshad , Johansson Jarkko , Nordin Kristin , Karalija Nina , Bäckman Lars , Nyberg Lars , Salami Alireza
Published: November 2024

A key question in human neuroscience is to understand how individual differences in brain function are related to cognitive differences. However, the optimal condition of brain function to study between-person differences in cognition remains unclear. Additionally, there is a lack of objective biomarkers to accurately predict cognitive function, with brain age emerging as a potential candidate. Recent research suggests that brain age offers minimal additional information on cognitive decline beyond what chronological age provides, prompting a shift toward approaches focused directly on cognitive prediction. Using a novel deep learning approach, we evaluated the predictive power of the functional connectome during various states (resting state, movie-watching, and n-back) on episodic memory and working memory performance. Our findings show that while task-based connectomes, especially during movie watching, better predict working memory, resting state connectomes are equally effective in predicting episodic memory. Furthermore, individuals with a negative brain-cognition gap (where brain predictions underestimate actual performance) exhibited lower physical activity, lower education, and higher cardiovascular risk compared to those with a positive gap. This shows that knowledge of the brain-cognition gap provides insights into factors contributing to cognitive resilience. Further lower PET-derived measures of dopamine binding were linked to a greater brain-cognition gap, mediated by regional functional variability. Together, our study introduces the brain-cognitive gap, as a new marker, modulated by the dopamine system, to identify individuals at risk of compromised brain function.
Tetanus Toxoid Utilizes Dual-Faceted Anticancer Mechanism Through Targeting Tumoral Sialic Acids and Enhancing Cytotoxic CD4+ T cell Responses Against Pancreatic Cancer
Authors: Giurini Eileena F , Pappas Sam G , Gupta Kajal H
Published: November 2024

Pancreatic ductal adenocarcinoma (PDAC) remains profoundly resistant to conventional chemotherapy and immunotherapeutic interventions. Innovative therapeutic modalities, particularly microbe-derived immunotherapies, have demonstrated durable anti-tumor efficacy in preclinical PDAC models. This study elucidates that administration of the FDA-approved Haemophilus influenzae type b (H Flu - Hiberix) vaccine attenuates tumor progression and enhances survival outcomes in murine PDAC. H Flu treatment significantly augmented CD4+ T cell, CD8+ T cell, and natural killer (NK) cell infiltration within the tumor microenvironment, concurrently inducing a cytotoxic T cell phenotype, evidenced by upregulation of CD69, granzyme B, and perforin. Additionally, H Flu therapy promoted the accumulation of CD44+ CD62L-memory T cells within tumors of pre-immunized mice. Mechanistic investigations revealed that depletion of CD4+ T cells or NK cells, but not CD8+ T cells, negated the anti-tumor efficacy of H Flu, suggesting that CD4+ T cells and NK cells are critical mediators of H Flu-induced anti-tumor immunity. To further elucidate the mechanistic basis of H Flu’s anti-tumor activity, we assessed the individual constituents of the H Flu vaccine: tetanus toxoid (TT) and polyrobosyl ribitol phosphate (PRP). Notably, TT administration achieved superior tumor growth suppression, characterized by enhanced CD4+ T cell cytotoxicity and increased NK cell infiltration, relative to PRP or PBS-treated controls. Furthermore, TT induced apoptosis in PDAC cells and reduced their proliferation, potentially by targeting tumor-associated sialic acids. This disruption might interfere with the interaction between sialic acids and siglec receptors, thereby impairing mechanisms of immune evasion.TT-mediated modulation of sialic acid expression in cancer cells underscores its potential to augment immunotherapeutic efficacy in PDAC. Collectively, these findings reveal a novel anti-cancer mechanism for TT, leveraging both immunostimulatory and sialic acid-targeting pathways to suppress PDAC progression.

