A steady-state N balance approach for sustainable smallholder farming.

Hundreds of millions of smallholders in emerging countries substantially overuse nitrogen (N) fertilizers, driving local environmental pollution and global climate change. Despite local demonstration-scale successes, widespread mobilization of smallholders to adopt precise N management practices remains a challenge, largely due to associated high costs and complicated sampling and calculations. Here, we propose a long-term steady-state N balance (SSNB) approach without these complications that is suitable for sustainable smallholder farming. The hypothesis underpinning the concept of SSNB is that an intensively cultivated soil-crop system with excessive N inputs and high N losses can be transformed into a steady-state system with minimal losses while maintaining high yields. Based on SSNB, we estimate the optimized N application range across 3,824 crop counties for the three staple crops in China. We evaluated SSNB first in ca. 18,000 researcher-managed on-farm trials followed by testing in on-farm trials with 13,760 smallholders who applied SSNB-optimized N rates under the guidance of local extension staff. Results showed that SSNB could significantly reduce N fertilizer use by 21 to 28% while maintaining or increasing yields by 6 to 7%, compared to current smallholder practices. The SSNB approach could become an effective tool contributing to the global N sustainability of smallholder agriculture.

Switchable Chemo-, Regio- and Pseudo-Stereodivergence in Palladium-Catalyzed Cycloaddition of Allenes.

Here, we report a strategy enabling triple switchable chemo-, regio-, and stereodivergence in newly developed palladium-catalyzed cycloadditions of allenes. An asymmetric pseudo-stereodivergent cycloaddition of allenes bearing a primary leaving group at the α-position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio-determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di-substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O-attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4-dihydro-2H-1,4-benzoxazines in high efficiency and selectivity.

Cost-Effectiveness Analyses of Digital Health Technology for Improving the Uptake of Vaccination Programs: Systematic Review.

BACKGROUND: Vaccination is the most effective strategy to prevent infectious diseases, yet vaccination coverage has not reached the target level. To promote vaccination uptake, digital health interventions (DHIs) have been used in various vaccination programs. OBJECTIVE: This study aimed to perform a systematic review of the cost-effectiveness analyses of DHIs for the improvement of the uptake of vaccination programs. METHODS: A literature review was conducted in MEDLINE (Ovid), Embase (Ovid), APA PsycINFO (Ovid), Web of Science, Scopus, CINAHL Ultimate (EBSCOhost), Center for Review and Dissemination, and Institute for IEEE Xplore up to October 2022. Health economic evaluations that met the following inclusion criteria were included: (1) adult or pediatric vaccination programs; (2) interventions delivered through digital technology; (3) full-scale health economic analyses including cost-effectiveness, cost-utility, cost-benefit, or cost-consequence analyses; and (4) evaluations conducted by model-based or trial-based analyses. The quality of each included study was evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). RESULTS: The systematic review included 7 studies. Four of the cost-effectiveness studies were conducted by model-based analyses, and 3 were trial-based analyses. One study reported the additional cost per quality-adjusted life years (QALYs) gained, whereas 6 studies reported the additional cost per individual vaccinated (or return case). The vaccines targeted the human papillomavirus (HPV) vaccine, influenza vaccination, measles-mumps-rubella (MMR) vaccine, and children immunization at different ages. The DHIs were delivered by television campaign, web-based decision aid, SMS text message, telephone, and computer-generated recall letters. The studies were classified as very good (n=5) and good (n=2) qualities. One study concluded that the DHI was cost-saving, and 6 studies concluded that the DHI was cost-effective. CONCLUSIONS: This study is the first systematic review on cost-effectiveness analyses of DHIs to improve vaccination uptake. All included studies have good to very good quality on study assessment and reported the DHIs to be cost-saving or cost-effective in the improvement of vaccination uptake.

Construction of Acyclic All-Carbon Quaternary Stereocenters and 1,3-Nonadjacent Stereoelements via Organo/Metal Dual Catalyzed Asymmetric Allenylic Substitution of Aldehydes.

