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Abstract Proteins containing both intrinsically disordered regions (IDRs) and RNA binding domains (RBDs) can phase separate in vitro, forming bodies similar to cellular biomolecular condensates. However, how IDR and RBD domains contribute to in vivo recruitment of proteins to biomolecular condensates remains poorly understood. Here, we analyzed the roles of IDRs and RBDs in L-bodies, biomolecular condensates present in Xenopus oocytes. We show that a cytoplasmic isoform of hnRNPAB, which contains two RBDs and an IDR, is highly enriched in L-bodies. While both of these domains contribute to hnRNPAB self-association and phase separation in vitro and mediate enrichment into L-bodies in oocytes, neither the RBDs nor the IDR replicate the localization of full-length hnRNPAB. Our results suggest a model where the combined effects of the IDR and RBDs regulate hnRNPAB partitioning into L-bodies. This model likely has widespread applications as proteins containing RBD and IDR domains are common biomolecular condensate residents.

Abstract Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

Objective To investigate the effect of the covid-19 pandemic on the number of patients with group A streptococcal infections and related antibiotic prescriptions.Design Retrospective cohort study in England using OpenSAFELY-TPP.Setting Primary care practices in England that used TPP SystmOne software, 1 January 2018 to 31 March 2023, with the approval of NHS England.Participants Patients registered at a TPP practice at the start of each month of the study period. Patients with missing data for sex or age were excluded, resulting in a population of 23 816 470 in January 2018, increasing to 25 541 940 by March 2023.Main outcome measures Monthly counts and crude rates of patients with group A streptococcal infections (sore throat or tonsillitis, scarlet fever, and invasive group A streptococcal infections), and recommended firstline, alternative, and reserved antibiotic prescriptions linked with a group A streptococcal infection before (pre-April 2020), during, and after (post-April 2021) covid-19 restrictions. Maximum and minimum count and rate for each infectious season (time from September to August), as well as the rate ratio of the 2022-23 season compared with the last comparably high season (2017-18).Results The number of patients with group A streptococcal infections, and antibiotic prescriptions linked to an indication of group A streptococcal infection, peaked in December 2022, higher than the peak in 2017-18. The rate ratios for monthly sore throat or tonsillitis (possible group A streptococcal throat infection), scarlet fever, and invasive group A streptococcal infection in 2022-23 relative to 2017-18 were 1.39 (95% confidence interval (CI) 1.38 to 1.40), 2.68 (2.59 to 2.77), and 4.37 (2.94 to 6.48), respectively. The rate ratio for prescriptions of first line, alternative, and reserved antibiotics to patients with group A streptococcal infections in 2022-23 relative to 2017-18 were 1.37 (95% CI 1.35 to 1.38), 2.30 (2.26 to 2.34), and 2.42 (2.24 to 2.61), respectively. For individual antibiotic prescriptions in 2022-23, azithromycin showed the greatest relative increase versus 2017-18, with a rate ratio of 7.37 (6.22 to 8.74). This finding followed a marked decrease in the recording of patients with group A streptococcal infections and associated prescriptions during the period of covid-19 restrictions where the maximum count and rates were lower than any minimum rates before the covid-19 pandemic.Conclusions Recording of rates of scarlet fever, sore throat or tonsillitis, and invasive group A streptococcal infections, and associated antibiotic prescribing, peaked in December 2022. Primary care data can supplement existing infectious disease surveillance through linkages with relevant prescribing data and detailed analysis of clinical and demographic subgroups.

Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%–26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6–34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor. Plain Language Summary The integrity of the human genome is maintained via multiple pathways of DNA repair, one of the most important of which is homologous recombination repair (HRR), which uses a sister chromatid as a template for high-fidelity restoration of altered DNA sequences. This study aimed to determine the prevalence of deleterious mutations, i.e., changes in the genetic code that interfere with proper cellular function, in the breast cancer genes BRCA1 and BRCA2 and in 13 other genes involved in HRR in various types of solid tumors in patients with advanced or metastatic cancer. The researchers found that 4.7% of tumor samples had BRCA1/2 mutations, 13.6% had mutations in any of the HRR genes and 20.6% had genomic loss of heterozygosity (gLOH) of at least 16% i.e., loss of sections of chromosomes affecting 16% or more of the genome. BRCA1/2 mutations were most common in ovarian cancer (13.1%), prostate cancer (9.3%), breast cancer (8.2%) and pancreatic cancer (4.9%). Prevalence for mutations in HRR genes ranges from 2.4 to 26.0% and gLOH ≥16% ranged from 2.6 to 34.4% depending on the tumor type. In conclusion, the prevalence of mutations in the BRCA1/2 genes, HRR genes and gLOH ≥16% varied widely across 15 tumor types. Tweetable Abstract Among 9457 patients across 15 solid tumor types, we found that 4.7% had BRCA1/2 mutations, 13.6% had mutations in homologous recombination repair genes and 20.6% had gLOH ≥16%. The prevalence of mutations varied by tumor type. The prevalence of mutations in homologous recombination repair (HRR) genes and of genomic loss of heterozygosity (gLOH) and the allelic and hereditary status of these mutations across solid tumor types are not well described. This study reports the prevalence of mutations in BRCA1/2 and in 13 other HRR genes and of gLOH across 15 tumor types, including tumor types beyond those more commonly associated with these biomarkers. Almost 5% of tumor samples had BRCA1/2 mutations, 14% had mutations in any of the HRR genes and 21% had a high prevalence of gLOH (gLOH ≥16%). The highest prevalences of were BRCA1/2 mutations in ovarian (13.1%), prostate (9.3%), breast (8.2%) and pancreatic (4.9%) cancers. The prevalence of BRCA1/2 mutations in mesothelioma, bladder cancer, endometrial cancer and gastric cancer were not negligible. Among tumors where biallelic status was determined, the biallelic proportions of BRCA1/2 mutations were 95% in prostate, 86% in ovarian, 83% in breast, 77% in pancreatic cancer and from 23% (gastric cancer) to 38% (bladder cancer) in other tumor types. Among tumors where heritable status was determined, germline BRCA1/2 mutations predominated in pancreatic and breast cancers, whereas somatic mutations were the majority in ovarian and most of the other tumor types. Across all tumor types, the proportion of gLOH ≥16% was highest in those with biallelic mutations of BRCA1, BRCA2 and PALB2. The prevalence of mutations in HRR genes varied considerably across tumor types. Evaluation of HRR gene alterations and gLOH may enable identification of tumors that are susceptible to drugs that act by causing double-strand DNA breaks. [ABSTRACT FROM AUTHOR]

Proteins containing both intrinsically disordered regions (IDRs) and RNA binding domains (RBDs) can phase separate in vitro, forming bodies similar to cellular biomolecular condensates. However, how IDR and RBD domains contribute to in vivo recruitment of proteins to biomolecular condensates remains poorly understood. Here, we analyzed the roles of IDRs and RBDs in L-bodies, biomolecular condensates present in Xenopus oocytes. We show that a cytoplasmic isoform of hnRNPAB, which contains two RBDs and an IDR, is highly enriched in L-bodies. While both of these domains contribute to hnRNPAB self-association and phase separation in vitro and mediate enrichment into L-bodies in oocytes, neither the RBDs nor the IDR replicate the localization of full-length hnRNPAB. Our results suggest a model where the combined effects of the IDR and RBDs regulate hnRNPAB partitioning into L-bodies. This model likely has widespread applications as proteins containing RBD and IDR domains are common biomolecular condensate residents. [ABSTRACT FROM AUTHOR]