Graphical Abstract
An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer
Authors: Xie Wenyan , Yu Xin , Yang Qingxin , Ke Nengwen , Wang Ping , Kong Hao , Wu Xiangji , Ma Panpan , Chen Lang , Yang Jie , Feng Xiuqing , Wang Yuan , Shi Hubing , Chen Lu , Liu Yun-Hua , Ding Bi-Sen , Wei Qiang , Jiang Hong
Published: November 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly fibrotic and stiff tumor, and tumor-associated macrophages (TAMs) are pivotal in driving ECM remodeling, PDAC progression and immune evasion. The contribution of mechanical cues to monocyte differentiation into TAMs remains largely unexplored. Here we show that mechanical force is required for monocyte-to-macrophage differentiation. PYK2, as an innovative immunomechanical checkpoint, de facto governs this differentiation process. We demonstrated that PYK2 responds to mechanical signals within the tumor microenvironment (TME) via Piezo1 and integrins, leading to its activation and subsequent F-actin polymerization. Activated PYK2 then translocates to the nucleus, where it engages with promoters of genes governing mechanotransduction and differentiation, includingACTR3andRELA. Targeted deletion of PYK2 impairs the differentiation and polarization of monocyte-derived macrophages, reshapes the PDAC microenvironment, and enhances the efficacy of anti-PD-1 immunotherapy. These findings underscore the critical role of mechanical cues in monocyte differentiation and suggest that targeting PYK2 is a promising strategy to modulate TAM function and improve immunotherapy outcomes in patients with PDAC.
Beta-DIA: Integrating learning-based and function-based feature scores to optimize the proteome profiling of single-shot diaPASEF mass spectrometry data
Authors: Song Jian , Liu Hebin , Shen Chengpin , Wu Xiaohui
Published: November 2024

We present a freely available diaPASEF data analysis software, Beta-DIA, that utilizes deep learning methods to score coelution consistency in retention time-ion mobility dimensions and spectrum similarity. Beta-DIA integrates these learning-based scores with traditional function-based scores, enhancing the qualitative analysis performance. In some low detection datasets, Beta-DIA identifies twice as many protein groups as DIA-NN. The success of Beta-DIA has paved another way for the application of deep learning in fundamental proteome profiling.
Humidity-dependent structural adaptations ofDrosophila melanogasterhygrosensilla
Authors: Giri Ganesh , Enjin Anders
Published: November 2024

Understanding how organisms detect environmental humidity remains a fundamental problem in sensory biology. While specialized sensory neurons in insect antennae can detect changes in humidity, the mechanism underlying this ability is not fully understood. Here, we present an integrated approach combining precise humidity control, rapid cryo-preservation, and serial block-face scanning electron microscopy (SBF-SEM) to investigate the ultrastructure of hygrosensilla in the vinegar flyDrosophila melanogaster. We developed a deep learning-based segmentation pipeline to analyze three-dimensional structural features of sensilla exposed to different humidity conditions at stable temperature. Our analysis reveals consistent differences in sensilla width between high (80% RH) and low (26% RH) humidity conditions across all chambers of the sacculus. Additionally, we identified chamber-specific patterns in sensilla tapering, indicating specialized structural adaptations across different sensilla populations. The observed structural changes suggest a potential role for mechanical transduction in humidity sensing. This study establishes a technical framework for high-resolution analysis of sensory organs while providing new insights into the structural basis of humidity detection. Our findings advance our understanding of how specialized sensory organs might transduce environmental signals into neural responses.
Aggregation and disaggregation of red blood cells: depletion versus bridging
Authors: Moreno Nicolas , Korneev Kirill , Semenov Alexey , Topuz Alper , Jhon Thomas , Lettinga Minne Paul , Ellero Marco , Wagner Christian , Fedosov Dmitry A.
Published: November 2024