A method for the asymmetric construction of functionalized acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements has been developed via organo/metal dual catalyzed asymmetric allenylic substitution of branched and linear aldehydes, by developing an unknown acyclic secondary-secondary diamine as the enabling organocatalyst. Although it is believed that secondary-secondary diamines are difficult to be used as the organocatalysts in organo/metal dual catalysis, this study demonstrates that such diamines can be successfully combined with a metal catalyst in organo/metal dual catalysis. Our study enables the asymmetric construction of two important classes of motifs which were previously difficult to access, axially chiral allene-containing acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements bearing allenyl axial chirality and central chirality, in good yields with high enantio- and diastereoselectivity.

Direct Catalytic Asymmetric and Regiodivergent N1- and C3-Allenylic Alkylation of Indoles.

Herein we report a Pd-catalyzed asymmetric allenylic alkylation strategy for the direct functionalization of 1H-indoles by employing P-chiral BIBOP-type ligands. The regioselectivity (N1/C3) of this process can be switched efficiently. Using Cs2 CO3 at elevated temperatures in MeCN, N1-alkylated indoles bearing axial chirality with a stereocenter non-adjacent (ß) to the nitrogen are produced in good yields with high enantioselectivity and complete N1-regioselectivity regardless of the electronic properties and substitution patterns of diverse indoles. Using K2 CO3 at room temperature in CH2 Cl2 , chiral C3-alkylated indoles can also be obtained. Notably, we introduce a new class of tri-substituted allenylic electrophiles that proceeded through different pathways from di-substituted allenylic electrophiles.

Evaluation of variation in background nitrous oxide emissions: A new global synthesis integrating the impacts of climate, soil, and management conditions.

Robust global simulation of soil background N2 O emissions (BNEs) is a challenge due to the lack of a comprehensive system for quantification of the variations in their magnitude and location. We mapped global BNEs based on 1353 field observations from globally distributed sites and high-resolution climate and soil data. We then calculated global and national total BNE budgets and compared them to the IPCC-estimated values. The average BNE was 1.10, 0.92, and 0.84 kg N ha-1  year-1 with variations from 0.18 to 3.47 (5th-95th percentile, hereafter), 0.20 to 3.44, and -1.16 to 3.70 kg N ha-1  year-1 for cropland, forestland, and grassland, respectively. Soil pH, soil N mineralization, atmospheric N deposition, soil volumetric water content, and soil temperature were the principle significant drivers of BNEs. The total BNEs of three land use types was lower than IPCC-estimated total BNEs by 0.83 Tg (1012  g) N year-1 , ranging from -47% to 94% across countries. The estimated BNE with cropland values were slightly higher than the IPCC estimates by 0.11 Tg N year-1 , and forestland and grassland lower than the IPCC estimates by 0.4 and 0.54 Tg N year-1 , respectively. Our study underlined the necessity for detailed estimation of the spatial distribution of BNEs to improve the estimates of global N2 O emissions and enable the establishment of more realistic and effective mitigation measures.

Does the provision of informal care matter for caregivers' mental health? Evidence from China.

This paper investigates the causal effect of informal care on the mental health of caregivers and disentangles the mechanisms of such effect. Using 2011-2018 CHARLS data, the fixed effects and instrumental variable approaches was conducted to address fundamental endogeneity problems. This study found that there was no impact of informal caregiving on caregivers' mental health in general. However, the intensity of caregiving was shown to negatively impair mental health. The impact of informal caregiving varied by kinship, cultural context, and residential area. Participation in social and exercise activities and life satisfaction mediated the association between the provision of informal care and caregivers' mental health. Long-term care insurance and the provision of formal care substantially modified the negative impacts of informal caregiving.

Enantioselective synthesis of chiral α-alkynylated thiazolidones by tandem S-addition/acetalization of alkynyl imines.

A SPINOL-derived chiral phosphoric acid catalyzed asymmetric formal [2 + 3]-annulation of in situ generated alkynyl imines and 1,4-dithiane-2,5-diol has been developed to afford enantiopure α-alkynylated thiazolidones with up to 72% yield and 98.5 : 1.5 er. This tandem annulation involved a tandem S-addition of alkynyl imines/intramolecular acetalization, followed by PDC-mediated oxidation. The α-alkynylated thiazolidones could facilely afford the corresponding chiral α-alkynylated or α-alkenylated cyclic sulfoxides via further elaboration.