Immunotherapy has become a mainstay treatment for HNSCC, with the FDA (Food and Drug Administration) approval of the anti-PD-1 immune checkpoint inhibitors (ICIs) nivolumab and pembrolizumab in 2016. Five drugs/combinations have received FDA breakthrough designation and are undergoing expedited development in HNSCC. Despite these advances, primary or acquired resistance to ICIs and the FDA-approved EGFR targeting agent cetuximab reduces patient survival, underscoring the need for the development of improved agents and strategies. Areas covered: Here we describe novel agents, their mechanism(s) of action, preclinical results, and ongoing clinical trials in HNSCC. Expert opinion: Established therapeutic targets in HNSCC include EGFR (cetuximab) and PD-1 (pembrolizumab and nivolumab). Despite the detection of many other possible targets in HNSCC cell lines and patient tumors, no other therapies have successfully advanced to date. Identification of predictive biomarkers may guide the use of targeted agents and combination therapies. Clinical trials supported by strong preclinical data in relevant models are more likely to advance treatment options. [ABSTRACT FROM AUTHOR]

Contemporary discussion of the baroreflex includes the efferent vascular-sympathetic and cardiovagal arms. Since sympathetic postganglionic neurons also innervate the left ventricle (LV), it is often assumed that the LV produces a sympathetically mediated increase in contractility during baroreceptor unloading, but this has not been characterized using a load-independent index of contractility. We aimed to determine 1) whether LV contractility increases in response to baroreceptor unloading and 2) whether such increases are mediated via the sympathetic or parasympathetic arm of the autonomic nervous system. Ten male Wistar rats were anesthetized (urethane) and instrumented with arterial and LV pressure-volume catheters to measure mean arterial pressure (MAP) and load-independent LV contractility [maximal rate of increase in pressure adjusted to end-diastolic volume (PAdP/dtmax)], respectively. Rats were placed in a servo-controlled lower-body negative pressure (LBNP) chamber to reduce MAP by 10% for 60 s to mechanically unload baroreceptors under control conditions. LBNP was repeated in each animal following infusions of cardiac autonomic blockers using esmolol (sympathetic), atropine (parasympathetic), and esmolol + atropine. Under control conditions, PAdP/dtmax increased during baroreceptor unloading (26 ± 6 vs. 31 ± 9 mmHg·s−1·μL−1, P = 0.031). During esmolol, there was no increase in LV contractility during baroreceptor unloading (11 ± 2 vs. 12 ± 2, P = 0.125); however, during atropine, there was an increase in LV contractility during baroreceptor unloading (26 ± 6 vs. 31 ± 9, P = 0.019). During combined esmolol and atropine, there was a small increase in contractility versus control (13 ± 3 vs. 15 ± 4, P = 0.046). Our results demonstrate that, in anesthetized rats, LV contractility increases in response to baroreceptor unloading, which is largely sympathetically mediated. NEW & NOTEWORTHY: This study empirically demonstrates a sympathetically mediated increase in LV contractility in response to baroreceptor unloading using a load-independent index of cardiac contractility in the anesthetized rat. [ABSTRACT FROM AUTHOR]

Abstract Background The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors’ self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs. Methods We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs. Results We found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML. Conclusion Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.

Abstract The mesophilic methanogenic archaeal model organism Methanosarcina mazei strain Gö1 is crucial for climate and environmental research due to its ability to produce methane. Here, we establish a Ribo-seq protocol for M. mazei strain Gö1 under two growth conditions (nitrogen sufficiency and limitation). The translation of 93 previously annotated and 314 unannotated small ORFs, coding for proteins ≤ 70 amino acids, is predicted with high confidence based on Ribo-seq data. LC-MS analysis validates the translation for 62 annotated small ORFs and 26 unannotated small ORFs. Epitope tagging followed by immunoblotting analysis confirms the translation of 13 out of 16 selected unannotated small ORFs. A comprehensive differential transcription and translation analysis reveals that 29 of 314 unannotated small ORFs are differentially regulated in response to nitrogen availability at the transcriptional and 49 at the translational level. A high number of reported small RNAs are emerging as dual-function RNAs, including sRNA154, the central regulatory small RNA of nitrogen metabolism. Several unannotated small ORFs are conserved in Methanosarcina species and overproducing several (small ORF encoded) small proteins suggests key physiological functions. Overall, the comprehensive analysis opens an avenue to elucidate the function(s) of multitudinous small proteins and dual-function RNAs in M. mazei.

Abstract The Simcyp Simulator is a software platform widely used in the pharmaceutical industry to conduct stochastic physiologically‐based pharmacokinetic (PBPK) modeling. This approach has the advantage of combining routinely generated in vitro data on drugs and drug products with knowledge of biology and physiology parameters to predict a priori potential pharmacokinetic changes in absorption, distribution, metabolism, and excretion for populations of interest. Combining such information with pharmacodynamic knowledge of drugs enables planning for potential dosage adjustment when clinical studies are feasible. Although the conduct of dedicated clinical studies in some patient groups (e.g., with hepatic or renal diseases) is part of the regulatory path for drug development, clinical studies for all permutations of covariates potentially affecting pharmacokinetics are impossible to perform. The role of PBPK in filling the latter gap is becoming more appreciated. This tutorial describes the different input parameters required for the creation of a virtual population giving robust predictions of likely changes in pharmacokinetics. It also highlights the considerations needed to qualify the models for such contexts of use. Two case studies showing the step‐by‐step development and application of population files for obese or morbidly obese patients and individuals with Crohn's disease are provided as the backbone of our tutorial to give some hands‐on and real‐world examples.

Abstract Structural information deficits about aging bridges have led to several avoidable catastrophes in recent years. Data-driven methods for bridge vibration monitoring enable frequent, accurate structural assessments; however, the high costs of widespread deployments of these systems make important condition information a luxury for bridge owners. Smartphone-based monitoring is inexpensive and has produced structural information, i.e., modal frequencies, in crowdsensing applications. Even so, current methods cannot extract spatial vibration characteristics with uncontrolled datasets that are needed for damage identification. Here we present an extensive real-world study with crowdsourced smartphone-vehicle trips within motor vehicles in which we estimate absolute value mode shapes and simulate damage detection capabilities. Our method analyzes over 800 trips across four road bridges with main spans ranging from 30 to 1300 m in length, representing about one-quarter of bridges in the United States. We demonstrate a bridge health monitoring platform compatible with ride-sourcing data streams that check conditions daily. The result has the potential to commodify data-driven structural assessments globally.

ABSTRACT Bacterial dormancy is a valuable strategy to survive stressful conditions. Toxins from chromosomal toxin-antitoxin systems have the potential to halt cell growth, induce dormancy, and eventually promote a stress-tolerant persister state. Due to their potential toxicity when overexpressed, sophisticated expression systems are needed when studying toxin genes. Here, we present a moderate expression system for toxin genes based on an artificial 5′ untranslated region. We applied the system to induce expression of the toxin gene tisB from the chromosomal type I toxin-antitoxin system tisB/istR-1 in Escherichia coli. TisB is a small hydrophobic protein that targets the inner membrane, resulting in depolarization and ATP depletion. We analyzed TisB-producing cells by RNA-sequencing and revealed several genes with a role in recovery from TisB-induced dormancy, including the chaperone genes ibpAB and spy. The importance of chaperone genes suggested that TisB-producing cells are prone to protein aggregation, which was validated by an in vivo fluorescent reporter system. We moved on to show that TisB is an essential factor for protein aggregation upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin in E. coli wild-type cells. The occurrence of protein aggregates correlates with an extended dormancy duration, which underscores their importance for the life cycle of TisB-dependent persister cells.IMPORTANCEProtein aggregates occur in all living cells due to misfolding of proteins. In bacteria, protein aggregation is associated with cellular inactivity, which is related to dormancy and tolerance to stressful conditions, including exposure to antibiotics. In Escherichia coli, the membrane toxin TisB is an important factor for dormancy and antibiotic tolerance upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin. Here, we show that TisB provokes protein aggregation, which, in turn, promotes an extended state of cellular dormancy. Our study suggests that protein aggregation is a consequence of membrane toxins with the potential to affect the duration of dormancy and the outcome of antibiotic therapy.