The aggregation of red blood cells (RBCs) is a complex phenomenon that strongly impacts blood flow and tissue perfusion. Despite extensive research for more than 50 years, physical mechanisms that govern RBC aggregation are still under debate. Two proposed mechanisms are based on bridging and depletion interactions between RBCs due to the presence of macromolecules in blood plasma. The bridging hypothesis assumes the formation of bonds between RBCs through adsorbing macromolecules, while the depletion mechanism results from the exclusion of macromolecules from the inter-cellular space, leading to effective attraction. Existing experimental studies generally cannot differentiate between these two aggregation mechanisms, though several recent investigations suggest concurrent involvement of the both mechanisms. We explore dynamic aggregation and disaggregation of two RBCs using three simulation models: a potential-based model mimicking depletion interactions, a bridging model with immobile bonds, and a new bridging model with mobile bonds which can slide along RBC membranes. Simulation results indicate that dynamic aggregation of RBCs primarily arises from depletion interactions, while disaggregation of RBCs involves both mechanisms. The bridging model with mobile bonds reproduces well the corresponding experimental data, offering insights into the interplay between bridging and depletion interactions and providing a framework for studying similar interactions between other biological cells.
Slow and fast gamma oscillations show phase-amplitude coupling with distinct high-frequency bands in macaque primary visual cortex
Authors: Prabhu Pooja , Ray Supratim
Published: November 2024

Gamma oscillations (25-70 Hz) can be induced in the visual cortex by presenting stimuli like gratings. Large stimuli produce two distinct gamma oscillations in primate primary visual cortex (V1) – slow (25-40 Hz) and fast (40-70 Hz), possibly due to different interneuronal networks. While fast-gamma has been shown to strongly lock spikes, slow-gamma does not, and hence its role in cortical processing is unclear. Here, we studied potential influence of gamma rhythms on neural activity using phase-amplitude coupling (PAC). We recorded spikes, local field potential and electrocorticogram (ECoG) from V1 of two adult female monkeys while presenting stimuli that simultaneously induced both gamma rhythms, and developed a novel method that reduces the influence of spike-related-transient on PAC. Interestingly, while fast-gamma showed coupling with frequencies above 150 Hz, reflecting spike-locking, slow-gamma showed PAC in a distinct frequency range between 80-150 Hz, which was especially prominent in ECoG. PAC varied with orientation and spatial frequency in the same way as power in the respective frequency bands, confirming dissociation in the coupling of the two gamma rhythms. Thus, fast-gamma could be more involved in spike-locking, while slow-gamma could represent a modulatory signal acting by amplitude modulation between 80-150 Hz at a more global scale.

Significance Statement

Gamma oscillations in the visual cortex can be induced by stimuli like gratings, producing two distinct gamma oscillations: slow (20-40 Hz) and fast (40-70 Hz). While fast-gamma strongly locks spikes, the role of slow gamma is unclear. Oscillations have been proposed to influence processing through phase-amplitude coupling (PAC). We recorded spikes, local field potential (LFP) and electrocorticogram (ECoG) from female monkeys and developed a new method to study PAC. While fast-gamma showed PAC with 150-500 Hz, reflecting spike-locking, we found PAC between slow-gamma and 80-150 Hz, which was especially strong in ECoG. The two PAC signatures varied differently with stimulus, reflecting distinct origins. Thus, while fast-gamma could lock spikes, slow-gamma could modulate amplitudes between 80-150 Hz at a global scale.
Gaze when walking to grasp an object in the presence of obstacles
Authors: Voudouris Dimitris , Brenner Eli
Published: November 2024

People generally look at positions that are important for their current actions, such as objects they intend to grasp. What if there are obstacles on their path to such objects? We asked participants to walk into a room and pour the contents of a cup placed on a table into another cup elsewhere on the table. There were two small obstacles on the floor between the door and the table. There was a third obstacle on the table near the target cup. Participants mainly looked at the items on the table, but as they approached and entered the room they often looked at the floor near the obstacles, although there was nothing particularly informative to see there. They relied on peripheral vision and memory of where they had seen obstacles to avoid kicking the obstacles. From well before participants crossed the obstacles, they primarily looked at the object that they intended to grasp. We conclude that people look at positions at which they plan to interact with the environment in a specific manner, rather than at items that constrain such interactions.
Rho GTPases signaling mediates aggressiveness and differentiation in neuroblastoma tumors
Authors: Gómez-Muñoz María A. , Ojeda-Puertas Mónica , Luna-Ramírez Luis , Amador-Álvarez Aida , Rodríguez-Prieto Ismael , Cordero Varela Juan Antonio , Pardal Ricardo , Vega Francisco M.
Published: November 2024

