bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary NTRK-rearranged Spindle Cell Neoplasm of the Gastrointestinal Tract: A Clinicopathological and Molecular Analysis of 8 Cases
Authors: Gao Xiaojiao , Xu Song , Zhu Peipei , Lao I. Weng , Yu Lin , Wang Jian
Published: March 2024

NTRK-rearranged spindle cell neoplasm occurs predominantly in the superficial or deep soft tissues of extremities or trunk. Occurrence in the visceral organs is extremely rare. Herein, we describe 8 cases of NTRK-rearranged spindle cell neoplasm that arose primarily in the gastrointestinal tract. Patients included 5 males and 3 females with age at presentation ranging from 6 to 63 years (median: 29.5 years). Tumors occurred in the colon (n=3), small intestine (n=2), rectum (n=2), and stomach (n=1). Tumor size ranged from 3.5 to 9 cm (median: 5 cm). Morphologically, 4 tumors were low-grade, composed of haphazard or intertwining fascicles of spindle cells, with prominent interstitial collagen fibers and ring-like perivascular hyalinization being present in 2 tumors. The other 4 tumors were histologically high-grade sarcomas, consisting of sweeping fascicles of atypical spindle cells showing increased cellularity and brisk mitotic activity. Immunohistochemically, 6/6 cases (100%) showed diffuse and strong cytoplasmic staining of pan-TRK. Variable expression of TrkA, CD34, and S100 was noted in 5/5 (100%), 5/8 (62.5%), and 4/7 (57.1%) cases, respectively. Fluorescence in situ hybridization analysis showed NTRK1 rearrangement (n=7) and NTRK2 rearrangement (n=1). In cases with available materials, RNA sequencing identified LMNA::NTRK1 (n=3), TPM3::NTRK1 (n=2), and STRN::NTRK2 (n=1) fusions. At follow-up (range: 4 to 30 months; median: 12.5 months), 6 of 7 patients who underwent surgery had no evidence of disease at last follow-up. One patient was succumbed to the disease at 12 months despite adjunctive treatment with TRK inhibitor larotrectinib after surgery. One patient was treated with larotrectinib alone. He showed significant response at 7 months after treatment. NTRK-rearranged spindle cell neoplasm represents an exceptionally rare entity in the gastrointestinal tract. The presence of interstitial collagen fibers and ring-like perivascular hyalinization and co-expression of CD34 and S100 are diagnostic clues to low-grade neoplasms. However, high-grade sarcomas pose a considerable diagnostic challenge to pathologists owing to the lack of specific features. The final diagnosis relies on molecular assays. Patients with advanced disease may benefit from TRK inhibitor treatment.
Metastatic Melanoma Treatment in Special Populations
Authors: Miceli Madeline , Boatwright Christina , Mehnert Janice M.
Published: March 2024

This review outlines the most up-to-date metastatic melanoma treatment recommendations and relevant risks for patients with solid organ transplants, patients with renal dysfunction, and patients with preexisting autoimmune conditions. These specific treatment populations were excluded from the original clinical trials, which studied immune checkpoint inhibitors and BRAF/MEK inhibitors in the advanced melanoma setting. We have synthesized the current body of literature, mainly case series and retrospective analyses, to reflect the evidence for the treatment of these special patient populations at present.
Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma
Authors: Los Christy , Klobuch Sebastian , Haanen John B. A. G.
Published: March 2024

Major progress in prolonging survival of patients with advanced melanoma has been made in the past decade because of the development and approval of immune checkpoint inhibitor and targeted therapies. However, for nonresponding or relapsing patients, their prognosis is still dismal. Based on clinical trial data, treatment with adoptive cell therapies holds great promise. In patients with metastatic melanoma progressing on or nonresponsive to single-agent anti–programmed cell death 1, infusion of tumor-infiltrating lymphocytes can produce responses in up to half of patients, with durable complete responses in up to 20%. Genetic modification of peripheral blood T cells with T-cell receptors derived from tumor-specific T cells, or with chimeric antigen receptors, has the potential to further improve treatment outcomes in this refractory population. In this review, we will discuss the historical development, current status, and future perspectives of adoptive T-cell therapies in melanoma.
Treatment of Stage III Resectable Melanoma—Adjuvant and Neoadjuvant Approaches
Authors: Tarhini Ahmad A. , Castellano Ella , Eljilany Islam
Published: March 2024

Patients with stage III resectable melanoma carry a high risk of melanoma recurrence that ranges from approximately 40% to 90% at 5 years following surgical management alone. Postoperative systemic adjuvant therapy targets residual micrometastatic disease that could be the source of future recurrence and death from melanoma. Randomized phase III adjuvant trials reported significant improvements in overall survival with high-dose interferon α in 2 of 3 studies (compared with observation and GMK ganglioside vaccine) and with anti–cytotoxic T-lymphocyte antigen 4 ipilimumab at 10 mg/kg compared with placebo and ipilimumab 3 mg/kg compared with high-dose interferon α. In the modern era, more recent phase III trials demonstrated significant recurrence-free survival improvements with anti–programmed cell death protein 1, pembrolizumab, and BRAF-MEK inhibitor combination dabrafenib-trametinib (for BRAF mutant melanoma) versus placebo. Furthermore, anti–programmed cell death protein 1, nivolumab and pembrolizumab have both been shown to significantly improve recurrence-free survival as compared with ipilimumab 10 mg/kg. For melanoma patients with clinically or radiologically detectable locoregionally advanced disease, emerging data support an important role for preoperative systemic neoadjuvant therapy. Importantly, a recent cooperative group trial (S1801) reported superior event-free survival rates with neoadjuvant versus adjuvant therapy. Collectively, current data from neoadjuvant immunotherapy and targeted therapy trials support a future change in clinical practice in favor of neoadjuvant therapy for eligible melanoma patients.
Current Role and Status for Intratumoral Injection Therapies in Metastatic Melanoma
Authors: Haugh Alexandra M. , Daud Adil I.
Published: March 2024

