Cancer statistics for American Indian and Alaska Native individuals, 2022: Including increasing disparities in early onset colorectal cancer.

American Indian and Alaska Native (AIAN) individuals are diverse culturally and geographically but share a high prevalence of chronic illness, largely because of obstacles to high-quality health care. The authors comprehensively examined cancer incidence and mortality among non-Hispanic AIAN individuals, compared with non-Hispanic White individuals for context, using population-based data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries. Overall cancer rates among AIAN individuals were 2% higher than among White individuals for incidence (2014 through 2018, confined to Purchased/Referred Care Delivery Area counties to reduce racial misclassification) but 18% higher for mortality (2015 through 2019). However, disparities varied widely by cancer type and geographic region. For example, breast and prostate cancer mortality rates are 8% and 31% higher, respectively, in AIAN individuals than in White individuals despite lower incidence and the availability of early detection tests for these cancers. The burden among AIAN individuals is highest for infection-related cancers (liver, stomach, and cervix), for kidney cancer, and for colorectal cancer among indigenous Alaskans (91.3 vs. 35.5 cases per 100,000 for White Alaskans), who have the highest rates in the world. Steep increases for early onset colorectal cancer, from 18.8 cases per 100,000 Native Alaskans aged 20-49 years during 1998 through 2002 to 34.8 cases per 100,000 during 2014 through 2018, exacerbated this disparity. Death rates for infection-related cancers (liver, stomach, and cervix), as well as kidney cancer, were approximately two-fold higher among AIAN individuals compared with White individuals. These findings highlight the need for more effective strategies to reduce the prevalence of chronic oncogenic infections and improve access to high-quality cancer screening and treatment for AIAN individuals. Mitigating the disparate burden will require expanded financial support of tribal health care as well as increased collaboration and engagement with this marginalized population.

CRISPR/Cas9 boosts wheat yield by reducing brassinosteroid signaling.

A modern green revolution is needed to ensure global food security. Recently, Song et al. reported a new strategy to create high-yielding, semi-dwarf wheat varieties with improved nitrogen-use efficiency by inhibiting brassinosteroid (BR) signaling through clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein9 (Cas9)-mediated knockout of the ZnF-B gene encoding a zinc-finger RING-type E3 ligase.

Alcohol Use Disorder Treatment: Problems and Solutions.

Alcohol use disorder (AUD) afflicts over 29 million individuals and causes more than 140,000 deaths annually in the United States. A heuristic framework for AUD includes a three-stage cycle-binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation-that provides a starting point for exploring the heterogeneity of AUD with regard to treatment. Effective behavioral health treatments and US Food and Drug Administration-approved medications are available but greatly underutilized, creating a major treatment gap. This review outlines challenges that face the alcohol field in closing this treatment gap and offers solutions, including broadening end points for the approval of medications for the treatment of AUD; increasing the uptake of screening, brief intervention, and referral to treatment; addressing stigma; implementing a heuristic definition of recovery; engaging early treatment; and educating health-care professionals and the public about challenges that are associated with alcohol misuse. Additionally, this review focuses on broadening potential targets for the development of medications for AUD by utilizing the three-stage heuristic model of addiction that outlines domains of dysfunction in AUD and the mediating neurobiology of AUD.

Changes in well-being among socially isolated older people during the COVID-19 pandemic: An outcome-wide analysis.

Older adults experienced major changes during the COVID-19 pandemic and ensuing restrictions, and it might be expected that those who were already socially isolated before the pandemic were particularly vulnerable. We apply an outcome-wide longitudinal design on 4,636 participants (mean age 66.8 y) from the English Longitudinal Study of Ageing, observed in 2018/19 and early (June/July 2020) and later (November/December 2020) in the pandemic. Social isolation is defined using an index including marital status, social contact, and social participation in 2018/19. Using mixed models, we compare changes in well-being, health, health behaviors, financial well-being, and Internet use, between isolated and nonisolated participants. From before to during the pandemic, isolated participants (29%) experienced smaller declines in life satisfaction and quality of life and a smaller increase in loneliness. They showed greater declines in smoking and physical activity and were more likely to remain worried about their future financial situation. They also did not change in their likelihood of regular Internet use, contrasting with nonisolated participants who increased in this regard. The groups followed a similar trend for general health and sleep quality (no change), depression and anxiety (increase), and expectations of future financial difficulties (decrease). Although isolated older adults generally show poorer outcomes than their socially connected counterparts, they were somewhat protected during the pandemic on some fronts. Our findings highlight the need to continually care for isolated older adults but also to be attentive in times of unexpected crises to those experiencing extreme changes related to necessary policy responses.