Safeguarding Food Supply and Groundwater Safety for Maize Production in China.

Quantifying sustainable nitrogen (N) management at the national scale is critical for developing targeted policies and strategies to simultaneously achieve food security and groundwater protection. In this study, we report county-scale optimization scenarios for Chinese maize production and evaluate their outcomes for safeguarding food supply and groundwater safety. First, we performed random forest regression modeling to simulate in situ NO3- leaching based on a meta-analysis that integrates climate, soil, water, and N balance parameters. The NO3- leaching was then mapped for 1406 counties based on data compiled from 2.89 million farmer surveys. Average NO3- leaching during the maize growth season was estimated to be 27.6 kg N ha-1, and 56% of counties had groundwater whose nitrate concentrations exceeded drinking water safety levels during 2005-2014. The top 5% farmers in each county produced not only more grain but also greater NO3- leaching. Scenario analysis of potential management changes found that when these top producers combined optimal N management practices, national N use in Chinese maize system was reduced by 25%, from 9.1 to 6.9 Mt, while maize production increased by 6.1%. Modeled NO3- leaching was 0.58 Mt, which was 31% lower than groundwater safety levels and 53% lower than the current leaching amount. This study provides evidence that integrated crop and N management practices implemented at the county level safeguard both maize crop food security and enhance environment sustainability.

Newer and select maize, wheat, and rice varieties can help mitigate N footprint while producing more grain.

Sustainably feeding the growing population amid a changing climate and dwindling resources is a grand challenge facing mankind. Decades-long advancement in crop breeding has progressively elevated yield potential, markedly enhancing global food production capacity. However, relevant impact on reactive N (Nr) emissions associated with crop variety improvement has not been explicitly described. Here, we report multitiered evidence that newer and select maize, wheat, and rice varieties developed in China have the capacity to substantially lower Nr losses while producing more grain. First, we pooled studies featuring side-by-side comparison of different varieties, totaling 269 paired observations, to demonstrate that collectively, relatively newer varieties of maize, wheat, and rice had less Nr emissions (9.6%-23.5%) while yielding more grains (7.3%-11.2%) compared to older varieties under wide-ranging conditions. Next, we built an extended database (142 field studies with 833 observations) and comprehensively evaluated the Nr-loss reduction potential of newer varieties (2000 and after) versus older ones (1985-1999). We found that newer varieties had Nr emission factors (N loss as a percentage of N applied after correcting for background emissions) 18.2%-75.7% less for N2 O, 18.3%-75.7% less for NO 3 - , and -8.5% to 22.8% less for NH3 , while producing more grains (16.0%-24.4%). Individual varieties differed markedly in yield-emission scores. A nationwide farmer survey (2.47 million responses) indicated tremendous opportunities for a new way of management intervention. Coupling variety selection with sound N and other agronomic management can help lower N footprint while producing more grain.

Genes in immune pathways associated with abnormal white matter integrity in first-episode and treatment-naïve patients with schizophrenia.

BACKGROUND: Previous studies have inferred a strong genetic component in schizophrenia. However, the genetic variants involved in the susceptibility to schizophrenia remain unclear.AimsTo detect potential gene pathways and networks associated with schizophrenia, and to explore the relationship between common and rare variants in these pathways and abnormal white matter integrity in schizophrenia. METHOD: The analysis included 100 first-episode treatment-naïve patients with schizophrenia and 140 healthy controls. A network-based analysis was carried out on the data collected from the Psychiatric Genomics Consortium Phase I (PGC-I). Based on our genome-wide association study and whole-exome sequencing data-sets, we performed a gene-set analysis to detect associations between the combining effects of common and rare genetic variants and abnormal white matter integrity in schizophrenia. RESULTS: Patients had significantly reduced functional anisotropy in the left and right anterior cingulate cortex, left and right precuneus and extra-nuclear (t = 4.61-5.10, PFDR < 0.01), compared with controls. Generated from co-expression network analysis of the PGC-1 summary statistics of schizophrenia, a subnetwork of 207 genes associated with schizophrenia was identified (P < 0.01), and 176 genes were co-expressed in four gene modules. Functional enrichment analysis for genes in each module revealed that the yellow module was enriched with highly co-expressed, innate immune response genes. Furthermore, rare variants of enriched genes in the yellow module were associated with reduced functional anisotropy in the left anterior cingulate cortex (P = 0.006; Padjusted = 0.024) in patients only. CONCLUSIONS: The pathogenesis of schizophrenia may be substantially influenced by genes involved in the immune system, via both pathway and network.Declaration of interestsNone.