Background

Neuroblastoma (NB) is a pediatric cancer with highly variable outcomes, necessitating improved understanding of the molecular pathways driving its progression. Intratumor cellular heterogeneity related to neural differentiation has emerged as a defining characteristic that can explain its aggressive behavior. Although recurrent driver mutations are not typically observed in these tumors, Rho GTPases signaling genes have been identified as one of the most frequently mutated in aggressive NB cases. Rho GTPases are key regulators of cell morphology, migration, and differentiation, yet their role in NB remains underexplored. This study aims to comprehensively evaluate the expression and clinical significance of Rho GTPase signaling networks in NB tumors.

Methods

We analyzed the expression profiles of Rho GTPases, their regulators, and effectors, across multiple NB patient cohorts. Gene expression correlations with clinical parameters were assessed, and bioinformatics analyses were employed to identify gene expression patterns and interactions in tumors. Functional studies were performed in NB cell lines and in vivo models to validate the role of key Rho GTPases, including Cdc42, in NB progression and differentiation.

Results

Our analysis revealed widespread dysregulation of Rho GTPase signaling in NB tumors. Specific GTPases, such asRHOAorRHOV, were upregulated in advanced disease stages, while others, includingRHOB,RHOUandCDC42, were downregulated and associated with poor prognosis. A minimal Rho-related gene signature was identified as a strong predictor of NB patient survival. Functional validation highlighted Cdc42 as a key regulator of NB differentiation, where its downregulation was necessary for maintaining the malignant, undifferentiated phenotype of NB cells. We also identifiedARHGAP31/CdGAP as a critical regulator of Cdc42 in NB progenitor cells, suggesting a mechanism for Cdc42 suppression in aggressive NB.

Conclusions

An important role for Rho GTPase signaling in NB progression is revealed, providing a foundation for further exploration of Rho GTPase-targeted therapies in NB. In particular, Cdc42 signaling intervene in the balance between differentiation and stemness in NB cells, suggesting specific signaling events controlling the identity and plasticity of NB cells.
Inactive structures of the vasopressin V2 receptor reveal distinct antagonist binding modes for Tolvaptan and Mambaquaretin toxin
Authors: Fouillen Aurélien , Bous Julien , Couvineau Pierre , Orcel Hélène , Mary Charline , Pierre Timothé , Mendre Christiane , Gilles Nicolas , Schulte Gunnar , Granier Sébastien , Mouillac Bernard
Published: November 2024

Abstract

Antagonists of the arginine-vasopressin (AVP) V2 receptor (V2R) are key therapeutic compounds to treat hyponatremia or polycystic kidney diseases. Compounds such as Tolvaptan (TVP) and Conivaptan are marketed drugs but their mechanisms of inhibition are not known. In addition, TVP presents unwanted side effects such as serious liver injury. Conivaptan also targets AVP V1a receptor subtype and thus is not selective to V2R. To develop novel molecules with less side effects and better selectivity, rational drug design based on experimental three-dimensional G protein-coupled receptor (GPCR) structures is a powerful and successful avenue. The lack of antagonist-bound V2R structures has however impaired this strategy for this GPCR. To fill this gap of knowledge, we solved here the cryo-electron microscopy structures of the vasopressin V2R in complex with two selective antagonists, the nonpeptide TVP and the green mamba snake Mambaquaretin toxin (MQ1). Both ligands, known to be competitive, bind into the orthosteric AVP binding site but with substantial differences. The small molecule binds deeper than MQ1, and directly contacts the toggle switch residue W2846.48in the transmembrane domain 6 (TM6), whereas the peptide Kunitz- fold toxin presents more extensive contacts with the receptor through additional interactions with extracellular and transmembrane residues. As anticipated from the pharmacological properties of TVP and MQ1, both structures represent inactive conformations of the V2R. Their comparison with those of the active AVP-bound V2R reveals the molecular mechanisms modulating receptor activity. Finally, the structure of the V2R bound to a mini-protein such as MQ1 opens a new pharmacology era in the field of water homeostasis and renal diseases.
Modelling the prebiotic origins of regulation & agency in evolving protocell ecologies
Authors: Shirt-Ediss Ben , Ferrero-Fernández Arián , De Martino Daniele , Bich Leonardo , Moreno Alvaro , Ruiz-Mirazo Kepa
Published: November 2024