Land in limbo: Nearly one third of Indonesia's cleared old-growth forests left idle.

Indonesia has experienced rapid primary forest loss, second only to Brazil in modern history. We examined the fates of Indonesian deforested areas, immediately after clearing and over time, to quantify deforestation drivers in Indonesia. Using time-series satellite data, we tracked degradation and clearing events in intact and degraded natural forests from 1991 to 2020, as well as land use trajectories after forest loss. While an estimated 7.8 Mha (SE = 0.4) of forest cleared during this period had been planted with oil palms by 2020, another 8.8 Mha (SE = 0.4) remained unused. Of the 28.4 Mha (SE = 0.7) deforested, over half were either initially left idle or experienced crop failure before a land use could be detected, and 44% remained unused for 5 y or more. A majority (54%) of these areas were cleared mechanically (not by escaped fires), and in cases where idle lands were eventually converted to productive uses, oil palm plantations were by far the most common outcome. The apparent deliberate creation of idle deforested land in Indonesia and subsequent conversion of idle areas to oil palm plantations indicates that speculation and land banking for palm oil substantially contribute to forest loss, although failed plantations could also contribute to this dynamic. We also found that in Sumatra, few lowland forests remained, suggesting that a lack of remaining forest appropriate for palm oil production, together with an extensive area of banked deforested land, may partially explain slowing forest loss in Indonesia in recent years.

Null mutants of a tomato Rho of plants exhibit enhanced water use efficiency without a penalty to yield.

Improving water use efficiency in crops is a significant challenge as it involves balancing water transpiration and CO2 uptake through stomatal pores. This study investigates the role of SlROP9, a tomato Rho of Plants protein, in guard cells and its impact on plant transpiration. The results reveal that SlROP9 null mutants exhibit reduced stomatal conductance while photosynthetic CO2 assimilation remains largely unaffected. Notably, there is a notable decrease in whole-plant transpiration in the rop9 mutants compared to the wild type, especially during noon hours when the water pressure deficit is high. The elevated stomatal closure observed in rop9 mutants is linked to an increase in reactive oxygen species formation. This is very likely dependent on the respiratory burst oxidase homolog (RBOH) NADPH oxidase and is not influenced by abscisic acid (ABA). Consistently, activated ROP9 can interact with RBOHB in both yeast and plants. In diverse tomato accessions, drought stress represses ROP9 expression, and in Arabidopsis stomatal guard cells, ABA suppresses ROP signaling. Therefore, the phenotype of the rop9 mutants may arise from a disruption in ROP9-regulated RBOH activity. Remarkably, large-scale field experiments demonstrate that the rop9 mutants display improved water use efficiency without compromising fruit yield. These findings provide insights into the role of ROPs in guard cells and their potential as targets for enhancing water use efficiency in crops.

Spatially resolved land and grid model of carbon neutrality in China.

China has committed to achieve net carbon neutrality by 2060 to combat global climate change, which will require unprecedented deployment of negative emissions technologies, renewable energies (RE), and complementary infrastructure. At terawatt-scale deployment, land use limitations interact with operational and economic features of power systems. To address this, we developed a spatially resolved resource assessment and power systems planning optimization that models a full year of power system operations, sub-provincial RE siting criteria, and transmission connections. Our modeling results show that wind and solar must be expanded to 2,000 to 3,900 GW each, with one plausible pathway leading to 300 GW/yr combined annual additions in 2046 to 2060, a three-fold increase from today. Over 80% of solar and 55% of wind is constructed within 100 km of major load centers when accounting for current policies regarding land use. Large-scale low-carbon systems must balance key trade-offs in land use, RE resource quality, grid integration, and costs. Under more restrictive RE siting policies, at least 740 GW of distributed solar would become economically feasible in regions with high demand, where utility-scale deployment is limited by competition with agricultural land. Effective planning and policy formulation are necessary to achieve China's climate goals.

