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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.

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 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 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 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.

IntroductionUsing the conservation of resources (COR) theory, our study explores the interaction between role ambiguity and leader-member exchange (LMX) quality on burnout using work addiction as a mediator among Canadian first-level healthcare managers.MethodsCross-sectional data was collected among 165 first-level managers working in healthcare with the support of interprofessional associations in Canada. Linear regression was used to test the presented hypotheses.ResultsWork addiction fully mediated the positive relationship between role ambiguity and burnout among first-level managers. In addition, high LMX exacerbated both the direct and indirect effects of role ambiguity.ConclusionOur study contributes by identifying role ambiguity as a context under which LMX can have adverse effects for first-level managers in healthcare. Moreover, work addiction acted as a mediator, theorized as a risky resource investment which depletes managers’ resources. Having a good relationship with their team further entices managers to develop a pathological relationship with their work to protect its members, which in turn is related to higher levels of burnout.

Inherited retinal diseases are a leading and untreatable cause of blindness and are therefore candidate diseases for gene therapy. Recombinant vectors derived from adeno-associated virus (rAAV) are currently the most promising vehicles for in vivo therapeutic gene delivery to the retina. However, there is a need for novel AAV-based vectors with greater efficacy for ophthalmic applications, as underscored by recent reports of dose-related inflammatory responses in clinical trials of rAAV-based ocular gene therapies. Improved therapeutic efficacy of vectors would allow for decreases in the dose delivered, with consequent reductions in inflammatory reactions. Here, we describe the development of new rAAV vectors using bioconjugation chemistry to modify the rAAV capsid, thereby improving the therapeutic index. Covalent coupling of a mannose ligand, via the formation of a thiourea bond, to the amino groups of the rAAV capsid significantly increases vector transduction efficiency of both rat and nonhuman primate retinas. These optimized rAAV vectors have important implications for the treatment of a wide range of retinal diseases.

A growing body of research has explored the conditions that motivate employees to engage at work. While employees’ attitudes and behaviors are socially influenced by their significant others’ perceptions, the divergent perceptions of organizational climate are underexplored. This study examines the socio-psychological mechanisms by which employees’ and managers’ perceptions of social climate enhance employee engagement at work. Based on the postulate that “ psychological state engagement” are the primary catalyst for “ behavioral engagement,” this study presents a serial mediation model that examines the role of divergent perceptions of social climate (as characterized by cooperation, shared codes and language, benevolence, and integrity) in fostering individual engagement through the mechanisms of organizational identification and growth satisfaction. Data were collected from both managers and employees, using a time-lagged design at two-time points. The findings revealed that managers’ collective perceptions of social climate were associated with organizational identification and growth satisfaction, which in turn fostered employee engagement at work. Contrary to expectations, there was no statistically significant relationship between employees’ collective perceptions of social climate and their engagement. However, individuals who had more favorable perceptions of the social climate (compare to colleagues’ collective perception) reported higher levels of organizational identification. These results point to ways in which social climate can impact employee engagement, and underscore the importance of taking divergent perceptions of organizations into account. They advance theories on the inherent tension between individuals’ desire for inclusion and the need to maintain a sense of individuality and distinctiveness.