How did natural systems develop the first mechanisms of regulation and what for? How could they turn into adaptive agents in a minimal (though deeply meaningful) biological sense? A novel simulation platform, ‘Araudia’, has been implemented to address these questions, which are deeply interrelated, in a prebiotic scenario where metabolically diverse protocells are allowed to modify their dynamic behaviour in response to changes in their boundary conditions (e.g., nutrient concentrations in the medium) and/or in the activity of other protocells, including cross-feeding relationships. We extend ‘consumer-resource models’ (CRMs) to a stochastic evolutionary framework in which novelty appearsbottom-up(i.e., from small changes at the individual protocell level), and a short-term memory may also come forth and spread in the population, to demonstrate that simple adaptive/learning processes can have relevant effects at somatic times (i.e., within the lifetime of single protocells). Our interest in exploring the interplay between metabolic-physiological aspects and ecological-evolutionary ones derives from the fact that it provides a complex causal domain, where various spatial and temporal scales intermingle, and where both theactualand thepotential(pathways/behaviours) must be considered. It is in such a complex domain where the appearance of regulation acquires full significance, as an effective means to navigate phenotypic spaces that become too big for unguided exploration, given the large number of possible functionalities (or functional states) accessible to each proto-cellular agent. The results obtained for several minimalist cases below show that, despite the non-trivial combination of --both endogenous and exogenous--factors involved in the constitution of regulatory mechanisms, these are bound to play a critical role in the survival of infra-biological systems, especially under rapidly changing environmental conditions that longer-term adaptive mechanisms would not be able to cope with.
Differential Engagement of Associative-Limbic and Sensorimotor Regions of the Cerebellum and Basal Ganglia in Explicit vs. Implicit Emotional Processing
Authors: Ceravolo Leonardo , Thomasson Marine , Constantin Ioana Medeleine , Chassot Émilie , Pierce Jordan , Cionca Alexandre , Grandjean Didier , Assal Frédéric , Péron Julie
Published: November 2024

Emotional prosody processing involves multiple brain regions, but the specific roles of the cerebellum and basal ganglia in explicit (conscious) and implicit (incidental) tasks are not well known or understood. This study investigated how the cerebellum and basal ganglia contribute to explicit (emotion categorization) and implicit (gender categorization) processing of emotional prosody. Twenty-eight healthy French-speaking participants underwent high-resolution functional MRI while performing a vocal emotion processing task under such implicit and explicit conditions. Behavioral data analyses indicated greater accuracy in the gender discrimination task (implicit processing). Neuroimaging partially supported our hypothesis according to which explicit emotion processing yielded increased activations in associative-limbic regions (e.g., inferior frontal gyrus, Crus I and caudate) linked to higher-order functions, while implicit emotion processing engaged sensorimotor regions (primary motor cortex, primary somatosensory cortex) and areas associated with automatic processing (putamen, posterior insula, cerebellar lobules VIIIa-b and IX). Unexpected activity during task conditions suggest motor preparation effects and more complex brain network dynamics. These results challenge modular views of brain function and highlight the need to consider emotional processing as complex, dynamic, network-based interactions.