Intratumoral therapies represent a unique avenue for drug development in melanoma as patients often have accessible lesions that are particularly amenable to these approaches. In addition, a majority of intratumoral therapies have focused on stimulating antitumor immune responses, making them a particularly attractive option for use in melanoma. In this review, we describe applications for talimogene laherparepvec, a US Food and Drug Administration–approved intratumoral therapy in melanoma, as well as several classes of intratumoral therapies in development including novel oncolytic viruses, mRNA-based intratumoral injections, and cytokines and other signaling molecules.
What Is the Timing and Role of Targeted Therapy in Metastatic Melanoma?
Authors: Hadfield Matthew J. , Sullivan Ryan J.
Published: March 2024

Melanoma is the most lethal cutaneous malignancy worldwide. The last 15 years have ushered in several regulatory approvals that have dramatically altered the landscape of treatment options for patients with melanoma. Many patients with melanoma harbor activating mutations in the BRAF proto-oncogene, a key component of the mitogen-activated protein kinase (MAPK) intracellular signaling pathway. Therapies targeting BRAF have led to remarkable improvements in both response rates and survival in patients with metastatic disease. In parallel with these developments in MAPK-targeted therapy has been the clinical development of immune checkpoint inhibitors, which also have improved response rates and survival in patients with metastatic disease including randomized trials compared with MAPK-targeted therapy in patients with advanced, BRAF-mutant melanoma. Immune checkpoint inhibitors have become the preferred first-line standard-of-care treatment for patients with newly diagnosed metastatic disease in patients irrespective of BRAF mutational status. Given these developments, it is now less clear how to optimize the use of MAPK-targeted therapy regarding treatment setting and in sequence with immune checkpoint inhibitor.
An Executive Summary of the National Trauma Research Action Plan (NTRAP)
Authors: Bulger Eileen M. , Bixby Pamela J. , Price Michelle A. , Villarreal Cynthia Lizette , Moreno Ashley N. , Herrera-Escobar Juan Pablo , Bailey Jeffrey A. , Brasel Karen J. , Cooper Zara R. , Costantini Todd W. , Gibran Nicole S. , Groner Jonathan I. , Joseph Bellal A. , Newgard Craig D. , Stein Deborah M.
Published: March 2024

The National Trauma Research Action Plan (NTRAP) project successfully engaged multidisciplinary experts to define opportunities to advance trauma research and has fulfilled the recommendations related to trauma research from the National Academies of Sciences, Engineering and Medicine (NASEM) report. These panels identified more than 4,800 gaps in our knowledge regarding injury prevention and the optimal care of injured patients and laid out a priority framework and tools to support researchers to advance this field. Trauma research funding agencies and researchers can use this executive summary and supporting manuscripts to strategically address and close the highest priority research gaps. Given that this is the most significant public health threat facing our children, young adults, and military service personnel, we must do better in prioritizing these research projects for funding and providing grant support to advance this work. Through the Coalition for National Trauma Research (CNTR), the trauma community is committed to a coordinated, collaborative approach to address these critical knowledge gaps and ultimately reduce the burden of morbidity and mortality faced by our patients.
Reducing low-value interhospital transfers for mild traumatic brain injury
Authors: Shen Aricia , Mizraki Nathaniel , Maya Marcel , Torbati Sam , Lahiri Shouri , Chu Ray , Margulies Daniel R. , Barmparas Galinos
Published: March 2024

BACKGROUND

The modified Brain Injury Guidelines (mBIG) were developed to stratify traumatic brain injuries (TBIs) and improve health care utilization by selectively requiring repeat imaging, intensive care unit admission, and neurosurgical (NSG) consultation. The goal of this study is to assess safety and potential resource savings associated with the application of mBIG on interhospital patient transfers for TBI.

METHODS

Adult patients with TBI transferred to our Level I trauma center from January 2017 to December 2022 meeting mBIG inclusion criteria were retrospectively stratified into mBIG1, mBIG2, and mBIG3 based on initial clinicoradiological factors. At the time, our institution routinely admitted patients with TBI and intracranial hemorrhage (ICH) to the intensive care unit and obtained a repeat head computed tomography with NSG consultation, independent of TBI severity or changes in neurological examination. The primary outcome was progression of ICH on repeat imaging and/or NSG intervention. Secondary outcomes included length of stay and financial charges. Subgroup analysis on isolated TBI without significant extracranial injury was performed.