Plasma neuropeptides as circulating biomarkers of multifactorial schizophrenia.

BACKGROUND: Promising biomarkers would be used to improve the determination of diagnosis and severity, as well as the prediction of symptomatic and functional outcomes of schizophrenia. BASIC PROCEDURES: In this study, we used three different mouse models induced by a genetic factor (PV-Cre; ErbB4-/-, G group), an environmental stressor (adolescent social isolation, G group), and a combination of genetic factor and environmental stressor (PV-Cre; ErbB4-/- mice with isolation, G × E group). Attenuated PPI (%) confirmed the successful establishment of three schizophrenia-like mouse models. To evaluate whether neuropeptide levels in plasma would be potential biomarkers of different schizophrenia models in our work, we used MILLIPLEX® MAP method to simultaneously measure 6 critical neuropeptides in plasma. MAIN FINDINGS: Among the evaluated neuropeptides, increased neurotensin tends to be associated with genetic factors of schizophrenia, increased orexin A seems to be a biomarker of an interplay between genetic and social isolation, while higher plasma oxytocin might be more apt to be responsive to social isolation. The potential biomarkers are mostly independent of sex. CONCLUSIONS: This research would provide novel clues to develop circulating biomarkers of plasma neuropeptides for multifactorial schizophrenia.

Neural substrate of unrelenting negative symptoms in schizophrenia: a longitudinal resting-state fMRI study.

Developing a mechanistic insight into the specific brain processes that underpin improvement in negative symptoms can help us design novel chemical and physical treatments against these unrelenting symptoms. The aim of the present study is to explore the longitudinal changes in the brain's regional functional efficiency that accompany improvement in negative symptoms seen in first-episode patients with schizophrenia when treated with antipsychotic for 1 year. Forty-seven first-episode patients with schizophrenia were scanned at a drug-naive baseline state and followed up for 1 year to identify negative symptom responders (Rn) and non-responders (NRn). Fractional amplitude of low-frequency fluctuations (fALFF) and Granger analysis of effective connectivity (EC) were used to examine the different patterns of regional function and connectivity between Rn and NRn during the 1 year follow-up. Increase of fALFF in the left superior temporal gyrus (STG) and increase of EC from the left STG to the dorsolateral prefrontal cortex (DLPFC) was found in Rn compared to NRn. We further validated that the identified changes in fALFF/EC of STG occur specifically in relation to negative symptoms only (i.e., not pseudo-specific in relation to positive, extrapyramidal or depressive symptoms), and occur irrespective of arbitrary clinical categorization of treatment response. An increase in fALFF in the precuneus and the inferior parietal lobule, and a decrease in EC from the left STG to the occipital cortex, were also found at the 1 year follow-up irrespective of improvement in negative symptoms. Interventions that improve the functional efficiency of left STG and its prefrontal connectivity may show efficacy in alleviating negative symptoms in first-episode schizophrenia.

[A twin study on externalizing problem behavior in adolescents in Chongqing City].