Ammonia (NH3) is the most abundant alkaline component in the atmosphere. Changes in NH3 concentrations have important implications for atmospheric chemistry, air quality, and ecosystem integrity. We present a long-term ammonia (NH3) assessment in the western and central African regions within the framework of the International Network to study Deposition and Atmospheric chemistry in Africa (INDAAF) programme. We analyse seasonal variations and trends in NH3 concentrations and total column densities along an African ecosystem transect spanning dry savannas in Banizoumbou, Niger, and Katibougou, Mali; wet savannas in Djougou, Benin, and Lamto, Côte d'Ivoire; and forests in Bomassa, Republic of the Congo, and Zoétélé, Cameroon. We use a 21-year record of observations (1998–2018) from INDAAF passive samplers and an 11-year record of observations (2008–2018) of atmospheric vertical column densities from the Infrared Atmospheric Sounding Interferometer (IASI) to evaluate NH3 ground-based concentrations and total column densities, respectively. Climatic data (air temperature, rainfall amount, and leaf area index), as well as ammonia emission data of biomass combustion from the fourth version of the Global Fire Emissions Database (GFED4) and anthropogenic sources from the Community Emissions Data System (CEDS), were compared with total NH3 concentrations and total columns over the same periods. Annual mean ground-based NH3 concentrations are around 5.7–5.8 ppb in dry savannas, 3.5–4.7 ppb in wet savannas, and 3.4–5.6 ppb in forests. Annual IASI NH3 total column densities are 10.0–10.7 × 1015 molec. cm−2 in dry savanna, 16.0–20.9 × 1015 molec. cm−2 in wet savanna, and 12.4–13.8 × 1015 molec. cm−2 in forest stations. Non-parametric statistical Mann–Kendall trend tests applied to annual data show that ground-based NH3 concentrations increase at Bomassa (+2.56 % yr−1) but decrease at Zoétélé (−2.95 % yr−1) over the 21-year period. The 11-year period of IASI NH3 total column density measurements show yearly increasing trends at Katibougou (+3.46 % yr−1), Djougou (+2.24 % yr−1), and Zoétélé (+3.42 % yr−1). From the outcome of our investigation, we conclude that air temperature, leaf area index, and rainfall combined with biomass burning, agricultural, and residential activities are the key drivers of atmospheric NH3 in the INDAAF stations. The results also show that the drivers of trends are (1) agriculture in the dry savanna of Katibougou; (2) air temperature and agriculture in the wet savanna of Djougou and Lamto; and (3) leaf area index, air temperature, residential, and agriculture in the forest of Bomassa.

Abstract The role of iron in the two major sites of adaptive thermogenesis, namely the beige inguinal (iWAT) and brown adipose tissues (BAT) has not been fully understood yet. Body iron levels and distribution is controlled by the iron regulatory peptide hepcidin. Here, we explored iron homeostasis and thermogenic activity in brown and beige fat in wild-type and iron loaded Hepcidin KO mice. Hepcidin-deficient mice displayed iron overload in both iWAT and BAT, and preferential accumulation of ferritin in stromal cells compared to mature adipocytes. In contrast to BAT, the iWAT of Hepcidin KO animals featured with defective thermogenesis evidenced by an altered beige signature, including reduced UCP1 levels and decreased mitochondrial respiration. This thermogenic modification appeared cell autonomous and persisted after a 48 h-cold challenge, a potent trigger of thermogenesis, suggesting compromised de novo adipogenesis. Given that WAT browning occurs in both mice and humans, our results provide physiological results to interrogate the thermogenic capacity of patients with iron overload disorders.

Carbon (C) in soils persists on a range of timescales depending on physical, chemical, and biological processes that interact with soil organic matter (SOM) and affect its rate of decomposition. Together these processes determine the age distribution of soil C. Most attempts to measure this age distribution have relied on operationally defined fractions using properties like density, aggregate stability, solubility, or chemical reactivity. Recently, thermal fractionation, which relies on the activation energy needed to combust SOM, has shown promise for separating young from old C by applying increasing heat to decompose SOM. Here, we investigated radiocarbon (14C) and 13C of C released during thermal fractionation to link activation energy to the age distribution of C in bulk soil and components previously separated by density and chemical properties. While physically and chemically isolated fractions had very distinct mean 14C values, they contributed C across the full temperature range during thermal analysis. Thus, each thermal fraction collected during combustion of bulk soil integrates contributions from younger and older C derived from components having different physical and chemical properties but the same activation energy. Bulk soil and all density and chemical fractions released progressively older and more 13C-enriched C with increasing activation energy, indicating that each operationally defined fraction itself was not homogeneous but contained a mix of C with different ages and degrees of microbial processing. Overall, we found that defining the full age distribution of C in bulk soil is best quantified by first separating particulate C prior to thermal fractionation of mineral-associated SOM. For the Podzol analyzed here, thermal fractions confirmed that ∼ 95 % of the mineral-associated organic matter (MOM) had a relatively narrow 14C distribution, while 5 % was very low in 14C and likely reflected C from the < 2 mm parent shale material in the soil matrix. After first removing particulate C using density or size separation, thermal fractionation can provide a rapid technique to study the age structure of MOM and how it is influenced by different OM–mineral interactions.