RESULTS

Over the 6-year study period, 289 patients were classified into mBIG1 (61; 21.1%), mBIG2 (69; 23.9%), and mBIG3 (159; 55.0%). Of mBIG1 patients, 2 (2.9%) had radiological progression to mBIG2 without clinical decline, and none required NSG intervention. Of mBIG2, 2 patients (3.3%) progressed to mBIG3, and both required NSG intervention. More than 35% of transferred patients had minor isolated TBI. For mBIG1 and mBIG2, the median hospitalization charges per patient were $152,296 and $149,550, respectively, and the median length of stay was 4 and 5 days, respectively, with the majority downgraded from the intensive care unit within 48 hours.

CONCLUSION

Clinically significant progression of ICH occurred infrequently in 1.5% of patients with mBIG1 and mBIG2 injuries. More than 35% of interfacility transfers for minor isolated TBI meeting mBIG1 and 2 criteria are low value and may potentially be safely deferred in an urban health care setting.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
To close or not to close? Wound management in emergent colorectal surgery, an EAST multicenter prospective cohort study
Authors: Feather Cristina B. , Rehrig Scott , Allen Rebecca , Barth Nadine , Kugler Emmalee M. , Cullinane Daniel C. , Falank Carolyne R. , Bhattacharya Bishwajit , Maung Adrian A. , Seng Sirivan , Ratnasekera Asanthi , Bass Gary Alan , Butler Dale , Pascual Jose L. , Srikureja Daniel , Winicki Nolan , Lynde Jennifer , Nowak Brittany , Azar Faris , Thompson Lauren A. , Nahmias Jeffry , Manasa Morgan , Tesoriero Ronald , Kumar Sandhya B. , Collom Morgan , Kincaid Michelle , Sperwer Kimberly , Santos Ariel P. , Klune J. Robert , Turcotte Justin
Published: March 2024

BACKGROUND

This study aimed to determine the clinical impact of wound management technique on surgical site infection (SSI), hospital length of stay (LOS), and mortality in emergent colorectal surgery.

METHODS

A prospective observational study (2021–2023) of urgent or emergent colorectal surgery patients at 15 institutions was conducted. Pediatric patients and traumatic colorectal injuries were excluded. Patients were classified by wound closure technique: skin closed (SC), skin loosely closed (SLC), or skin open (SO). Primary outcomes were SSI, hospital LOS, and in-hospital mortality rates. Multivariable regression was used to assess the effect of wound closure on outcomes after controlling for demographics, patient characteristics, intensive care unit admission, vasopressor use, procedure details, and wound class. A priori power analysis indicated that 138 patients per group were required to detect a 10% difference in mortality rates.

RESULTS

In total, 557 patients were included (SC, n = 262; SLC, n = 124; SO, n = 171). Statistically significant differences in body mass index, race/ethnicity, American Society of Anesthesiologist scores, EBL, intensive care unit admission, vasopressor therapy, procedure details, and wound class were observed across groups. Overall, average LOS was 16.9 ± 16.4 days, and rates of in-hospital mortality and SSI were 7.9% and 18.5%, respectively, with the lowest rates observed in the SC group. After risk adjustment, SO was associated with increased risk of mortality (OR, 3.003; p = 0.028) in comparison with the SC group. Skin loosely closed was associated with increased risk of superficial SSI (OR, 3.439; p = 0.014), after risk adjustment.

CONCLUSION

When compared with the SC group, the SO group was associated with mortality but comparable when considering all other outcomes, while the SLC was associated with increased superficial SSI. Complete skin closure may be a viable wound management technique in emergent colorectal surgery.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Corpus callosum and cerebellum participate in semantic dysfunction of Parkinson’s disease: a diffusion tensor imaging-based cross-sectional study
Authors: Liu Hang , Zhong Yuke , Liu Guohui , Su Huahua , Liu Zhihui , Wei Jiahao , Mo Lijuan , Tan Changhong , Liu Xi , Chen Lifen
Published: March 2024

Language dysfunction is common in Parkinson’s disease (PD) patients, among which, the decline of semantic fluency is usually observed. This study aims to explore the relationship between white matter (WM) alterations and semantic fluency changes in PD patients. 127 PD patients from the Parkinson’s Progression Markers Initiative cohort who received diffusion tensor imaging scanning, clinical assessment and semantic fluency test (SFT) were included. Tract-based special statistics, automated fiber quantification, graph-theoretical and network-based analyses were performed to analyze the correlation between WM structural changes, brain network features and semantic fluency in PD patients. Fractional anisotropy of corpus callosum, anterior thalamic radiation, inferior front-occipital fasciculus, and uncinate fasciculus, were positively correlated with SFT scores, while a negative correlation was identified between radial diffusion of the corpus callosum, inferior longitudinal fasciculus, and SFT scores. Automatic fiber quantification identified similar alterations with more details in these WM tracts. Brain network analysis positively correlated SFT scores with nodal efficiency of cerebellar lobule VIII, and nodal local efficiency of cerebellar lobule X. WM integrity and myelin integrity in the corpus callosum and several other language-related WM tracts may influence the semantic function in PD patients. Damage to the cerebellum lobule VIII and lobule X may also be involved in semantic dysfunction in PD patients.
CXCL13/CXCR5 promote chronic postsurgical pain and astrocyte activation in rats by targeting NLRP3
Authors: Yi Hongda , Zhu Bin , Zheng Caihong , Ying Zhenyang , Cheng Mei
Published: March 2024