OBJECTIVE: To explore the relations of adolescents externalizing problem behavior to genetic and environmental factors through twin study. METHODS: The externalizing problem behavior of 66 twin pairs from Chongqing City( aged from 12 to 18years) were investigated with the Youth Self-Report( YSR). The Parenting Styles and Dimensions Questionnaire( PSDQ) and Family Stresses Questionnaire( FSQ), Family Adaptability and Cohesion Scale( FACES) and Stressful Life Event( SLE) were applied to assess their environment factors. The blood sample was collected to identify zygosity oftwins. Structural equation modeling( SEM) was performed to evaluate the relations of adolescents externalizing problem behavior to the additive genetic factors( A), shared environment factors( C) and individual specific environmental factors( E). RESULTS: The effects of A and E on adolescent externalizing problem behavior were 0. 57( 95% CI 0. 37-0. 72) and 0. 43( 95% CI 0. 28-0. 63), respectively. There were significantly negative correlation between externalizing problem behavior and family cohesion( r =-0. 221, P <0. 05), the scores of adolescent externalizing problem behavior were positively correlated with the scores of family stresses( r = 0. 226, P < 0. 05), the scores of stress life events( r = 0. 194, P < 0. 05), the scores of Authoritarian-parenting-style( r = 0. 235, P <0. 05), the scores of Permissive-parenting-style( r = 0. 212, P < 0. 05). The scores of adolescents externalizing behavioral problems were not significantly correlated with the parenting education level and occupation. CONCLUSION: Adolescents externalizing problem behavior are influenced by additive genetic factors and individual specific environmental factors. Additive genetic factors play an important role. Family environment and parental rearing-pattern also have correlation with externalizing behavioral problems.

An Arylation Strategy to Propargylamines: Catalytic Asymmetric Friedel-Crafts-type Arylation Reactions of C-Alkynyl Imines.

The first arylation strategy for the synthesis of enantioenriched propargylamines is disclosed. This approach, which is complementary to previous alkynylation and alkylation strategies, involves a C(sp2 )-C(sp3 ) bond formation, and is based on the first asymmetric Friedel-Crafts-type arylation reaction of C-alkynyl imines. Asymmetric Friedel-Crafts reactions with electron-deficient phenols, a longstanding unsolved challenge, have thus been realized for the first time, enabled by the combination of our recently introduced C-alkynyl N-Boc-protected N,O-acetals as electrophiles and chiral phosphoric acids as catalysts. The synthetic utility of the resulting structurally diverse and polyfunctional chiral propargylamines was demonstrated by a series of selective transformations, including controlled reduction of the alkynyl group and iterative cross-couplings.

Genetic influences on resting-state functional networks: A twin study.

Alterations in resting-state networks (RSNs) are often associated with psychiatric and neurologic disorders. Given this critical linkage, it has been hypothesized that RSNs can potentially be used as endophenotypes for brain diseases. To validate this notion, a critical step is to show that RSNs exhibit heritability. However, the investigation of the genetic basis of RSNs has only been attempted in the default-mode network at the region-of-interest level, while the genetic control on other RSNs has not been determined yet. Here, we examined the genetic and environmental influences on eight well-characterized RSNs using a twin design. Resting-state functional magnetic resonance imaging data in 56 pairs of twins were collected. The genetic and environmental effects on each RSN were estimated by fitting the functional connectivity covariance of each voxel in the RSN to the classic ACE twin model. The data showed that although environmental effects accounted for the majority of variance in wide-spread areas, there were specific brain sites that showed significant genetic control for individual RSNs. These results suggest that part of the human brain functional connectome is shaped by genomic constraints. Importantly, this information can be useful for bridging genetic analysis and network-level assessment of brain disorders.

[Association of gender, age, education and polymorphism of DRD4 gene with cognitive functions in adults].

OBJECTIVE: To assess the association of cognitive functions with gender, age, education and polymorphism of dopamine receptor D4 (DRD4) gene in healthy adults. METHODS: Four hundred and fifty-five healthy participants have completed 3 cognitive function tests including Tower of Hanoi (TOH), Wisconsin Card Sorting Test (WCST) and Trail Making Test (TMT). Peripheral blood samples were collected from all participants, and genomic DNA was extracted according to a standard phenol-chloroform procedure. Rs3758653 in the promoter region of the DRD4 gene was genotyped using Illumina GoldenGate genotyping assay. RESULTS: Males have performed better than females in terms of TOH executive time and TOH total score, but did worse in TOH planning time. Most of the measured cognitive domains were affected by age and education. Cognitive ability has decreased along with increased age and decline of educational years. The polymorphism of rs3758653 has mainly correlated with the TOH executive time. Compared with A allele carriers, G allele carriers did worse in TOH executive time. CONCLUSION: Gender, age, education and the rs3758653 polymorphism of the DRD4 gene play an important role in cognitive functions in healthy adults.

