Human Brain Organoid Research and Applications: Where and How to Meet Legal Challenges?

An ethical and legal framework is needed to regulate the rapidly developing human brain organoid research field properly. However, considering the legal issues involved in human brain organoid research remains underdeveloped and scattered. This article reviews the legal issues of human brain organoid research, grouping them into the following five broad themes: (1) consciousness, (2) legal status, (3) consent, (4) ownership, and (5) transplantation. The issues in each topic include both the urgent (e.g., appropriate forms of consent) and the speculative (e.g., protection of conscious human brain organoids). Therefore, we have attempted to be as explicit as possible about the timescale within which each issue will be realized and to prioritize each. Examining these issues has revealed legal issues specific to human brain organoid research and issues common to research in other fields. Further discussion of human brain organoid research from a legal perspective is needed in the future, considering discussions in related fields.

Magnetic Tunability via Control of Crystallinity and Size in Polycrystalline Iron Oxide Nanoparticles.

Iron oxide nanoparticles (IONPs) are widely used for biomedical applications due to their unique magnetic properties and biocompatibility. However, the controlled synthesis of IONPs with tunable particle sizes and crystallite/grain sizes to achieve desired magnetic functionalities across single-domain and multi-domain size ranges remains an important challenge. Here, a facile synthetic method is used to produce iron oxide nanospheres (IONSs) with controllable size and crystallinity for magnetic tunability. First, highly crystalline Fe3O4 IONSs (crystallite sizes above 24 nm) having an average diameter of 50 to 400 nm are synthesized with enhanced ferrimagnetic properties. The magnetic properties of these highly crystalline IONSs are comparable to those of their nanocube counterparts, which typically possess superior magnetic properties. Second, the crystallite size can be widely tuned from 37 to 10 nm while maintaining the overall particle diameter, thereby allowing precise manipulation from the ferrimagnetic to the superparamagnetic state. In addition, demonstrations of reaction scale-up and the proposed growth mechanism of the IONSs are presented. This study highlights the pivotal role of crystal size in controlling the magnetic properties of IONSs and offers a viable means to produce IONSs with magnetic properties desirable for wider applications in sensors, electronics, energy, environmental remediation, and biomedicine.

Genome-wide atlas of rust resistance loci in wheat.

Rust diseases, including leaf rust, stripe/yellow rust, and stem rust, significantly impact wheat (Triticum aestivum L.) yields, causing substantial economic losses every year. Breeding and deployment of cultivars with genetic resistance is the most effective and sustainable approach to control these diseases. The genetic toolkit for wheat breeders to select for rust resistance has rapidly expanded with a multitude of genetic loci identified using the latest advances in genomics, mapping and cloning strategies. The goal of this review was to establish a wheat genome atlas that provides a comprehensive summary of reported loci associated with rust resistance. Our atlas provides a summary of mapped quantitative trait loci (QTL) and characterised genes for the three rusts from 170 publications over the past two decades. A total of 920 QTL or resistance genes were positioned across the 21 chromosomes of wheat based on the latest wheat reference genome (IWGSC RefSeq v2.1). Interestingly, 26 genomic regions contained multiple rust loci suggesting they could have pleiotropic effects on two or more rust diseases. We discuss a range of strategies to exploit this wealth of genetic information to efficiently utilise sources of resistance, including genomic information to stack desirable and multiple QTL to develop wheat cultivars with enhanced resistance to rust disease.

Sex-Differential Gene Expression in Developing Human Cortex and Its Intersection With Autism Risk Pathways.

Background: Sex-differential biology may contribute to the consistently male-biased prevalence of autism spectrum disorder (ASD). Gene expression differences between males and females in the brain can indicate possible molecular and cellular mechanisms involved, although transcriptomic sex differences during human prenatal cortical development have been incompletely characterized, primarily due to small sample sizes. Methods: We performed a meta-analysis of sex-differential expression and co-expression network analysis in 2 independent bulk RNA sequencing datasets generated from cortex of 273 prenatal donors without known neuropsychiatric disorders. To assess the intersection between neurotypical sex differences and neuropsychiatric disorder biology, we tested for enrichment of ASD-associated risk genes and expression changes, neuropsychiatric disorder risk genes, and cell type markers within identified sex-differentially expressed genes (sex-DEGs) and sex-differential co-expression modules. Results: We identified 101 significant sex-DEGs, including Y-chromosome genes, genes impacted by X-chromosome inactivation, and autosomal genes. Known ASD risk genes, implicated by either common or rare variants, did not preferentially overlap with sex-DEGs. We identified 1 male-specific co-expression module enriched for immune signaling that is unique to 1 input dataset. Conclusions: Sex-differential gene expression is limited in prenatal human cortex tissue, although meta-analysis of large datasets allows for the identification of sex-DEGs, including autosomal genes that encode proteins involved in neural development. Lack of sex-DEG overlap with ASD risk genes in the prenatal cortex suggests that sex-differential modulation of ASD symptoms may occur in other brain regions, at other developmental stages, or in specific cell types, or may involve mechanisms that act downstream from mutation-carrying genes.

Males are more commonly diagnosed with autism spectrum disorder than females, and sex differences in brain development may contribute to this difference. Here, we define differences in gene expression patterns between males and females in human prenatal brain tissue from 273 donors to identify 101 genes that are expressed at different levels in males and females and gene sets that show sex-specific expression correlations. Genes with autism-associated DNA variants and genes with altered expression in autism do not preferentially overlap with sex-differential genes, suggesting that sex-differential biology may influence autism risk mechanisms in other brain regions, at other developmental stages, or in specific cell types.

Development and evaluation of one-step RT-qPCR TaqMan multiplex panels applied to six viruses occurring in lily and tulip bulbs.

One-step RT-qPCR TaqMan assays have been developed for six plant viruses with considerable economic impact in the growing of tulip and lily bulbs: lily mottle virus, lily symptomless virus, lily virus X, Plantago asiatica mosaic virus, tulip breaking virus and tulip virus X. To enhance efficacy and cost-efficiency these assays were combined into multiplex panels. Four different multiplex panels were designed, each consisting of three virus assays and an adapted assay for the housekeeping gene nad5 of lilies and tulips, that acts as an internal amplification control. To eliminate false negative results due to variation in the viral genome sequences, for each target virus two assays were developed on distinct conserved genomic regions. Specificity, PCR efficiency and compatibility of primers and probes were tested using gBlock constructions. Diagnostic samples were used to evaluate the strategy. High Throughput Sequencing of a set of the diagnostic samples, further verified the presence or absence of the viruses in the RNA samples and sequence variations in the target genes. This interchangeable multiplex panel strategy may be a valuable tool for the detection of viruses in certification, surveys and virus diagnostics.

Molecular and functional mapping of the neuroendocrine hypothalamus: a new era begins.

BACKGROUND: Recent advances in neuroscience tools for single-cell molecular profiling of brain neurons have revealed an enormous spectrum of neuronal subpopulations within the neuroendocrine hypothalamus, highlighting the remarkable molecular and cellular heterogeneity of this brain area. RATIONALE: Neuronal diversity in the hypothalamus reflects the high functional plasticity of this brain area, where multiple neuronal populations flexibly integrate a variety of physiological outputs, including energy balance, stress and fertility, through crosstalk mechanisms with peripheral hormones. Intrinsic functional heterogeneity is also observed within classically 'defined' subpopulations of neuroendocrine neurons, including subtypes with distinct neurochemical signatures, spatial organisation and responsiveness to hormonal cues. AIM: The aim of this review is to critically evaluate past and current research on the functional diversity of hypothalamic neuroendocrine neurons and their plasticity. It focuses on how this neuronal plasticity in this brain area relates to metabolic control, feeding regulation and interactions with stress and fertility-related neural circuits. CONCLUSION: Our analysis provides an original framework for improving our understanding of the hypothalamic regulation of hormone function and the development of neuroendocrine diseases.

Effects of social environments on male primate HPG and HPA axis developmental programming.

Developmental plasticity is particularly important for humans and other primates because of our extended period of growth and maturation, during which our phenotypes adaptively respond to environmental cues. The hypothalamus-pituitary-gonadal (HPG) and hypothalamus-pituitary-adrenal (HPA) axes are likely to be principal targets of developmental "programming" given their roles in coordinating fitness-relevant aspects of the phenotype, including sexual development, adult reproductive and social strategies, and internal responses to the external environment. In social animals, including humans, the social environment is believed to be an important source of cues to which these axes may adaptively respond. The effects of early social environments on the HPA axis have been widely studied in humans, and to some extent, in other primates, but there are still major gaps in knowledge specifically relating to males. There has also been relatively little research examining the role that social environments play in developmental programming of the HPG axis or the HPA/HPG interface, and what does exist disproportionately focuses on females. These topics are likely understudied in males in part due to the difficulty of identifying developmental milestones in males relative to females and the general quiescence of the HPG axis prior to maturation. However, there are clear indicators that early life social environments matter for both sexes. In this review, we examine what is known about the impact of social environments on HPG and HPA axis programming during male development in humans and nonhuman primates, including the role that epigenetic mechanisms may play in this programming. We conclude by highlighting important next steps in this research area.

Refugee health and physiological profiles in transitional settlements in Serbia and Kenya: Comparative evidence for effects of gender and social support.

When armed conflict compels people to flee from their homelands, they embark on protracted journeys during which they experience wide ranging physical, social, and psychological challenges. Few studies have focused on refugee psychosocial and physiological profiles during the transitional phase of forced migration that often involves temporary sheltering. Transient refugees' experiences can vary substantially based on local socio-ecological conditions in temporary settlements, including the length of stay, living conditions, as well as the availability and accessibility of physical and social resources. In this study, we compared physiological and psychosocial data from refugees (N=365; 406 observations) in Serbia and Kenya, respectively, with divergent temporal (length of stay) and socio-ecological conditions. In Serbia, refugees resided in asylum centers (mean stay: 0.9 y); in Kenya they were living in Kakuma Refugee Camp (mean stay: 8.8 y), one of the world's largest camps at the time. We had limited ability to directly compare psychosocial measures and used meta-analytic techniques to evaluate predictors of refugee mental and physical health at the two sites, including based on perceived social support. Refugees in Serbia had higher fingernail cortisol (p < 0.001) and were less likely to have elevated C-reactive protein (CRP) levels (p < 0.01) than refugees in Kakuma. We found common gender differences in both settings; women had lower cortisol but higher EBV antibody titers and higher likelihood of having elevated CRP compared to men (all p < 0.01). Woman also reported poorer mental and physical health (p < 0.001). These physiological and health differences may reflect variation between men and women in their psychosocial and physical experiences of factors such as stress, violence, and trauma during their journeys and as transitional refugees. Finally, we also found that refugees with lower levels of perceived social support reported poorer physical and mental health (p < 0.001). Although our results are cross-sectional, they suggest that this intermittent phase of the refugee experience is a key window for helping enhance refugee well-being through an emphasis on interpersonal and community support systems.

Men's physical health and life history transitions in the Philippines: Evidence for 'marital selection' but not protective effects of partnering and fatherhood.

In Euro-American societies, married people typically have lower overall risks for total mortality and for certain chronic conditions compared to non-married people. However, people becoming partnered and parents also tend to gain weight in Euro-American settings. Few studies have tested whether links between physical health and life history status translate to other cultural contexts where the socio-ecological dynamics of family life may differ. This limits the application of these insights to men's well-being in global public health. To help address this gap, we drew on a large, long-running birth cohort study of Filipino men, using data collected at three waves between 2005 and 2014 when men were 21.5-30.5 years old (N = 607, obs. = 1760). We tested for the effects of the transition to partnering (marriage/cohabitation) and fatherhood on men's physical health (waist circumference, fat-free mass index, and grip strength). Men becoming partnered or partnered fathers (P/PF) had comparable longitudinal physical health trajectories to men remaining single non-fathers. However, men who became P/PF by their mid 20s had higher fat-free mass index values than single non-fathers at each wave, with the largest effect observed when all men were single non-fathers at baseline. Men who became P/PF by their early 30s were also stronger than the reference group at baseline. Thus, men who were more muscular and stronger at baseline were more likely to transition to P/PF status, consistent with a 'marital selection' model. In complementary analyses, men did not exhibit adverse health effects when they became partnered fathers as young adults or parents to infants, respectively. These findings suggest that links between health and life history transitions in this setting differ from those commonly observed in Euro-American societies. While transitions to marriage and fatherhood are promising windows for interventions to improve men's health, our results highlight the importance of tailoring such approaches to local dynamics.

Leg Lymphoedema After Inguinal and Ilio-Inguinal Lymphadenectomy for Melanoma: Results from a Prospective, Randomised Trial.

BACKGROUND: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema. METHODS: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex®) > 10 or change of L-Dex® > 10 from baseline. RESULTS: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection. CONCLUSIONS: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study's small sample did not have the statistical evidence to support an overall difference between the surgical groups.

Barbary macaques show sex-related differences in body weight based on anthropogenic food exposure despite comparable female-male stable isotope ratios.

As the human-primate interface expands, many nonhuman primate (NHP) populations exploit anthropogenic foods to survive, while some populations opportunistically target them. Though anthropogenic food consumption is sometimes associated with greater reproductive output and survival in these populations, there is a dearth of research on possible health effects. We explore how differential exposure to anthropogenic foods is linked to variation in isotopic compositions (δ13C and δ15N) and body weights in Barbary macaques (Macaca sylvanus) in the Upper Rock Nature Reserve, Gibraltar. We placed monkeys into three categories based on anthropogenic food exposure. We then analyzed individuals for isotopic signatures (N = 147) and body weight measurements (N = 80). Using the lowest exposure category as the comparison, we found body weights and δ15N values, but not δ13C values, significantly differed across key categories. Within categories, we found no significant associations between sex and δ13C or δ15N values, suggesting that individuals within categories consumed similar foods regardless of sex. We found a significant interaction effect between category and sex for predicting body weights. These results suggest that sex plays a role in how anthropogenic foods are accessed and consumed regardless of exposure, which may result in differential health profiles for female and male macaques.

High-performance monolayer MoS2nanosheet GAA transistor.

In this article, a 0.7 nm thick monolayer MoS2nanosheet gate-all-around field effect transistors (NS-GAAFETs) with conformal high-κmetal gate deposition are demonstrated. The device with 40 nm channel length exhibits a high on-state current density of ~410µAµm-1with a large on/off ratio of 6 × 108at drain voltage = 1 V. The extracted contact resistance is 0.48 ± 0.1 kΩµm in monolayer MoS2NS-GAAFETs, thereby showing the channel-dominated performance with the channel length scaling from 80 to 40 nm. The successful demonstration of device performance in this work verifies the integration potential of transition metal dichalcogenides for future logic transistor applications.

Use of continuous genotypes for genomic prediction in sugarcane.

Genomic selection in sugarcane faces challenges due to limited genomic tools and high genomic complexity, particularly because of its high and variable ploidy. The classification of genotypes for single nucleotide polymorphisms (SNPs) becomes difficult due to the wide range of possible allele dosages. