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The transfer of carbon from land to the near-coastal ocean is increasingly being recognized in global carbon budgets. However, a more direct transfer of terrestrial organic carbon to the deep sea is comparatively overlooked. Among systems that connect coastal to deep-sea environments, the submarine Congo Canyon is of particular interest since the canyon head starts 30 km into the Congo River estuary, which delivers ∼7 % of the dissolved and particulate organic carbon from the world's rivers. However, sediment and particulate organic carbon transport mechanisms that operate in the Congo Canyon and submarine canyons more globally are poorly constrained compared to rivers because monitoring of deep-sea canyons remains challenging. Using a novel array of acoustic instruments, sediment traps, and cores, this study seeks to understand the hydrodynamic processes that control delivery of particulate organic carbon via the submarine Congo Canyon to the deep sea. We show that particulate organic carbon transport in the canyon axis is modulated by two processes. First, we observe periods where the canyon dynamics are dominated by tides, which induce a background oscillatory flow (speeds of up to 0.15 m s−1) through the water column, keeping muds in suspension, with a net upslope transport direction. Second, fast-moving (up to 8 m s−1) turbidity currents occur for 35 % of the time during monitoring periods and transport particulate organic carbon with mud and sand at an estimated transit flux that is more than 3 to 6 times the flux induced by tides. Organic carbon transported and deposited in the submarine canyon has a similar isotopic composition to organic carbon in the Congo River and in the deep-sea fan at 5 km of water depth. Episodic turbidity currents thus promote efficient transfer of river-derived particulate organic carbon in the Congo submarine fan, leading to some of the highest terrestrial carbon preservation rates observed in marine sediments globally.

Abstract T-cell-based adoptive immunotherapy is a new pillar of cancer care. Tumor-redirected B cells could also contribute to therapy if their manipulation to rewire immunoglobulin (Ig) genes is mastered. We designed a single-chain Ig-encoding cassette (“scFull-Ig”) that redirects antigen specificity when inserted at a single position of the IgH locus. This design, which places combined IgH and IgL variable genes downstream of a pVH promoter, nevertheless preserves all Ig functional domains and the intrinsic mechanisms that regulate expression from the IgM B cell receptor (BCR) expression to Ig secretion, somatic hypermutation and class switching. This single-locus editing provides an efficient and safe strategy to both disrupt endogenous Ig expression and encode a new Ig paratope. As a proof of concept, the functionality of scFull BCR and/or secreted Ig was validated against two different classical human tumor antigens, HER2 and hCD20. Once validated in cell lines, the strategy was extended to primary B cells, confirming the successful engineering of BCR and Ig expression and the ability of scFull-Ig to undergo further class switching. These results further pave the way for future B cell-based adoptive immunotherapy and strategies to express a therapeutic mAb with a variety of switched H-chains that provide complementary functions.

Background: National school curriculum statements detail what it is important to learn and are highly context- and discipline-specific. The health and physical education (H&PE) learning areas have multiple learning purposes, and facilitating this in curriculum design is a significant and challenging task. Objective: There is little reporting on 'behind-the-scenes' practices of H&PE curriculum writing, despite this being a key mechanism by which the shaping of curricula occurs. This article offers a descriptive case study of curriculum development for the Tokelau National Curriculum H&PE learning area for Years 0-13. Prior to 2021, this learning area did not formally exist in the Tokelau National Curriculum Framework. Design, Setting and Methods: The case reports on the processes and decisions of a multi-national transdisciplinary writing team from Tokelau, New Zealand and New Caledonia. We explore the questions: 'Why the need for an H&PE curriculum, and who is it for?' Document collection and team-based interviews formed the basis for deductive descriptive analysis of the writing processes. Results: Three key themes were developed. Related to 'why', findings illustrate the importance of formalising H&PE learning, representing knowledge, skills and capabilities useful for present and future generations of young people in Tokelau. Considering 'for whom', findings emphasise the involvement of the community in curriculum decisions, and the inclusion of distinctive features aligned with community values, needs and aspirations. Conclusion: The case study illustrates the requisite coming together of different groups and expertise in the creation of a curriculum, a synthesis of pre-existing and new knowledge and experiences. The focus on health promotion and health and physical literacies exemplifies the everyday use of school curriculum goals to support community health.

Abstract PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8+PD-1+ T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.93 (95% CI 0.85-1.00) and iii) high CD8B/FOXP3 and high CD8B/ENTPD1 ratios are significantly associated with positive response to NACT + P, while KDR and VEGFR2 expression are associated with resistance. These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2+ endothelial cells, could overcome immune resistance of ovarian cancers.