In areas where the access to an off-grid electricity is not possible or not reliable, the transport and conservation of vaccine and medicines is not possible. Nevertheless, these areas need and have right to access medicine. This need is much more critical nowadays since preservation of COVID-19 vaccines require cold-chain at some level of degree. Solar energy can be used to power the refrigerator destined to keep the medicines and vaccines cool. Even tough stand-alone photovoltaic (PV) is already used to power these coolers, our work shows that the use of a Photovoltaic-Thermoelectric hybrid generators could allow a great improvement of the autonomy. The output power of the PV alone and the hybrid are investigated under Niger meteorological conditions. These two systems coupled with a medical cooler are investigated. The results show that the hybrid system produces considerably more power to be stored in the battery, indicating much longer autonomy. Under the same conditions, when the PV reached its lowest efficiency of 12.24% , the hybrid was at his efficiency peak 19.62%. Thus, a rise of 5.88% was achieved. Our work presented here is important for giving a message to the international organizations that sustainable cold chains needed for equitable COVID-19 vaccine distribution is clearly possible with solar PV/TE driven DC refrigerators.

In cell and gene therapy, achieving the stable engraftment of an abundant and highly polyclonal population of gene-corrected cells is one of the key factors to ensure the successful and safe treatment of patients. Because integrative vectors have been associated with possible risks of insertional mutagenesis leading to clonal dominance, monitoring the relative abundance of individual vector insertion sites in patients’ blood cells has become an important safety assessment, particularly in hematopoietic stem cell-based therapies. Clinical studies often express clonal diversity using various metrics. One of the most commonly used is the Shannon index of entropy. However, this index aggregates two distinct aspects of diversity, the number of unique species and their relative abundance. This property hampers the comparison of samples with different richness. This prompted us to reanalyze published datasets and to model the properties of various indices as applied to the evaluation of clonal diversity in gene therapy. A normalized version of the Shannon index, such as Pielou’s index, or Simpson’s probability index is robust and useful to compare sample evenness between patients and trials. Clinically meaningful standard values for clonal diversity are herein proposed to facilitate the use of vector insertion site analyses in genomic medicine practice.

BACKGROUND: The development of immunotherapy and tyrosine kinase inhibitors dramatically improved the prognosis of metastatic melanoma. Consequently, chemotherapy is now rarely used. Here, we describe the characteristics of long-surviving patients with metastatic melanoma treated with immunochemotherapy. MATERIAL AND METHODS: We retrieved retrospective clinical and pathological data for patients diagnosed with metastatic melanoma between January 1993 and December 2015 who received the CVD-INF (cisplatin, vinblastine, dacarbazine, and interferon α-2b) regimen at the Hôpitaux Universitaires de Genève. We estimated their progression-free survival and overall survival. This ad hoc study’s primary aim was to describe the clinical and biological characteristics of long-term survivors, defined as patients surviving more than two years after immunochemotherapy initiation. The spatial distribution pattern of CD8+ T cells (inflamed, excluded, or desert) was immunohistochemically determined. RESULTS: Ninety patients received CVD-INF. Their median age at metastatic melanoma diagnosis was 55 years (20–75). Their median progression-free survival was 2.8 months, and median overall survival was 7.2 months. Eleven (12%) patients were long-term survivors. In multivariate analysis, central nervous system metastases (hazard ratio [HR]: 2.66; 95% confidence interval [CI]: 1.43–4.95; p = 0.001), multiple metastases (HR: 1.82; 95% CI: 1.01–3.29; p = 0.047), and elevated lactate dehydrogenase (LDH) (HR: 1.92; 95% CI: 1.12–3.30; p = 0.016) were independently associated with shorter survival. Most long-survivors (6/8; 75%) had a tumour-inflamed pattern compared to 25% of non-long survivors (5/20; Fisher’s test p = 0.030). CONCLUSIONS: A subset of patients with metastatic melanoma and a tumour-inflamed phenotype treated with CVD-INF survived over two years. Factors associated with prolonged survival are consistent with those previously reported in metastatic melanoma.