Effects of climate, land use, and human population change on human-elephant conflict risk in Africa and Asia.

Human-wildlife conflict is an important factor in the modern biodiversity crisis and has negative effects on both humans and wildlife (such as property destruction, injury, or death) that can impede conservation efforts for threatened species. Effectively addressing conflict requires an understanding of where it is likely to occur, particularly as climate change shifts wildlife ranges and human activities globally. Here, we examine how projected shifts in cropland density, human population density, and climatic suitability-three key drivers of human-elephant conflict-will shift conflict pressures for endangered Asian and African elephants to inform conflict management in a changing climate. We find that conflict risk (cropland density and/or human population density moving into the 90th percentile based on current-day values) increases in 2050, with a larger increase under the high-emissions "regional rivalry" SSP3 - RCP 7.0 scenario than the low-emissions "sustainability" SSP1 - RCP 2.6 scenario. We also find a net decrease in climatic suitability for both species along their extended range boundaries, with decreasing suitability most often overlapping increasing conflict risk when both suitability and conflict risk are changing. Our findings suggest that as climate changes, the risk of conflict with Asian and African elephants may shift and increase and managers should proactively mitigate that conflict to preserve these charismatic animals.

The Neuroscience of Drug Reward and Addiction.

Drug consumption is driven by a drug's pharmacological effects, which are experienced as rewarding, and is influenced by genetic, developmental, and psychosocial factors that mediate drug accessibility, norms, and social support systems or lack thereof. The reinforcing effects of drugs mostly depend on dopamine signaling in the nucleus accumbens, and chronic drug exposure triggers glutamatergic-mediated neuroadaptations in dopamine striato-thalamo-cortical (predominantly in prefrontal cortical regions including orbitofrontal cortex and anterior cingulate cortex) and limbic pathways (amygdala and hippocampus) that, in vulnerable individuals, can result in addiction. In parallel, changes in the extended amygdala result in negative emotional states that perpetuate drug taking as an attempt to temporarily alleviate them. Counterintuitively, in the addicted person, the actual drug consumption is associated with an attenuated dopamine increase in brain reward regions, which might contribute to drug-taking behavior to compensate for the difference between the magnitude of the expected reward triggered by the conditioning to drug cues and the actual experience of it. Combined, these effects result in an enhanced motivation to "seek the drug" (energized by dopamine increases triggered by drug cues) and an impaired prefrontal top-down self-regulation that favors compulsive drug-taking against the backdrop of negative emotionality and an enhanced interoceptive awareness of "drug hunger." Treatment interventions intended to reverse these neuroadaptations show promise as therapeutic approaches for addiction.

Synthetic Cannabinoids: A Pharmacological and Toxicological Overview.

Synthetic cannabinoids (SCs) are a chemically diverse group of new psychoactive substances (NPSs) that target the endocannabinoid system, triggering a plethora of actions (e.g., elevated mood sensation, relaxation, appetite stimulation) that resemble, but are more intense than, those induced by cannabis. Although some of these effects have been explored for therapeutic applications, anticipated stronger psychoactive effects than cannabis and reduced risk perception have increased the recreational use of SCs, which have dominated the NPS market in the United States and Europe over the past decade. However, rising SC-related intoxications and deaths represent a major public health concern and embody a major challenge for policy makers. Here, we review the pharmacology and toxicology of SCs. A thorough characterization of SCs' pharmacodynamics and toxicodynamics is important to better understand the main mechanisms underlying acute and chronic effects of SCs, interpret the clinical/pathological findings related to SC use, and improve SC risk awareness.

Adverse Impact of Cannabis on Human Health.