Abstract Background The objective was to assess the agreement between therapeutic proposals derived from basic critical care echocardiography performed by novice operators in ultrasonography after a limited training (residents) and by experts considered as reference. Secondary objectives were to assess the agreement between operators’ answers to simple clinical questions and the concordance between basic two-dimensional measurements. Methods This observational, prospective, single-center study was conducted over a 3-year period in a medical-surgical intensive care unit. Adult patients with acute circulatory and/or respiratory failure requiring a transthoracic echocardiography (TTE) examination were studied. In each patient, a TTE was performed by a resident novice in ultrasonography after a short training program and by an expert, independently but within 1 h and in random order. Each operator addressed standardized simple clinical questions and subsequently proposed a therapeutic strategy based on a predefined algorithm. Results Residents performed an average of 33 TTE studies in 244 patients (156 men; age: 63 years [52–74]; SAPS2: 45 [34–59]; 182 (75%) mechanically ventilated). Agreement between the therapeutic proposals of residents and experienced operators was good-to-excellent. The concordance was excellent for suggesting fluid loading, inotrope or vasopressor support (all Kappa values > 0.80). Inter-observer agreement was only moderate when considering the indication of negative fluid balance (Kappa: 0.65; 95% CI 0.50–0.80), since residents proposed diuretics in 23 patients (9.5%) while their counterparts had the same suggestion in 35 patients (14.4%). Overall agreement of responses to simple clinical questions was also good-to-excellent. Intraclass correlation coefficient exceeded 0.75 for measurement of ventricular and inferior vena cava size. Conclusions A limited training program aiming at acquiring the basic level in critical care echocardiography enables ICU residents novice in ultrasonography to propose therapeutic interventions with a good-to-excellent agreement with experienced operators.

Abstract Background Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions. Methods We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities. Results We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential. Conclusions Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.

Abstract Background Cellular iron homeostasis is regulated by iron regulatory proteins (IRP1 and IRP2) that sense iron levels (and other metabolic cues) and modulate mRNA translation or stability via interaction with iron regulatory elements (IREs). IRP2 is viewed as the primary regulator in the liver, yet our previous datasets showing diurnal rhythms for certain IRE-containing mRNAs suggest a nuanced temporal control mechanism. The purpose of this study is to gain insights into the daily regulatory dynamics across IRE-bearing mRNAs, specific IRP involvement, and underlying systemic and cellular rhythmicity cues in mouse liver. Results We uncover high-amplitude diurnal oscillations in the regulation of key IRE-containing transcripts in the liver, compatible with maximal IRP activity at the onset of the dark phase. Although IRP2 protein levels also exhibit some diurnal variations and peak at the light–dark transition, ribosome profiling in IRP2-deficient mice reveals that maximal repression of target mRNAs at this timepoint still occurs. We further find that diurnal regulation of IRE-containing mRNAs can continue in the absence of a functional circadian clock as long as feeding is rhythmic. Conclusions Our findings suggest temporally controlled redundancy in IRP activities, with IRP2 mediating regulation of IRE-containing transcripts in the light phase and redundancy, conceivably with IRP1, at dark onset. Moreover, we highlight the significance of feeding-associated signals in driving rhythmicity. Our work highlights the dynamic nature and regulatory complexity in a metabolic pathway that had previously been considered well-understood.

Abstract Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

Abstract The aim of this study was to investigate relationships between changes in training practices and human development index (HDI) levels, and identify strategies employed by athletes who consistently maintained their training quantity during the first 100 days of the COVID-19 pandemic. A total of 10,074 athletes (5290 amateur and 4787 professional athletes from 121 countries) completed an online survey between 17 May to 5 July 2020. We explored their training practices, including specific questions on training frequency, duration and quantity before and during lockdown (March–June 2020), stratified according to the human development index (HDI): low-medium, high, or very high HDI. During the COVID-19 lockdown, athletes in low-medium HDI countries focused on innovative training. Nevertheless, women and amateur athletes experienced a substantial reduction in training activity. Performance-driven athletes and athletes from higher HDI indexed countries, were likely to have more opportunities to diversify training activities during lockdowns, facilitated by the flexibility to perform training away from home. Factors such as lockdown rules, socioeconomic environment, and training education limited training diversification and approaches, particularly in low-medium and high HDI countries. Athletes (amateurs and professionals) who maintained the quantity of training during lockdown appeared to prioritize basic cardiovascular and strength training, irrespective of HDI level. Modifying training and fitness programs may help mitigate the decrease in training activities during lockdowns. Customized training prescriptions based on gender, performance, and HDI level will assist individuals to effectively perform and maintain training activities during lockdowns, or other challenging (lockdown-like) situations.