Caenorhabditis elegans is a model system widely used in fundamental research. Even though, nematodes are easy to maintain in the laboratory, obtaining large populations of worms require a lot of work and is time consuming. Furthermore, because C. elegans are mainly hermaphrodite it is even more complicated to obtain large amounts of males which make high-throughput experiments using C. elegans males very challenging.In order to overcome these limitations, we developed affordable and rapid methods to:(1) grow large synchronous worm populations(2) easily obtain large amounts of malesWe developed a culture method on plates to grow big synchronized worm populations with the standard incubators used on all worm labs. We also established an easy filtration method allowing to obtain large male populations in an hour. After filtering, the worm population contains more than 90% of adult males and no adult hermaphrodites since all the contaminants are larva and embryos.The culture and the filtering methods we developed are easy to implement and require a very limited investment in equipment and consumables beside the standard one present in worm labs. In addition, this filtering method could be applied to nematode's species similar in size to C. elegans.

With the expansion of mobile communications infrastructure, social media usage in the Global South is surging. Compared to the Global North, populations of the Global South have had less prior experience with social media from stationary computers and wired Internet. Many countries are experiencing violent conflicts that have a profound effect on their societies. As a result, social networks develop under different conditions than elsewhere, and our goal is to provide data for studying this phenomenon. In this dataset paper, we present a data collection of a national Twittersphere in a West African country of conflict. While not the largest social network in terms of users, Twitter is an important platform where people engage in public discussion. The focus is on Mali, a country beset by conflict since 2012 that has recently had a relatively precarious media ecology. The dataset consists of tweets and Twitter users in Mali and was collected in June 2022, when the Malian conflict became more violent internally both towards external and international actors. In a preliminary analysis, we assume that the conflictual context influences how people access social media and, therefore, the shape of the Twittersphere and its characteristics. The aim of this paper is to primarily invite researchers from various disciplines including complex networks and social sciences scholars to explore the data at hand further. We collected the dataset using a scraping strategy of the follower network and the identification of characteristics of a Malian Twitter user. The given snapshot of the Malian Twitter follower network contains around seven million accounts, of which 56,000 are clearly identifiable as Malian. In addition, we present the tweets. The dataset is available at: https://osf.io/mj2qt/

Background Non-communicable diseases (NCDs) are a major threat to health and development and account for 75% of deaths in the Pacific Islands Countries and Territories (PICTs). Childhood obesity has been identified as a main risk factor for NCDs later in life. This review compiled overweight and obesity (OWOB) prevalence (anthropometric data) for children aged six to 12 years old living in the Pacific region and identified possible related causes. Methods We conducted a systematic search using PubMed, Google Scholar and ScienceDirect for articles published between January 1980 and August 2022. We also searched for technical reports from Ministries of Health. Guided by the eligibility criteria, two authors independently read the selected articles and reports to extract and summarise relevant information related to overweight and obesity. Results We selected 25 articles, two worldwide analyses of population-based studies and four national reports. Information revealed that childhood OWOB prevalence reached 55% in some PICTs. This review also indicated that age, gender and ethnicity were linked to children’s weight status, while dietary practices, sleep time and level of physical activity played a role in OWOB development, as well as the living environment (socio-economic status and food availability), parenting practices and education level. Conclusion This review highlighted that anthropometric data are limited and that comparisons are difficult due to the paucity of surveys and non-standardized methodology. Main causes of overweight and obesity are attributed to individual characteristics of children and behavioural patterns, children’s socio-economic environment, parenting practices and educational level. Reinforcement of surveillance with standardised tools and metrics adapted to the Pacific region is crucial and further research is warranted to better understand root causes of childhood OWOB in the Pacific islands. More robust and standardized anthropometric data would enable improvements in national strategies, multisectoral responses and innovative interventions to prevent and control NCDs.