Desarrollar una buena labor a la hora de ofertar un servicio e implementar medidas que hagan evolucionarlo, además de retener y captar nuevos clientes requiere de información sobre la opinión de los mismos. El objetivo principal de este estudio fue evaluar la calidad percibida por los usuarios sobre las instalaciones y servicios deportivos de un polideportivo municipal. Además de conocer la percepción de diferentes dimensiones de manera más específica y pormenorizada, y las posibles diferencias de percepción de la calidad de un mismo servicio según el género de los usuarios. La muestra estuvo compuesta por 264 usuarios (114 hombres y 150 mujeres), con una edad media de 46,8 años (±11,1). El instrumento utilizado fue una adaptación de Scale of Service Quality in Recreational Sport (SSQRS); compuesto por cinco dimensiones: ‟Calidad del programa‟, ‟Calidad de la interacción‟, ‟Calidad del resultado‟, ‟Calidad del entorno físico o ambiente‟ y ‟Otros factores‟. Los datos obtenidos nos indican que la dimensión mejor percibida por los usuarios es la de ‟Calidad de interacción‟ con un 5,97 (±1,34) y la peor percibida la de ‟Calidad de ambiente‟ con un 5,01 (±1,64); otros datos obtenidos nos muestran que el sexo femenino percibe mejora la calidad que el masculino, siendo la mejor y peor evaluada de cada sexo, respectivamente, son ‟Calidad de interacción‟ con 6,27 (±1,06) y 5,59 (±1,56) y ‟Calidad de ambiente‟ 5,25 (±1,46) y 4,7 (±1,8). Algunas de las conclusiones que se han obtenido de este estudio son: que la calidad en la interacción entre usuarios y con monitores de las instalaciones son los factores mejor percibidos por parte de los usuarios de este cuestionario; para mejorar la percepción de ‟calidad de ambiente‟ se podrían tomar medidas como compra o restauración de materiales; y por último que el sexo femenino percibe la calidad mejor que los hombres.

Objective To investigate highest level of educational attainment in farming households compared to rural non-farming households in Wales. Approach We used the AD|ARC dataset of households in Wales receiving farming subsidies in 2010. We included farming households containing at least one member reporting an Agricultural Main Occupation (AMO) and households where all members reported Non-Agricultural Main Occupations (Non-AMO) but farming occurs. Utilising Census 2011 variables relating to age, gender, education and occupation we conducted comparative analyses of educational attainment within AMO, Non-AMO and non-farming rural households at both an individual and household level. Results Findings will be presented comparing the educational attainment for AMO individuals with matched individuals within Non-AMO and non-farming rural households. At the household level, we calculated the highest level of education attained within each household and will present results comparing the highest household level of education between each group. We will present detailed results regarding the structure and educational attainment within these households. Full results and findings will be presented at the conference but are currently subject to information governance restrictions. Conclusion One indicator of resilience amongst farmers and farm households is ability to respond to economic and non-economic pressures by adopting new practices and techniques or reducing reliance on farming via diversification or off-farm employment. As educational attainment is closely correlated to acquisition of skills and is a gateway to employment, understanding relative and absolute levels of attainment is important in identifying need and devising policies which support agricultural and rural communities.

Abstract In recent decades, fishing fleets and effort have grown in aggregate throughout the waters of lower-income coastal countries, much of which is carried out by vessels registered in higher-income countries. Fisheries access arrangements (FAAs) underpin this key trend in ocean fisheries and have their origins in UNCLOS’s promise to establish resource ownership as a mechanism to increase benefits to newly independent coastal and island states. Coastal states use FAAs to permit a foreign state, firm, or industry association to fish within its waters. This paper provides a conceptual approach for understanding FAAs across the global ocean and for exploring their potential to deliver on the promise of UNCLOS. Illustrated with the findings from multiple case studies, we advance understanding of FAAs by developing a geopolitical-economy of access that attends to the combination of contingent and context-specific economic, ecologic, and geopolitical forces that shape the terms, conditions and practices of the FAAs shaping this persistent phenomenon of higher-income industrial fleets fishing throughout lower-income countries’ waters.