Fertility preservation (FP) is an important aspect of the treatment of young women diagnosed with serous borderline ovarian tumors (SBOT), with fertility sparing surgery recommended when possible. Concurrent treatment with aromatase inhibitor letrozole during ovarian stimulation (OS) could be used in women with hormone-sensitive breast cancer, but very little is known in gynecological tumors. Here, we report the cases of 2 young nulliparous women with early stage SBOT who underwent successful OS with letrozole. Patient 1 is 22-years old, FIGO IIB. She had a bilateral ovarian recurrence 5 months after the first surgery. She underwent OS with letrozole (four oocytes were collected and vitrified), followed by cytoreduction. The patient is in complete remission since 2 years. Patient 2 is 27-years old, FIGO IC3, treated by right adnexectomy. Ten months after surgery, she was in complete remission. OS with letrozole was performed and 4 oocytes were retrieved, resulting in 2 blastocysts that were cryopreserved. She had a successful pregnancy after in-vitro fertilization. She underwent a delivery via C-Section for obstetrical reasons that revealed a macroscopic suspicious lesion on the left ovary. Cystectomy was performed during C-section, confirming tumor recurrence. She underwent a second pregnancy uneventfully. During the second C-section, a partial cystectomy and multiples peritoneal biopsies were performed revealing tumor recurrence limited to the left ovary. She underwent left adnexectomy two months after C-Section without any recurrence. In conclusion, our case report described successful oocytes cryopreservation, without changes in the appearance of ovarian cysts, in nulliparous women with early-stage SBOT who underwent OS with simultaneous administration of letrozole.

Abstract Organic carbon (OC) sedimentation in marine sediments is the largest long‐term sink of atmospheric CO2 after silicate weathering. Understanding the mechanistic and quantitative aspects of OC delivery and preservation in marine sediments is critical for predicting the role of the oceans in modulating global climate. Yet, estimates of the global OC sedimentation in marginal settings span an order of magnitude, and the primary controls of OC preservation remain highly debated. Here, we provide the first global bottom‐up estimate of OC sedimentation along the margins using a synthesis of literature data. We quantify both terrestrial‐ and marine‐sourced OC fluxes and perform a statistical analysis to discern the key factors influencing their magnitude. We find that the margins host 23.2 ± 3.5 Tmol of OC sedimentation annually, with approximately 84% of marine origin. Accordingly, we calculate that only 2%–3% of OC exported from the euphotic zone escapes remineralization before sedimentation. Surprisingly, over half of all global OC sedimentation occurs below bottom waters with oxygen concentrations greater than 180 μM, while less than 4% occurs in settings with

Abstract Ratios of glycerol dialkyl glycerol tetraethers (GDGT), which are membrane lipids of bacteria and archaea, are at the base of several paleoenvironmental proxies. They are frequently applied to soils as well as lake‐ and marine sediments to generate records of past temperature and soil pH. To derive meaningful environmental information from these reconstructions, high analytical reproducibility is required. Based on submitted results by 39 laboratories from across the world, which employ a diverse range of analytical and quantification methods, we explored the reproducibility of brGDGT‐based proxies (MBT′5ME, IR, and #ringstetra) measured on four soil samples and four soil lipid extracts. Correct identification and integration of 5‐ and 6‐methyl brGDGTs is a prerequisite for the robust calculation of proxy values, but this can be challenging as indicated by the large inter‐interlaboratory variation. The exclusion of statistical outliers improves the reproducibility, where the remaining uncertainty translates into a temperature offset from median proxy values of 0.3–0.9°C and a pH offset of 0.05–0.3. There is no apparent systematic impact of the extraction method and sample preparation steps on the brGDGT ratios. Although reported GDGT concentrations are generally consistent within laboratories, they vary greatly between laboratories. This large variability in brGDGT quantification may relate to variations in ionization efficiency or specific mass spectrometer settings possibly impacting the response of brGDGTs masses relative to that of the internal standard used. While ratio values of GDGT are generally comparable, quantities can currently not be compared between laboratories.

