Incorporating the acclimation of photosynthesis and leaf respiration in the Noah-MP land surface model: model development and evaluation

Realistic simulation of leaf photosynthetic and respiratory processes is needed for accurate prediction of the global carbon cycle. These two processes systematically acclimate to long-term environmental changes by adjusting photosynthetic and respiratory traits (e.g., the maximum photosynthetic capacity at 25°C (Vcmax,25) and the leaf respiration rate at 25°C (R25)) following increasingly well-understood principles. While some land surface models (LSMs) now account for thermal acclimation, they do so by assigning empirical parameterizations for individual plant functional types (PFTs). Here, we have implemented an Eco-Evolutionary Optimality (EEO)-based scheme to represent the universal acclimation of photosynthesis and leaf respiration to multiple environmental effects, and that therefore requires no PFT-specific parameterizations, in a standard version of the widely used LSM, Noah MP. We evaluated model performance with plant trait data from a 5-year experiment and extensive global field measurements, and carbon flux measurements from FLUXNET2015. We show that observed R25 and Vcmax,25 vary substantially both temporally and spatially within the same PFT (C.V. >20%). Our EEO-based scheme captures 62% of the temporal and 70% of the spatial variations in Vcmax,25 (73% and 54% of the variations in R25). The standard scheme underestimates gross primary production by 10% versus 2% for the EEO-based scheme and generates a larger spread in r (correlation coefficient) across flux sites (0.79 ± 0.16 vs. 0.84 ± 0.1, mean ± S.D.). The standard scheme greatly overestimates canopy respiration (bias: ∼200% vs. 8% for the EEO scheme), resulting in less CO2 uptake by terrestrial ecosystems. Our approach thus simulates climate-carbon coupling more realistically, with fewer parameters

The effect of HLA polymorphism on immune response to SARS‐CoV‐2 vaccination within an infection‐naïve, vulnerable population with end‐stage renal disease

HLA genes exhibit a high degree of polymorphism, contributing to genetic variability known to influence immune responses to infection. Here we investigate associations between HLA polymorphism and serological and T-lymphocyte responses to the BNT162b2 and ChAdOx1 SARS-CoV-2 vaccines within a population receiving maintenance haemodialysis (HD) for End-Stage Renal Disease (ESRD). Our primary objective was to identify HLA alleles associated with diminished serological and T-cellular responsiveness to vaccination. As a secondary objective, the associations between HLA type and COVID-19 disease outcomes were investigated using an independent ESRD cohort (n = 327). This aimed to determine if the alleles associated with poor vaccine response were also linked to unfavourable infection outcomes. In the main study, serum from 225 SARS-CoV-2 infection-naïve patients was HLA-typed using high-resolution Next Generation Sequencing, and serological titres were analysed for the presence of SARS-CoV-2 spike glycoprotein-specific antibodies after two doses of vaccination. A subset of patients (n = 33) was also tested for a T-lymphocyte response. Overall, 89% (n = 200) of patients seroconverted, but only 18% (n = 6) of the cellular response subgroup had a positive T-lymphocyte response. The HLA class II alleles DPB1*104:01, DRB1*04:03 and DRB1*14:04 and HLA class I alleles B*08:01 and B*18:01 were found to significantly correlate with seronegativity, and DQB1*06:01 correlated with serological responsiveness. We were unable to analyse the effect of HLA on disease outcome and T-lymphocyte response due to sample size limitations. Our results suggest pathways for further research and begin to elucidate the relationship between HLA polymorphism and immune responses in the vulnerable ESRD population

Three-dimensional analysis of the delta-ferrite to austenite phase transformation in an additively manufactured duplex stainless steel

A fundamental understanding of the δ-ferrite to austenite phase transformation and characteristics of the interfaces formed is currently lacking due to challenges in achieving fully ferritic starting microstructure during conventional processing. Here, a 2205 duplex stainless steel manufactured by laser powder bed fusion (LPBF) is used as a model system to reveal the fundamentals of the δ-ferrite to austenite phase transformation with the aid of three-dimensional electron backscattered diffraction (EBSD). A predominantly δ-ferritic non-equilibrium microstructure is obtained through the high cooling rate during LPBF. During a short thermal treatment of this starting microstructure, four distinct types of austenite (intergranular, instability-induced, sympathetic, and intragranular) are formed. The sympathetic and intragranular austenite present significantly higher area fractions of interfaces following the Kurdjumov-Sachs (Ksingle bondS) or Nishiyama-Wassermann (Nsingle bondW) orientation relationships (ORs) compared to intergranular austenite, owing to their different nucleation and growth mechanisms. The habit plane distributions of various interfaces reveal that ferrite and austenite terminate on (110) and (111) planes, respectively. Interestingly, the plane and curvature distributions do not always exhibit an inverse correlation in the sympathetic and intragranular transformation paths, while the non-K-S/N-W interfaces exhibit lower grain boundary curvatures compared to the K-S/N-W ones. This could be because the total energy minimization associated with phase transformation involves contributions from both the surface energy at grain boundaries and the elastic bulk energy. These new insights into the δ-ferrite to austenite transformation enable duplex microstructure design via additive manufacturing and subsequent post-processing to achieve superior properties