Chronic postsurgical pain (CPSP) with high incidence negatively impacts the quality of life. X-C motif chemokine 13 (CXCL13) has been associated with postsurgery inflammation and exacerbates neuropathic pain in patients with CPSP. This study was aimed to illustrate the relationship between CXCL13 and nod-like receptor protein-3 (NLRP3), which is also involved in CPSP. A CPSP model was constructed by skin/muscle incision and retraction (SMIR) in right medial thigh, and the rats were divided into three groups: Sham, SMIR, and SMIR + anti-CXCL13 (intrathecally injected with anti-CXCL13 antibody). Then, the paw withdrawal threshold (PWT) score of rats was recorded. Primary rat astrocytes were isolated and treated with recombinant protein CXCL13 with or without NLRP3 inhibitor INF39. The expressions of CXCL13, CXCR5, IL-1β, IL-18, GFAP, NLRP3, and Caspase-1 p20 were detected by real-time quantitative reverse transcription PCR, western blot, ELISA, immunocytochemistry, and immunofluorescence analyses. The anti-CXCL13 antibody alleviated SMIR-induced decreased PWT and increased expression of GFAP, CXCL13, CXCR5, NLRP3, and Caspase-1 p20 in spinal cord tissues. The production of IL-1β, IL-18, and expression of CXCL13, CXCR5, GFAP, NLRP3, and Caspase-1 p20 were increased in recombinant protein CXCL13-treated primary rat astrocytes in a dose-dependent manner. Treatment with NLRP3 inhibitor INF39 inhibited the function of recombinant protein CXCL13 in primary rat astrocytes. The CXCL13/CXCR5 signaling could promote neuropathic pain, astrocytes activation, and NLRP3 inflammasome activation in CPSP model rats by targeting NLRP3. NLRP3 may be a potential target for the management of CPSP.
Nerolidol reduces depression-like behavior in mice and suppresses microglia activation by down-regulating DNA methyltransferase 1
Authors: Zhang Guangcai , Zhou Xiaohui , Feng Qifan , Ke Weihua , Pan Jiahui , Zhang Haiying , Luan Yixian , Lei Beibei
Published: March 2024

Modern medicine has unveiled that essential oil made from Aquilaria possesses sedative and hypnotic effects. Among the chemical components in Aquilaria, nerolidol, a natural sesquiterpene alcohol, has shown promising effects. This study aimed to unravel the potential of nerolidol in treating depression. Chronic unpredictable mild stress (CUMS) was utilized to induce depression-like behavior in mice, and open field test, sucrose preference, and tail suspension test was conducted. The impacts of nerolidol on the inflammatory response, microglial activation, and DNA methyltransferase 1 (DNMT1) were assessed. To study the regulatory role of DNMT1, lipopolysaccharide (LPS) was used to treat BV2 cells, followed by the evaluation of cell viability and DNMT1 level. Additionally, the influence of DNMT1 overexpression on BV2 cell activation was determined. Behavioral analysis revealed that nerolidol reduced depression-like behavior in mice. Nerolidol reduced the levels of inflammatory factors and microglial activation caused by CUMS. Nerolidol treatment was found to reduce DNMT1 levels in mouse brain tissue and it also decrease the LPS-induced increase in DNMT1 levels in BV2 cells. DNMT1 overexpression reversed the impacts of nerolidol on the inflammation response and cell activation. This study underscores the potential of nerolidol in reducing CUMS-induced depressive-like behavior and inhibiting microglial activation by downregulating DNMT1. These findings offer valuable insights into the potential of nerolidol as a therapeutic option for depression.
Opportunities and limits of lunar gravitational-wave detection
Authors: Cozzumbo Andrea , Mestichelli Benedetta , Mirabile Marco , Paiella Lavinia , Tissino Jacopo , Harms Jan
Published: March 2024

A new era of lunar exploration has begun with participation of all major space agencies. This activity brings opportunities for revolutionary science experiments and observatories on the Moon. The idea of a lunar gravitational-wave detector was already proposed during the Apollo programme. The key characteristic of the Moon is that it is seismically extremely quiet. It was also pointed out that the permanently shadowed regions at the lunar poles provide ideal conditions for gravitational-wave detection. In recent years, three different detector concepts were proposed with varying levels of technological complexity and science potential. In this paper, we confront the three concepts in terms of their observational capabilities based on a first more detailed modelling of instrumental noise. We identify important technological challenges and potential show-stoppers.