Cannabis, the most commonly used recreational drug, is illicit in many areas of the world. With increasing decriminalization and legalization, cannabis use is increasing in the United States and other countries. The adverse effects of cannabis are unclear because its status as a Schedule 1 drug in the United States restricts research. Despite a paucity of data, cannabis is commonly perceived as a benign or even beneficial drug. However, recent studies show that cannabis has adverse cardiovascular and pulmonary effects and is linked with malignancy. Moreover, case reports have shown an association between cannabis use and neuropsychiatric disorders. With growing availability, cannabis misuse by minors has led to increasing incidences of overdose and toxicity. Though difficult to detect, cannabis intoxication may be linked to impaired driving and motor vehicle accidents. Overall, cannabis use is on the rise, and adverse effects are becoming apparent in clinical data sets.

Novel Therapeutic and Program-Based Approaches to Opioid Use Disorders.

Opioid use disorder continues to drive overdose deaths in many countries, including the United States. Illicit fentanyl and its analogues have emerged as key contributors to the complications and mortality associated with opioid use disorder. Medications for opioid use disorder treatment, such as methadone and buprenorphine, are safe and substantially reduce opioid use, infectious complications, and mortality risk, but remain underutilized. Polysubstance use and emerging substances such as xylazine and designer benzodiazepines create additional treatment challenges. Recent clinical and policy innovations in treatment delivery, including telemedicine, bridge clinics, and expanded models for accessing methadone have the potential to increase access to life-saving care for people living with opioid use disorder.

Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.

Despite whole-genome sequencing (WGS), many cases of single-gene disorders remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection. Since early WGS data analytic steps prioritize protein-coding sequences, to simultaneously prioritize variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool that integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants/DNA from 4,867,167 to 21,486, without deleting disease-causal variants. In three unsolved cases (two related), GROFFFY identified ultra-rare deletions within the 3' untranslated region (UTR) of the tumor suppressor SMAD4, where germline loss-of-function alleles cause combined HHT and colonic polyposis (MIM: 175050). Sited >5.4 kb distal to coding DNA, the deletions did not modify or generate microRNA binding sites, but instead disrupted the sequence context of the final cleavage and polyadenylation site necessary for protein production: By iFoldRNA, an AAUAAA-adjacent 16-nucleotide deletion brought the cleavage site into inaccessible neighboring secondary structures, while a 4-nucleotide deletion unfolded the downstream RNA polymerase II roadblock. SMAD4 RNA expression differed to control-derived RNA from resting and cycloheximide-stressed peripheral blood mononuclear cells. Patterns predicted the mutational site for an unrelated HHT/polyposis-affected individual, where a complex insertion was subsequently identified. In conclusion, we describe a functional rare variant type that impacts regulatory systems based on RNA polyadenylation. Extension of coding sequence-focused gene panels is required to capture these variants.

The global human day.

The daily activities of ≈8 billion people occupy exactly 24 h per day, placing a strict physical limit on what changes can be achieved in the world. These activities form the basis of human behavior, and because of the global integration of societies and economies, many of these activities interact across national borders. Yet, there is no comprehensive overview of how the finite resource of time is allocated at the global scale. Here, we estimate how all humans spend their time using a generalized, physical outcome-based categorization that facilitates the integration of data from hundreds of diverse datasets. Our compilation shows that most waking hours are spent on activities intended to achieve direct outcomes for human minds and bodies (9.4 h/d), while 3.4 h/d are spent modifying our inhabited environments and the world beyond. The remaining 2.1 h/d are devoted to organizing social processes and transportation. We distinguish activities that vary strongly with GDP per capita, including the time allocated to food provision and infrastructure, vs. those that do not vary consistently, such as meals and transportation time. Globally, the time spent directly extracting materials and energy from the Earth system is small, on the order of 5 min per average human day, while the time directly dealing with waste is on the order of 1 min per day, suggesting a large potential scope to modify the allocation of time to these activities. Our results provide a baseline quantification of the temporal composition of global human life that can be expanded and applied to multiple fields of research.

Tropical forests post-logging are a persistent net carbon source to the atmosphere.