Abstract Three-dimensional echocardiography (3DE) imaging has permitted advancements in the quantification of left ventricular (LV) and right ventricular (RV) volumes and ejection fraction. We evaluated the availability of 3DE equipment / analysis software, the integration of 3DE assessment of the LV and RV in routine clinical practice, current training provisions in 3DE, and aimed to ascertain barriers preventing the routine use of 3DE for volumetric analysis. Through the British Society of Echocardiography (BSE) regional representatives’ network, echocardiographers were invited to participate in an open online survey. A total of 181 participants from echocardiography departments in the United Kingdom (UK), the majority from tertiary centres (61%), completed the 28-question survey. For 3DE quantification, 3DE-LV was adopted more frequently than 3DE-RV (48% vs 11%, respectively). Imaging feasibility was a recognised factor in 3DE RV and LV adoption. Many respondents had access to 3D probes (93%). The largest observed barriers to 3DE routine use were training deficiencies, with 83% reporting they would benefit from additional training opportunities and the duration of time permitted for the scan, with 68% of responders reporting allowances of less than the BSE standard of 45–60 min per patient (8%

Abstract Regional fisheries management organisations (RFMOs) determine conservation measures for transboundary fisheries resources. They are also a forum for collective action toward the management of marine resources. One of the most complex and controversial aspects of this process is the allocation of catches between RFMO members. There are a variety of processes that can be used for catch allocation. In recent years, there has been a trend in some RFMOs towards establishing a system of criteria or indicators to determine the volume or percentage of catch that should be allocated to each RFMO member. Establishing such a system is challenging and the position of countries negotiating at RFMOs is also shaped by fisheries access arrangements. The debate on allocation has been ongoing at the Indian Ocean Tuna Commission for more than a decade, where one key point of disagreement is the treatment of historical catch taken in the waters of a coastal State. On the one hand, coastal states claim that catches historically taken in their exclusive economic zones (EEZ) should be attributed to them based on their sovereign rights over living resources. On the other, some fishing countries from outside the region claim catch history based on fishing conducted in the coastal State’s waters pursuant to access agreements. We analysed UNCLOS articles, publicly available fisheries access agreements, and national legislation to unpack the linkage between fisheries access arrangements and catch allocation discussions, and we also explored examples from other regions and RFMOs. We point out that the sovereign rights of coastal states over their EEZ provide a strong basis for allocation negotiations. In the absence of specific agreements to the contrary, any catch history that arises from foreign vessels fishing inside the EEZ should be attributed to the coastal State. We also argue that it is time for members of RFMOs—and especially of the Indian Ocean Tuna Commission—to move beyond the historical catch debate. They need to resolve their differences or consider other ways to allocate participatory rights in shared fisheries.

Summary: In budding yeast, the nucleolus serves as the site to sequester Cdc14, a phosphatase essential for mitotic exit. Nucleolar proteins Tof2, Net1, and Fob1 are required for this sequestration. Although it is known that these nucleolar proteins are SUMOylated, how SUMOylation regulates their activity remains unknown. Here, we show that Tof2 exhibits cell-cycle-regulated nucleolar delocalization and turnover. Depletion of the nuclear small ubiquitin-like modifier (SUMO) protease Ulp2 not only causes Tof2 polySUMOylation, nucleolar delocalization, and degradation but also leads to Cdc14 nucleolar release and activation. This outcome depends on polySUMOylation and the activity of downstream enzymes, including SUMO-targeted ubiquitin ligase and Cdc48/p97 segregase. We further developed a system to tether SUMO machinery to Tof2 and generated a SUMO-deficient tof2 mutant, and the results indicate that Tof2 polySUMOylation is necessary and sufficient for its nucleolar delocalization and degradation. Together, our work reveals a polySUMO-dependent mechanism that delocalizes Tof2 from the nucleolus to facilitate mitotic exit.