This article is part of a discussion meeting issue ‘Astronomy from the Moon: the next decades (part 2)’.
Modes of the Dark Ages 21 cm field accessible to a lunar radio interferometer
Authors: Bull Philip , Guandalin Caroline , Addis Chris
Published: March 2024

At redshifts beyondz≳30, the 21 cm line from neutral hydrogen is expected to be essentially the only viable probe of the three-dimensional matter distribution. The lunar far-side is an extremely appealing site for future radio arrays that target this signal, as it is protected from terrestrial radio frequency interference, and has no ionosphere to attenuate and absorb radio emission at low frequencies (tens of MHz and below). We forecast the sensitivity of low-frequency lunar radio arrays to the bispectrum of the 21 cm brightness temperature field, which can in turn be used to probe primordial non-Gaussianity generated by particular early universe models. We account for the loss of particular regions of Fourier space due to instrumental limitations and systematic effects, and predict the sensitivity of different representative array designs to local-type non-Gaussianity in the bispectrum, parametrized byfNL. Under the most optimistic assumption of sample variance-limited observations, we find thatσ(fNL)≲0.01could be achieved for several broad redshift bins atz≳30if foregrounds can be removed effectively. These values degrade to betweenσ(fNL)∼0.03and 0.7 forz=30toz=170, respectively, when a large foreground wedge region is excluded.

This article is part of a discussion meeting issue ‘Astronomy from the Moon: the next decades (part 2)’.
Modelling science return from the lunar crater radio telescope on the far side of the moon
Authors: Pisanti Dario , Goel Ashish , Gupta Gaurangi , Arya Manan , Byron Benjamin , Chahat Nacer , Lazio Joseph , Goldsmith Paul , Bandyopadhyay Saptarshi
Published: March 2024

The era following the separation of CMB photons from matter, until the emergence of the first stars and galaxies, is known as the Cosmic Dark Ages. Studying the electromagnetic radiation emitted by neutral hydrogen having the 21 cm rest wavelength is the only way to explore this significant phase in the Universe’s history, offering opportunities to investigate essential questions about dark matter physics, the standard cosmological model and inflation. Due to cosmological redshift, this signal is now only observable at frequencies inaccessible from the Earth’s surface due to ionospheric absorption and reflection. With the Lunar Crater Radio Telescope (LCRT), we aim to conduct unprecedented measurements of the sky-averaged redshifted signal spectrum in the 4.7–47 MHz band, by deploying a 350 m diameter parabolic reflector mesh inside a lunar crater on the far side of the Moon and suspending a receiver at its focus. This work discusses the feasibility of the LCRT science goals through the development of a science model, with emphasis on post-processing techniques to extract the Dark Ages signal from the galactic foreground dominating the expected raw data. This model can be used to vary critical instrument and mission parameters to understand their effect on the quality of the retrieved signal.

This article is part of a discussion meeting issue ‘Astronomy from the Moon: the next decades (part 2)’.
Potential and perils: paths to protecting lunar sites of extraordinary scientific importance (SESIs) for astronomy before it is too late
Authors: Krolikowski Alanna , Elvis Martin
Published: March 2024

The Moon presents unique opportunities for high-impact astronomy that could enhance our understanding of our solar system, the possibility of life beyond Earth, and the evolution of the universe. A handful of locations on the lunar surface are ‘sites of extraordinary scientific importance’ (SESIs) for such studies, presenting opportunities for astronomical research unmatched anywhere else. For instance, the farside of the Moon, the most radio-quiet location in the inner solar system, could allow for the emplacement of telescopes to study the cosmic Dark Ages in ways that are impossible elsewhere. However, we are also on the cusp of a broader lunar renaissance. A flurry of upcoming missions, both scientific and non-scientific, will target some of these very same sites and threatens to degrade their value to science. Protecting these sites is an urgent matter. Two major international efforts to create rules for activities on the Moon are afoot, but so far neither emphasizes protecting SESIs. To safeguard the exceptional scientific opportunities on the Moon, astronomers should engage these international rulemaking efforts and steer them towards ensuring the preservation of SESIs for research and discovery. We propose elements of a programme of action to adopt during a crucial, but closing, window.

This article is part of a discussion meeting issue ‘Astronomy from the Moon: the next decades (part 2)’.
X-ray astronomy from the lunar surface
Authors: Gandhi Poshak
Published: March 2024

Motivated by efforts to return humanity to the Moon, three cases are reviewed for X-ray astronomy from the lunar surface: (i) facilitation of ambitious engineering designs including high-throughput telescopes, long focal length optics and X-ray interferometery; (ii) occultation studies and the gain they enable in astrometric precision; and (iii) multi-messenger time-domain coordinated observations. The potential benefits of, and challenges presented by, operating from the Moon are discussed. Some of these cases have relatively low mass budgets and could be conducted as early pathfinders, while others are more ambitious and will likely need to await improvements in technology or well-developed lunar bases.

This article is part of a discussion meeting issue ‘Astronomy from the Moon: the next decades (part 2)’.
Unveiling the control of N and P on DOM fate in a Mediterranean coastal environment
Authors: Dignan Clara , Lenoble Véronique , Santinelli Chiara , Bachi Giancarlo , Dang Duc Huy , Garcia Nicole , Misson Benjamin
Published: March 2024