[A twin study on genetic and environmental factors of adolescents violence behaviors].

OBJECTIVE: To explore the influence of genetic and environmental factors on adolescents violence behaviors. METHODS: The violence behaviors of 111 twin pairs from Chongqing (aged from 11 to 18 years) were investigated with risk behavior questionnaire-adolescent (RBQ-A). The Parenting Styles and Dimensions Questionnaire (PSDQ) and Stressful Life Event (SLE) and the General Functioning Scale of the MacMaster Family Activity Device (FAD-GFS) were applied to assess their environment factors. Structural equation modeling was performed to evaluate the effects of the additive genetic factors (A), shared environment factors (C) and individual specific environmental factors (E) on the adolescents violence behaviors. RESULTS: The effects of A and E on adolescents violence behaviors were 0.41 (95% CI 0.19-0.58) and 0.59 (95% CI 0.42-0.81) respectively. There were significantly negative correlation between violence behaviors and authoritative-parenting-style (r = -0.140, P < 0.05), the score of adolescents violence behaviors was positively correlated with repressive-parenting-style score (r = 0.133, P < 0.05), the score of adolescents violence behaviors were not significantly correlated with the family functions, stress life events and the parenting education level and occupation. CONCLUSION: Adolescents violence behaviors were influenced by additive genetic factors and individual specific environmental factors. Environmental plays an important role. It should not been ignored that parental rearing pattern play a role in adolescents violence behaviors.

[Effect of Risperidone on BDNF-TrkB Signaling Pathway in Rat Brain].

OBJECTIVE: To investigate the effect of risperidone on the expression of brain-derived neurotrophic factor (BDNF) and its receptors, tyrosine kinase receptor (TrkB) and P75 neurotrophin receptor (P75NTR) in rat brain. METHODS: Sixteen SD rats were divided into two groups (n = 8 for each group). The rats in experimental group were treated with risperidone [0.25 mg/(kg · d)] for 14 d, while the control group was given placebo. Total RNA sample in prefrontal cortex, temporal cortex and hippocampus was extracted, and the expression of BDNF, TrkB and P75NTR mRNA were determined by quantitative real-time PCR. RESULTS: The treatment of risperidone significantly up-regulated the expressions of BDNF and TrkB in prefrontal cortex, temporal cortex and hippocampus, while the expression of P75NTR was not significantly changed. CONCLUSION: Risperidone upregulated BDNF-TrkB signaling, but not BDNF-P75NTR signaling, which may be helpful for the further pharmacological study of risperidone.

Activated protease receptor-2 induces GATA6 expression to promote survival in irradiated colon cancer cells.

BACKGROUND AND AIMS: The resistance to irradiation is common and a great drawback in the treatment of cancer with radiotherapy; the underlying mechanism is unclear. GATA binding protein 6 (GATA6) is associated with the pathogenesis of cancer. This study aims to investigate the role of GATA6 on compromising irradiation effect on HT55 and HT29 cells, 2 colorectal cancer cell lines. METHODS: Human colon cancer cell lines, HT55 and HT29 cells, were treated with irradiation in the culture. Apoptosis of HT55 and HT29 cells was determined by flow cytometry. The expression of PAR2 and GATA6 in HT55 and HT29 cells was analyzed by real time RT-PCR and Western blotting. The gene silence and gene over expression were employed to observe the effect of GATA6 on p53 expression in HT55 and HT29 cells. RESULTS: The results showed that HT55 and HT29 cells expressed protease-activated receptor-2 (PAR2). Irradiation induced 38.6% HT55 cell and 33.8% HT29 cell apoptosis, which reduced to 4.2% and 5.6%, respectively after activation of PAR2. Exposure to irradiation increased the expression of GATA6; the latter played a critical role in suppression of p53 expression in HT55 and HT29 cells. Inhibition of GATA6 significantly increased the effect of irradiation on HT55 and HT29 cells. CONCLUSIONS: Activation of PAR2 compromises the effect of irradiation on inducing colorectal cancer cell apoptosis, which can be prevented by inhibition of GATA6 expression.