There is clear evidence that the sympathetic nervous system (SNS) mediates bone metabolism. Histological studies show abundant SNS innervation of the periosteum and bone marrow–these nerves consist of noradrenergic fibers that immunostain for tyrosine hydroxylase, dopamine beta-hydroxylase, or neuropeptide Y. Nonetheless, the brain sites that send efferent SNS outflow to the bone have not yet been characterized. Using pseudorabies (PRV) viral transneuronal tracing, we report, for the first time, the identification of central SNS outflow sites that innervate bone. We find that the central SNS outflow to bone originates from 87 brain nuclei, sub-nuclei, and regions of six brain divisions, namely the midbrain and pons, hypothalamus, hindbrain medulla, forebrain, cerebral cortex, and thalamus. We also find that certain sites, such as the raphe magnus (RMg) of the medulla and periaqueductal gray (PAG) of the midbrain, display greater degrees of PRV152 infection, suggesting that there is considerable site-specific variation in the levels of central SNS outflow to the bone. This comprehensive compendium illustrating the central coding and control of SNS efferent signals to bone should allow for a greater understanding of the neural regulation of bone metabolism, and importantly and of clinical relevance, mechanisms for central bone pain.

Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are negatively affected in the future. Stress responses are established by an interplay between genetics, environment, and life experiences. Psychosocial stress is particularly impactful during adolescence, a critical period for the development of mood disorders. In this study we compared two established, selectively-bred Sprague Dawley rat lines, the “internalizing” bred Low Responder (bLR) line versus the “externalizing” bred High Responder (bHR) line, to investigate how genetic temperament and adolescent environment impact future responses to social interactions and psychosocial stress, and how these determinants of stress response interact. Male bLR and bHR rats were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interaction and anxiety-like behavior. Adolescent enrichment caused rats to display more social interaction, as well as nominally less social avoidance, less submission during defeat, and resilience to the effects of social stress on corticosterone, in a manner that seemed more notable in bLRs. For bHRs, enrichment also caused greater aggression during a neutral social encounter and nominally during defeat, and decreased anxiety-like behavior. To explore the neurobiology underlying the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regulation and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory activity were enriched with differential expression in both regions, with a particularly large effect on gene sets that regulate social behaviors. Our findings provide further evidence that adolescent enrichment can serve as an inoculating experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipulating their environment has translational implications, as it underscores the feasibility of intervention strategies targeted at genetically vulnerable adolescent populations.

Biodiversity genomics research requires reliable organismal identification, which can be difficult based on morphology alone. DNA-based identification using DNA barcoding can provide confirmation of species identity and resolve taxonomic issues but is rarely used in studies generating reference genomes. Here, we describe the development and implementation of DNA barcoding for the Darwin Tree of Life Project (DToL), which aims to sequence and assemble high quality reference genomes for all eukaryotic species in Britain and Ireland. We present a standardised framework for DNA barcode sequencing and data interpretation that is then adapted for diverse organismal groups. DNA barcoding data from over 12,000 DToL specimens has identified up to 20% of samples requiring additional verification, with 2% of seed plants and 3.5% of animal specimens subsequently having their names changed. We also make recommendations for future developments using new sequencing approaches and streamlined bioinformatic approaches.

There is global understanding of the use of scenarios in addressing continued environmental change in Africa. Scenarios are a powerful tool for exploring uncertainties posed by the Anthropocene. As such, there are increasing calls for the use of scenarios in participatory research to inform policy and decision making. However, very limited research has tackled the integration of Indigenous and local people in participatory scenario planning. This study is an attempt to review knowledge on existing research involving Indigenous and local people in scenario planning in Africa. To do so, we undertook a semi-systematic review of scenario planning for people and nature in Africa of 68 case studies. We found that most of the research on participatory scenarios for people and nature in Africa is undertaken and led by researchers affiliated with institutions outside of Africa and there is a lack of active participation of Indigenous and local communities (IPLC). Of those studies conducted, agriculture and economics are the most common topics covered in the scenarios developed. The findings from this study call for more integration of Indigenous peoples and local communities with their associated knowledge in visioning processes and scenario development and a more inclusive approach to working with researchers based on the African continent for enhanced agency, ownership, and access.

Cancer immunotherapy has witnessed rapid advancement in recent years, with a particular focus on neoantigens as promising targets for personalized treatments. The convergence of immunogenomics, bioinformatics, and artificial intelligence (AI) has propelled the development of innovative neoantigen discovery tools and pipelines. These tools have revolutionized our ability to identify tumor-specific antigens, providing the foundation for precision cancer immunotherapy. AI-driven algorithms can process extensive amounts of data, identify patterns, and make predictions that were once challenging to achieve. However, the integration of AI comes with its own set of challenges, leaving space for further research. With particular focus on the computational approaches, in this article we have explored the current landscape of neoantigen prediction, the fundamental concepts behind, the challenges and their potential solutions providing a comprehensive overview of this rapidly evolving field.

Abstract As more countries make net zero greenhouse gas emissions pledges, it is crucial to understand the effects on global climate after achieving net zero emissions. The climate has been found to continue to evolve even after the abrupt cessation of CO2 emissions, with some models simulating a small warming and others simulating a small cooling. In this study, we analyze if the temperature and precipitation changes post abrupt cessation of CO2 emissions are significantly different compared to natural climate variations. We find that the temperature changes are outside of natural variability for most models, whilst the precipitation changes are mostly non‐significant. We also demonstrate that post‐net zero temperature changes have implications for the remaining carbon budget. The possibility of further global warming post‐net zero adds to the evidence supporting more rapid emissions reductions in the near‐term.

IntroductionMost patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, there are no molecular markers to identify patients with poor prognosis who would be harmed by de-escalation. Herein we report the clinical and genomic characteristics of persistent HPV-positive OPSCC after definitive platinum-based chemoradiation therapy.MethodsPatients with HPV-positive OPSCC treated with curative intent platinum-based chemoradiation between 2007 and 2017 at two institutions and with a persistent locoregional disease were included. We evaluated clinical characteristics, including smoking status, age, stage, treatment, and overall survival. A subset of five patients had tissue available for targeted exome DNA sequencing and RNA sequencing. Genomic analysis was compared to a previously published cohort of 47 treatment-responsive HPV+ OPSCC tumors after batch correction. Mutational landscape, pathway activation, and OncoGPS tumor states were employed to characterize these tumors.ResultsTen patients met the inclusion criteria. The tumor and nodal stages ranged from T1 to T4 and N1 to N2 by AJCC 8th edition staging. All patients were p16-positive by immunohistochemistry, and eight with available in situ hybridization were confirmed to be HPV-positive. The 1-year overall survival from the time of diagnosis was 57%, and the 2-year overall survival was 17%. TP53 mutations were present in three of five (60%) persistent tumors compared to 2% (one of 47) of treatment-responsive HPV-positive tumors (p = 0.008). Other genes with recurrent mutations in persistent HPV-positive OPSCC tumors were NF1, KMT2D, PIK3C2B, and TFGBR2. Compared to treatment-responsive HPV-positive tumors, persistent tumors demonstrated activation of DNA Repair and p53, EMT, MYC, SRC, and TGF-beta signaling pathways, with post-treatment samples demonstrating significant activation of the PI3K-EMT-Stem pathways compared to pretreatment samples.ConclusionChemoradiation-resistant HPV-positive OPSCC occurs infrequently but portends a poor prognosis. These tumors demonstrate higher rates of p53 mutation and activation of MYC, SRC, and TGF-beta pathways. A comparison of tumors before and after treatment demonstrates PI3K-EMT-Stem pathways post-treatment in HPV-positive tumors with persistent disease after platinum-based chemoradiation.