Abstract The Amazon River mobilizes organic carbon across one of the world's largest terrestrial carbon reservoirs. Quantifying the sources of particulate organic carbon (POC) to this flux is typically challenging in large systems such as the Amazon River due to hydrodynamic sorting of sediments. Here, we analyze the composition of POC collected from multiple total suspended sediment (TSS) profiles in the mainstem at Óbidos, and surface samples from the Madeira, Solimões and Tapajós Rivers. As hypothesized, TSS and POC concentrations in the mainstem increased with depth and fit well to Rouse models for sediment sorting by grain size. Coupling these profiles with Acoustic Doppler Current Profiler discharge data, we estimate a large decrease in POC flux (from 540 to 370 kg per second) between the rising and falling stages of the Amazon River mainstem. The C/N ratio and stable and radiocarbon signatures of bulk POC are less variable within the cross‐section at Óbidos and suggest that riverine POC in the Amazon River is predominantly soil‐derived. However, smaller shifts in these compositional metrics with depth, including leaf wax n‐alkanes and fatty acids, are consistent with the perspective that deeper and larger particles carry fresher, less degraded organic matter sources (i.e., vegetation debris) through the mainstem. Overall, our cross‐sectional surveys at Óbidos highlight the importance of depth‐specific sampling for estimating riverine export fluxes. At the same time, they imply that this approach to sampling is perhaps less essential with respect to characterizing the composition of POC sources exported by the river.

Clear cell carcinoma is a rare and very aggressive subset of cervical cancer, with poor outcome if diagnosed at advanced stage. There are few data available on the optimal management of this histotype, and treatment recommendations that include surgery and chemoradiotherapy, are essentially based on those for squamous cell carcinoma. Here we report the case of a young patient newly diagnosed with advanced stage (FIGO IIB) clear cell carcinoma of the uterine cervix who received a window of opportunity one injection of nivolumab followed by standard chemoradiotherapy. She showed a persistent complete remission after 28 months of follow-up, but developed hypothyroidism, as a consequence of immunotherapy, and required lifelong thyroid hormone replacement.

Abstract Background In recent years, Acinetobacter baumannii-calcoaceticus complex (ABC) infections have attracted attention, mainly because of the impact of carbapenem-resistant isolates in hospital-acquired infections. However, acute community-acquired ABC infections are not uncommon in warm and humid countries, where they are responsible for community-acquired infections with specific clinical features. To date, such infection has not been reported in France. Case presentation We report the case of a 55-year-old non-immunocompromised patient living in France with no known risk factors for community-acquired ABC infections who presented pneumonia with bloodstream infection due to wild-type A. pittii. The outcome was favorable after 7 days of antibiotic treatment with cefepime. We confirmed bacterial identification with whole-genome sequencing, and we examined the A. pitii core-genome phylogeny for genomic clusters. Conclusions This situation is uncommon in Europe and occurred after a heat wave in France with temperatures above 38 °C. Herein, we discuss the possibility that this pneumonia may be emerging in the current context of global warming.

Background and Aim: Potato (Solanum tuberosum L.) is mainly characterized by its antioxidant and healing properties. Therefore, this study aimed to evaluate the effects of an ointment based on S. tuberosum L. “papa tumbay” on burns induced in Balb/c mice (Mus musculus). Materials and Methods: The experimental animals were divided into four groups (n = 5/group) 48 h before second-degree burns were inducted. After epilating the loin areas of the mice and anesthetizing them with ketamine/xylazine (80 mg/kg/10 mg/kg) through intraperitoneal (i.p.) route, a round metal rod (0.7 cm in diameter) was placed on the depilated skin at a temperature of 100°C for 5 s. Group I was not given any treatment, Group II was treated with silver sulfadiazine (1%), and the other two groups (III and IV) were treated with the ointment formulated based on S. tuberosum L. “papa tumbay” at 1% and 2%, respectively. After performing the treatment for 21 days, the mice were euthanized using i.p. sodium pentobarbital (185 mg/kg) to obtain skin samples. The samples were preserved in 10% neutral-buffered formalin and subjected to histopathological analysis. Results: We found statistically significant differences in the histopathological sections between the groups (p < 0.05). The abundant collagen and fibroblasts observed in the direction of the dermis in Groups III and IV indicate that the phytoconstituents present in the potato might promote the healing of the second-degree burns until day 21 of treatment. Conclusion: Our findings showed that the ointments based on the ethanolic extracts of S. tuberosum L. “papa tumbay,” especially the 2% ointment, might accelerate the healing of second-degree burns induced in Balb/c mice.