Logged and structurally degraded tropical forests are fast becoming one of the most prevalent land-use types throughout the tropics and are routinely assumed to be a net carbon sink because they experience rapid rates of tree regrowth. Yet this assumption is based on forest biomass inventories that record carbon stock recovery but fail to account for the simultaneous losses of carbon from soil and necromass. Here, we used forest plots and an eddy covariance tower to quantify and partition net ecosystem CO2 exchange in Malaysian Borneo, a region that is a hot spot for deforestation and forest degradation. Our data represent the complete carbon budget for tropical forests measured throughout a logging event and subsequent recovery and found that they constitute a substantial and persistent net carbon source. Consistent with existing literature, our study showed a significantly greater woody biomass gain across moderately and heavily logged forests compared with unlogged forests, but this was counteracted by much larger carbon losses from soil organic matter and deadwood in logged forests. We estimate an average carbon source of 1.75 ± 0.94 Mg C ha-1 yr-1 within moderately logged plots and 5.23 ± 1.23 Mg C ha-1 yr-1 in unsustainably logged and severely degraded plots, with emissions continuing at these rates for at least one-decade post-logging. Our data directly contradict the default assumption that recovering logged and degraded tropical forests are net carbon sinks, implying the amount of carbon being sequestered across the world's tropical forests may be considerably lower than currently estimated.

Epigenetic function during heroin self-administration controls future relapse-associated behavior in a cell type-specific manner.

Opioid use produces enduring associations between drug reinforcement/euphoria and discreet or diffuse cues in the drug-taking environment. These powerful associations can trigger relapse in individuals recovering from opioid use disorder (OUD). Here, we sought to determine whether the epigenetic enzyme, histone deacetylase 5 (HDAC5), regulates relapse-associated behavior in an animal model of OUD. We examined the effects of nucleus accumbens (NAc) HDAC5 on both heroin- and sucrose-seeking behaviors using operant self-administration paradigms. We utilized cre-dependent viral-mediated approaches to investigate the cell-type-specific effects of HDAC5 on heroin-seeking behavior, gene expression, and medium spiny neuron (MSN) cell and synaptic physiology. We found that NAc HDAC5 functions during the acquisition phase of heroin self-administration to limit future relapse-associated behavior. Moreover, overexpressing HDAC5 in the NAc suppressed context-associated and reinstated heroin-seeking behaviors, but it did not alter sucrose seeking. We also found that HDAC5 functions within dopamine D1 receptor-expressing MSNs to suppress cue-induced heroin seeking, and within dopamine D2 receptor-expressing MSNs to suppress drug-primed heroin seeking. Assessing cell-type-specific transcriptomics, we found that HDAC5 reduced expression of multiple ion transport genes in both D1- and D2-MSNs. Consistent with this observation, HDAC5 also produced firing rate depression in both MSN classes. These findings revealed roles for HDAC5 during active heroin use in both D1- and D2-MSNs to limit distinct triggers of drug-seeking behavior. Together, our results suggest that HDAC5 might limit relapse vulnerability through regulation of ion channel gene expression and suppression of MSN firing rates during active heroin use.

Can accurate demographic information about people who use prescription medications nonmedically be derived from Twitter?

Traditional substance use (SU) surveillance methods, such as surveys, incur substantial lags. Due to the continuously evolving trends in SU, insights obtained via such methods are often outdated. Social media-based sources have been proposed for obtaining timely insights, but methods leveraging such data cannot typically provide fine-grained statistics about subpopulations, unlike traditional approaches. We address this gap by developing methods for automatically characterizing a large Twitter nonmedical prescription medication use (NPMU) cohort (n = 288,562) in terms of age-group, race, and gender. Our natural language processing and machine learning methods for automated cohort characterization achieved 0.88 precision (95% CI:0.84 to 0.92) for age-group, 0.90 (95% CI: 0.85 to 0.95) for race, and 94% accuracy (95% CI: 92 to 97) for gender, when evaluated against manually annotated gold-standard data. We compared automatically derived statistics for NPMU of tranquilizers, stimulants, and opioids from Twitter with statistics reported in the National Survey on Drug Use and Health (NSDUH) and the National Emergency Department Sample (NEDS). Distributions automatically estimated from Twitter were mostly consistent with the NSDUH [Spearman r: race: 0.98 (P < 0.005); age-group: 0.67 (P < 0.005); gender: 0.66 (P = 0.27)] and NEDS, with 34/65 (52.3%) of the Twitter-based estimates lying within 95% CIs of estimates from the traditional sources. Explainable differences (e.g., overrepresentation of younger people) were found for age-group-related statistics. Our study demonstrates that accurate subpopulation-specific estimates about SU, particularly NPMU, may be automatically derived from Twitter to obtain earlier insights about targeted subpopulations compared to traditional surveillance approaches.