Dissolved organic matter (DOM) and heterotrophic prokaryotes (HP) are key players in the oceanic carbon cycle. Although several biotic and abiotic factors controlling DOM fates are known, the hierarchy of their respective influences is still debated. Two contrasting Mediterranean coastal sites were sampled: a harbour under strong continental and anthropogenic influence (T) and an open coastal area (G). Interestingly, similar dissolved organic carbon (DOC) concentrations were observed in both samples. However, they showed marked differences in dissolved inorganic nitrogen and organic phosphorus concentrations (60-fold and 80% higher value in T), as well as in DOM optical properties and molecular composition. Incubation experiments were performed to expose the HP communities of each site to dissolved substances from T and G for three weeks. DOC removal was similar (−10 %) regardless HP origin and dissolved substances characteristics. HP growth and their maximal abundance were higher (+ 300 %) with dissolved substances from T, regardless HP origins. This indicates different fates of DOC processed by microbial communities as a function of abiotic determinants. Higher HP growth was associated to elevated initial content and higher consumption of inorganic nitrogen, organic phosphorus, three fluorescent DOM components, nitrogen-containing molecules and carbohydrates. These results provide insights into the main drivers of marine DOM fate: at similar DOC concentrations and low inorganic P concentrations. We evience the preferential consumption of lignin-like compounds where theoretically more labile molecules were available, thus reinforcing the need of in depth molecular studies for a better understanding of DOM-microbes interactions in the ocean.
Machine learning predicts lifespan and underlying causes of death in agingC. elegans
Authors: Kern Carina C. , Manescu Petru , Cuffaro Matt , Au Catherine , Zhang Aihan , Wang Hongyuan , Gilliat Ann F. , Ezcurra Marina , Gems David
Published: March 2024

Senescence (aging) leads to senescent pathology that causes death, and genes control aging by determining such pathology. Here we investigate how senescent pathology mediates the effect of genotype on lifespan inC. elegansby means of a data-driven approach, using machine learning (ML). To achieve this we gathered extensive data on how diverse determinants of lifespan (sex, nutrition, genotype) affect patterns of age-related pathology. Our findings show that different life-extending treatments result in distinct patterns of suppression of senescent pathology. By analysing the differential effects on pathology and lifespan, our ML models were able to predict >70% of lifespan variation. Extent of pathology in the pharynx and intestine were the most important predictors of lifespan, arguing that elderlyC. elegansdie in part due to late-life disease in these organs. Notably, the mid-life pathogenetic burst characteristic of hermaphrodite senescence is absent from males.
RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity
Authors: Singh Shivendra , Fang Jie , Jin Hongjian , Van de Velde Lee-Ann , Wu Qiong , Cortes Andrew , Morton Christopher L. , Woolard Mary A. , Quarni Waise , Steele Jacob A. , Connelly Jon P. , He Liusheng , Thorne Rebecca , Turner Gregory , Confer Thomas , Johnson Melissa , Caufield William V. , Freeman Burgess B. , Lockey Timothy , Pruett-Miller Shondra M. , Wang Ruoning , Davidoff Andrew M. , Thomas Paul G. , Yang Jun
Published: March 2024

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage–specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.
Localized network damage related to white matter hyperintensities is linked to worse outcome after severe stroke
Authors: Olszówka Samuel C , Frey Benedikt M , Frontzkowski Lukas , Wróbel Paweł P , Backhaus Winifried , Higgen Focko L , Braaß Hanna , Wolf Silke , Choe Chi-un , Bönstrup Marlene , Cheng Bastian , Thomalla Götz , Koch Philipp J , Quandt Fanny , Gerloff Christian , Schulz Robert
Published: March 2024

White matter hyperintensities of presumed vascular origin (WMH), a manifestation of cerebral small vessel disease, are associated with various clinical sequelae. In stroke patients, total WMH burden is linked to recurrent cerebrovascular events and worse clinical outcome. As WMH also affect the integrity of structural large-scale brain networks, we hypothesize that the extent of WMH-related network damage carries relevant information to explain outcome variability in addition to global WMH volume. Clinical and structural brain imaging data of 33 severely affected acute stroke patients were analysed from two independent cohorts. Imaging data were acquired within the first two weeks after stroke. WMH-related localized and global network damage was derived, involving cortical and subcortical brain regions of an extended motor network. Using ordinal logistic regression analyses, network damage was associated with functional outcome, operationalized by the modified Rankin Scale, at follow-up after three to six months. WMH were linked to a significant disconnection of multiple ipsilesional and contralesional cortical and subcortical brain regions. Global as well as localized periventricular WMH-related network damage affecting distinct brain regions of both hemispheres, including the precentral and the inferior frontal gyrus, areas of the dorsolateral prefrontal cortex, the insula, and multiple subcortical nuclei, was independently associated with a worse outcome after adjustment for baseline symptom burden, age, brain infarct volume and total WMH volume. Total and deep WMH-related network disturbances did not show similar associations. This study shows that periventricular WMH-related network damage affecting specific brain regions of the frontal and insular lobe, and subcortical nuclei is linked to functional outcome in acute stroke patients. This supports the evolving concept of structural brain reserve and underscores the potential significance of pre-existing WMH-related network damage as a crucial factor in comprehending outcome variability after severe stroke.
Signal-independent activation reveals two-component regulatory networks
Authors: Claverie Cosme , Coppolino Francesco , Mazzuoli Maria-Vittoria , Guyonnet Cécile , Jacquemet Elise , Legendre Rachel , Sismeiro Odile , De Gaetano Giuseppe Valerio , Teti Giuseppe , Trieu-Cuot Patrick , Tazi Asmaa , Beninati Concetta , Firon Arnaud
Published: March 2024

Each bacterial species has specific regulatory systems to control physiology, adaptation, and host interactions. One challenge posed by this diversity is to define the evolving gene regulatory networks. This study aims to characterise two-component systems (TCS) inStreptococcus agalactiae, the main cause of neonatal meningitis. Here we demonstrate signal-independent activation of signalling pathways by systematically targeting the conserved mechanism of phosphatase activity of the 14 histidine kinases of the two main TCS families. Transcriptomic analysis resolves most pathways with high resolution, encompassing specialized, connected, and global regulatory systems. The activated network notably reveals the connection between CovRS and SaeRS signaling through the adhesin PbsP, linking the main regulators of host interactions to balance pathogenicity. Additionally, constitutive activation of the BceRS system reveals its role in cell envelope homeostasis beyond antimicrobial resistance. Overall, this study demonstrates the generalizability and versatility of TCS genetic activation to uncover regulatory logics and biological processes.
Detecting microbiome species unique or enriched in 20+ cancer types and building cancer microbiome heterogeneity networks
Authors: Ma Zhanshan (Sam) , Li Lianwei , Mei Jiandong
Published: March 2024

It is postulated that tumor tissue microbiome is one of the enabling characteristics that either promote or suppress cancer cells and tumors to acquire certain hallmarks (functional traits) of cancers, which highlights their critical importance to carcinogenesis, cancer progression and therapy responses. However, characterizing the tumor microbiomes is extremely challenging because of their low biomass and severe difficulties in controlling laboratory-borne contaminants, which is further aggravated by lack of comprehensively effective computational approaches to identify unique or enriched microbial species associated with cancers. Here we take advantages of two recent computational advances, one by Pooreet al(2020,Nature) that computationally generated the microbiome datasets of 33 cancer types [of 10481 patients, including primary tumor (PT), solid normal tissue (NT), and blood samples] from whole-genome and whole-transcriptome data deposited in “The Cancer Genome Atlas” (TCGA), another termed “specificity diversity framework” (SDF) developed recently by Ma (2023). By reanalyzing Poore’s datasets with the SDF framework, further augmented with complex network analysis, we produced the following catalogues of microbial species (archaea, bacteria and viruses) with statistical rigor including unique species (USs) and enriched species (ESs) in PT, NT, or blood tissues. We further reconstructed species specificity network (SSN) and cancer microbiome heterogeneity network (CHN) to identify core/periphery network structures, from which we gain insights on the codependency of microbial species distribution on landscape of cancer types, which seems to suggest that the codependency appears to be universal across all cancer types.
Surface Hydrophilicity Promotes Bacterial Twitching Motility
Authors: O’Hara Megan T. , Shimozono Tori M. , Dye Keane J. , Harris David , Yang Zhaomin
Published: March 2024

Twitching motility is a form of bacterial surface translocation powered by the type IV pilus (T4P). It is frequently analyzed by interstitial colony expansion between agar and the polystyrene surfaces of Petri dishes. In such assays, the twitching motility ofAcinetobacter nosocomialiswas observed with MacConkey but not Luria-Bertani (LB) agar media. One difference between these two media is the presence of bile salts as a selective agent in MacConkey but not in LB. Here, we demonstrate that the addition of bile salts to LB allowedA. nosocomialisto display twitching. Similarly, bile salts enhanced the twitching ofAcinetobacter baumanniiandPseudomonas aeruginosain LB. These observations suggest that there is a common mechanism whereby bile salts enhance bacterial twitching and promote interstitial colony expansion. Bile salts disrupt lipid membranes and apply envelope stress as detergents. Surprisingly, their stimulatory effect on twitching appears not to be related to a bacterial physiological response to stressors. Rather it is due to their ability to alter the physicochemical properties of a twitching surface. We observed that while other detergents promoted twitching like bile salts, stresses applied by antibiotics, including the outer membrane-targeting polymyxin B, did not enhanced twitching motility. More importantly, bacteria displayed increased twitching on hydrophilic surfaces such as those of glass and tissue culture-treated polystyrene plastics, and bile salts no longer stimulated twitching on these surfaces. Together, our results show that altering the hydrophilicity of a twitching surface significantly impacts T4P functionality.

Importance

The bacterial type IV pilus (T4P) is a critical virulence factor for many medically important pathogens, some of which are prioritized by the World Health Organization for their high levels of antibiotic resistance. The T4P is known to propel bacterial twitching motility, providing a convenient assay for T4P functionality. Here, we show that bile salts and other detergents augment the twitching of multiple bacterial pathogens. We identified the underlying mechanism as the alteration of surface hydrophilicity by detergents. Consequently, hydrophilic surfaces such as those of glass or plasma-treated polystyrene promote bacterial twitching, bypassing the requirement for detergents. The implication is that surface properties, such as those of tissues and medical implants, significantly impact the functionality of bacterial T4P as a virulence determinant. This offers valuable insights for developing countermeasures against the colonization and infection by bacterial pathogens of critical importance to human health on a global scale.
CMG helicase disassembly is essential and driven by two pathways in budding yeast
Authors: Rivera Cristian Polo , Deegan Tom D. , Labib Karim P.M.
Published: March 2024

The CMG helicase is the metastable core of the eukaryotic replisome and is ubiquitylated and disassembled during DNA replication termination. Fungi and animals use different enzymes to ubiquitylate the Mcm7 subunit of CMG, indicating that CMG ubiquitylation arose repeatedly during eukaryotic evolution. Until now, it was unclear whether cells also have ubiquitin-independent pathways for helicase disassembly and whether CMG disassembly is essential for cell viability. Using reconstituted assays with budding yeast CMG, we generated themcm7-10Rallele that compromises ubiquitylation by SCFDia2.mcm7-10Rdelays helicase disassemblyin vivo, driving genome instability in the next cell cycle. These data indicate that defective CMG ubiquitylation explains the major phenotypes of cells lacking Dia2. Notably, the viability ofmcm7-10Randdia2Δis dependent upon the related Rrm3 and Pif1 DNA helicases that have orthologues in all eukaryotes. We show that Rrm3 acts during S-phase to disassemble old CMG complexes from the previous cell cycle. These findings indicate that CMG disassembly is essential in yeast cells and suggest that Pif1-family helicases might have mediated CMG disassembly in ancestral eukaryotes.
Design of a sequestration-based network with tunable pulsing dynamics
Authors: Nakamura Eiji , Cuba Samaniego Christian , Blanchini Franco , Giordano Giulia , Franco Elisa
Published: March 2024

Incoherent feedforward networks exhibit the ability to generate temporal pulse behavior. However, exerting control over specific dynamic properties, such as amplitude and rise time, poses a challenge and is intricately tied to the network’s implementation. In this study, we focus on analyzing sequestration-based networks capable of exhibiting pulse behavior. By employing time-scale separation in the fast sequestration regime, we approximate the temporal dynamics of these networks. This approach allows us to establish a mapping that elucidates the impact of varying the kinetic rates and pulse specifications, including amplitude and rise time. Furthermore, we introduce a positive feedback mechanism to regulate the amplitude of the pulsing response.
Adolescents flexibly adapt action selection based on controllability inferences
Authors: Raab Hillary A. , Goldway Noam , Foord Careen , Hartley Catherine A.
Published: March 2024

From early in life, we encounter both controllable environments, in which our actions can causally influence the reward outcomes we experience, and uncontrollable environments, in which they cannot. Environmental controllability is theoretically proposed to organize our behavior. In controllable contexts, we can learn to proactively select instrumental actions that bring about desired outcomes. In uncontrollable environments, Pavlovian learning enables hard-wired, reflexive reactions to anticipated, motivationally salient events, providing “default” behavioral responses. Previous studies characterizing the balance between Pavlovian and instrumental learning systems across development have yielded divergent findings, with some studies observing heightened expression of Pavlovian learning during adolescence and others observing a reduced influence of Pavlovian learning during this developmental stage. In this study, we aimed to investigate whether a theoretical model of controllability-dependent arbitration between learning systems might explain these seemingly divergent findings in the developmental literature, with the specific hypothesis that adolescents’ action selection might be particularly sensitive to environmental controllability. To test this hypothesis, 90 participants, aged 8–27, performed a probabilistic-learning task that enables estimation of Pavlovian influence on instrumental learning, across both controllable and uncontrollable conditions. We fit participants’ data with a reinforcement-learning model in which controllability inferences adaptively modulate the dominance of Pavlovian versus instrumental control. Relative to children and adults, adolescents exhibited greater flexibility in calibrating the expression of Pavlovian bias to the degree of environmental controllability. These findings suggest that sensitivity to environmental reward statistics that organize motivated behavior may be heightened during adolescence.
Phenomenology of axionlike particles with universal fermion couplings revisited
Authors: Garcia Giovani Dalla Valle , Kahlhoefer Felix , Ovchynnikov Maksym , Zaporozhchenko Andrii
Published: March 2024

Axionlike particles (ALPs) emerge in many extensions of the Standard Model as pseudo-Goldstone bosons of a spontaneously broken global symmetry. Understanding their phenomenology in high-energy collisions is crucial for optimizing experimental searches and understanding the exploration potential of future experiments. In this paper, we revise the phenomenology of ALPs with universal couplings to fermions. In particular, we analyze the hierarchy and uncertainty of the various ALP production channels depending on the proton collision energy and the placement of the experiment, and provide improved calculations of the hadronic decay modes.

Published by the American Physical Society
2024
Free fermionic webs of heterotic
T
folds
Authors: Faraggi Alon E. , Groot Nibbelink Stefan , Percival Benjamin
Published: March 2024

Moduli stabilization is key to obtaining phenomenologically viable string models. Nongeometric compactifications, like T-duality orbifolds (T folds), are capable of freezing many moduli. However, in this paper we emphasize that T folds, admitting free fermionic descriptions, can be associated with a large number of different T folds with varying number of moduli, since the fermion pairings for bosonization are far from unique. Consequently, in one description a fermionic construction might appear to be asymmetric, and hence nongeometric, while in another it admits a symmetric orbifold description. We introduce the notion of intrinsically asymmetric T folds for fermionic constructions that do not admit any symmetric orbifold description after bosonization. Finally, we argue that fermion symmetries induce mappings in the bosonized description that extend the T-duality group.

Published by the American Physical Society
2024