Exploring the epidemiological impact of attractive targeted sugar bait against malaria in combination with standard malaria control

Attractive targeted sugar bait (ATSB) is a potential new vector control tool that exploits the sugar-feeding behaviour of mosquitoes. Little is known about the factors which drive ATSB efficacy, either as a standalone vector control tool or in combination with existing intervention strategies. It has been suggested that the percentage of wild mosquitoes caught fed on dye-containing sugar baits without the toxin could provide an entomological correlate of the potential epidemiological benefit of ATSB. A transmission dynamics mathematical model is combined with data from wild mosquitoes to investigate the relationship between the mosquito dyed fraction, bait-feeding rate and the potential epidemiological impact of ATSB in the presence of standard malaria control. The dyed fraction in Mali varies substantially in space and time (mean 0.34, standard deviation 0.15), causing estimates of the bait-feeding rate to be highly uncertain, especially in areas with existing vector control tools. The model indicates the dyed fractions observed in field experiments were broadly predictive of the reductions in mosquitoes caught when ATSB stations were deployed at scale in Mali (R2 = 0.90). Model projections suggest that if these bait-feeding rates were observed in all mosquitoes, then the widespread use of ATSB could substantially reduce malaria burden alone or in combinations with standard malaria control, though epidemiological impact is likely to vary substantially in different areas. For example, observing a dyed fraction of 5% would indicate a daily bait-feeding rate of 0.024 (range 0.008–0.049) which is projected to result in 0.13 clinical cases averted per person-year (range 0.051–0.22), a 39% efficacy (range 12–66%) in this particular site. Nevertheless, the uncertainty in the relationship between the observed dyed fraction and the true bait-feeding rate, and the underlying biology of mosquito sugar-feeding means that the epidemiological benefit of this new possible intervention remains unclear

The association of class II HLA alleles with tuberculosis-associated immune reconstitution inflammatory syndrome

Genetic associations within the human leukocyte antigen (HLA) gene complex and linked genes in TB-IRIS outcomes remains population specific and not well understood. Here, we conducted a study including well characterised HIV-TB coinfected patients with (n = 86) and without (n = 124) TB-IRIS from the randomized, double-blind, prophylactic prednisone trial (PredART study) with HLA, ERAP and KIR genotyping data. We confirmed the association of TB-IRIS with lower CD4 counts pre-ART initiation. We identified nine classical class I and II HLA alleles protective against TB-IRIS, while four alleles were linked to increased risk. Associations ranged from strongly protective (HLA-DQB1*05:01, OR: 0.07, 95%CI: 0.02-0.28, Pc < 0.001) to strongly risk associated (notably DRB1*01:02, OR: 5.92, 95%CI: 1.36-26.7, Pc = 0.028), with conflicting signals at the HLA-DRB1 locus. Conditional regression analysis revealed that residue E71 at the polymorphic position 71 within the HLA-DRB1 peptide-binding groove was critical, and grouping of HLA-DRB1 alleles by the residue at position 71 corresponded with differential TB-IRIS association. In conclusion, this study identifies population-specific genetic factors influencing TB-IRIS susceptibility and highlights a potential mechanistic role for specific HLA-DRB1 residues in modulating immune responses during ART

Thermodynamic limits on general far-from-equilibrium molecular templating networks

Cells maintain a highly specific, far-from-equilibrium population of RNA and protein molecules. They do so via complex reaction networks in which templates catalyse the assembly of desired products. We show that information transmission from templates to products in such networks is bounded by functions of the maximal difference in free-energy changes between assembly path-ways. Surprisingly, putative systems operating at the bounds do not have a high net flux around the network, as is typical in far-from-equilibrium systems and observed in biology. Instead, the upper bound on accuracy for a given network structure is achieved in “pseudo-equilibrium”. Here, each product is produced and degraded by time-reversed trajectories along a single (product-specific) pathway with negligible entropy production; product yields are determined by the free-energy changes along those pathways. The limit imposed by these free-energy changes induces a thermodynamic constraint on accuracy, even if a single templating process is arbitrarily kinetically selective

Global, regional, and national burden of suicide, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background Deaths from suicide are a tragic yet preventable cause of mortality. Quantifying the burden of suicide to understand its geographical distribution, temporal trends, and variation by age and sex is an essential step in suicide prevention. We aimed to present a comprehensive set of global, regional, and national estimates of suicide burden. Methods We produced estimates of the number of deaths and age-standardised mortality rates of suicide globally, regionally, and for 204 countries and territories from 1990 to 2021, and disaggregated these results by age and sex. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 estimates of deaths attributable to suicide were broken down into two comprehensive categories: those by firearms and those by other specified means. For this analysis, we also produced estimates of mean age at the time of death from suicide, incidence of suicide attempts compared with deaths, and age-standardised rates of suicide by firearm. We acquired data from vital registration, verbal autopsy, and mortality surveillance that included 23 782 study-location-years of data from GBD 2021. Point estimates were calculated from the average of 1000 randomly selected possible values of deaths from suicide by age, sex, and geographical location. 95% uncertainty intervals (UIs) were derived from the 2·5th and 97·5th percentiles from a 1000-draw distribution. Findings Globally, 746 000 deaths (95% UI 692 000–800 000) from suicide occurred in 2021, including 519 000 deaths (485 000–556 000) among males and 227 000 (200 000–255 000) among females. The age-standardised mortality rate has declined over time, from 14·9 deaths (12·8–15·7) per 100 000 population in 1990 to 9·0 (8·3–9·6) per 100 000 in 2021. Regionally, mortality rates due to suicide were highest in eastern Europe (19·2 [17·5–20·8] per 100 000), southern sub-Saharan Africa (16·1 [14·0–18·3] per 100 000), and central sub-Saharan Africa (14·4 [11·0–19·1] per 100 000). The mean age at which individuals died from suicide progressively increased during the study period. For males, the mean age at death by suicide in 1990 was 43·0 years (38·0–45·8), increasing to 47·0 years (43·5–50·6) in 2021. For females, it was 41·9 years (30·9–46·7) in 1990 and 46·9 years (41·2–52·8) in 2021. The incidence of suicide attempts requiring medical care was consistently higher at the regional level for females than for males. The number of deaths by suicide using firearms was higher for males than for females, and substantially varied by country and region. The countries with the highest age-standardised rate of suicides attributable to firearms in 2021 were the USA, Uruguay, and Venezuela. Interpretation Deaths from suicide remain variable by age and sex and across geographical locations, although population mortality rates have continued to improve globally since the 1990s. This study presents, for the first time in GBD, a quantification of the mean age at the time of suicide death, alongside comprehensive estimates of the burden of suicide throughout the world. These analyses will help guide future approaches to reduce suicide mortality that consider a public health framework for prevention

Conformal prediction of molecule-induced cancer cell growth inhibition challenged by strong distribution shifts

The drug discovery process often employs phenotypic and target-based virtual screening to identify potential drug candidates. Despite the longstanding dominance of target-based approaches, phenotypic virtual screening is undergoing a resurgence due to its potential being now better understood. In the context of cancer cell lines, a well-established experimental system for phenotypic screens, molecules are tested to identify their whole-cell activity, as summarized by their half-maximal inhibitory concentrations. Machine learning has emerged as a potent tool for computationally guiding such screens, yet important research gaps persist, including generalization and uncertainty quantification. To address this, we leverage a clustering-based validation approach, called Leave Dissimilar Molecules Out (LDMO). This strategy enables a more rigorous assessment of model generalization to structurally novel compounds. This study focuses on applying Conformal Prediction (CP), a model-agnostic framework, to predict the activities of novel molecules on specific cancer cell lines. A total of 4320 independent models were evaluated across 60 cell lines, 5 CP variants, 2 set features, and training-test splits, providing strong and consistent results. From this comprehensive evaluation, we concluded that, regardless of the cell line or model, novel molecules with smaller CP-calculated confidence intervals tend to have smaller predicted errors once measured activities are revealed. It was also possible to anticipate the activities of dissimilar test molecules across 50 or more cell lines. These outcomes demonstrate the robust efficacy that LDMO-based models can achieve in realistic and challenging scenarios, thereby providing valuable insights for enhancing decision-making processes in drug discovery