The productive performance of intercropping.

Crop diversification has been put forward as a way to reduce the environmental impact of agriculture without penalizing its productivity. In this context, intercropping, the planned combination of two or more crop species in one field, is a promising practice. On an average, intercropping saves land compared with the component sole crops, but it remains unclear whether intercropping produces a higher yield than the most productive single crop per unit area, i.e., whether intercropping achieves transgressive overyielding. Here, we quantified the performance of intercropping for the production of grain, calories, and protein in a global meta-analysis of several production indices. The results show that intercrops outperform sole crops when the objective is to achieve a diversity of crop products on a given land area. However, when intercropping is evaluated for its ability to produce raw products without concern for diversity, intercrops on average generate a small loss in grain or calorie yield compared with the most productive sole crop (-4%) but achieve similar or higher protein yield, especially with maize/legume combinations grown at moderate N supply. Overall, although intercropping does not achieve transgressive overyielding on average, our results show that intercropping performs well in producing a diverse set of crop products and performs almost similar to the most productive component sole crop to produce raw products, while improving crop resilience, enhancing ecosystem services, and improving nutrient use efficiency. Our study, therefore, confirms the great interest of intercropping for the development of a more sustainable agricultural production, supporting diversified diets.

Edible fungi crops through mycoforestry, potential for carbon negative food production and mitigation of food and forestry conflicts.

Demand for agricultural land is a potent accelerating driver of global deforestation, presenting multiple interacting issues at different spatiotemporal scales. Here we show that inoculating the root system of tree planting stock with edible ectomycorrhizal fungi (EMF) can reduce the food-forestry land-use conflict, enabling appropriately managed forestry plantations to contribute to protein and calorie production and potentially increasing carbon sequestration. Although, when compared to other food groups, we show that EMF cultivation is inefficient in terms of land use with a needed area of ~668 m2 y kg-1 protein, the additional benefits are vast. Depending on the habitat type and tree age, greenhouse gas emissions may range from -858 to 526 kg CO2-eq kg-1 protein and the sequestration potential stands in stark contrast to nine other major food groups. Further, we calculate the missed food production opportunity of not incorporating EMF cultivation into current forestry activities, an approach that could enhance food security for millions of people. Given the additional biodiversity, conservational and rural socioeconomic potential, we call for action and development to realize the sustainable benefits of EMF cultivation.

Minimizing habitat conflicts in meeting net-zero energy targets in the western United States.

The scale and pace of energy infrastructure development required to achieve net-zero greenhouse gas (GHG) emissions are unprecedented, yet our understanding of how to minimize its potential impacts on land and ocean use and natural resources is inadequate. Using high-resolution energy and land-use modeling, we developed spatially explicit scenarios for reaching an economy-wide net-zero GHG target in the western United States by 2050. We found that among net-zero policy cases that vary the rate of transportation and building electrification and use of fossil fuels, nuclear generation, and biomass, the "High Electrification" case, which utilizes electricity generation the most efficiently, had the lowest total land and ocean area requirements (84,000 to 105,000 km2 vs. 88,100 to 158,000 km2 across all other cases). Different levels of land and ocean use protections were applied to determine their effect on siting, environmental and social impacts, and energy costs. Meeting the net-zero target with stronger land and ocean use protections did not significantly alter the share of different energy generation technologies and only increased system costs by 3%, but decreased additional interstate transmission capacity by 20%. Yet, failure to avoid development in areas with high conservation value is likely to result in substantial habitat loss.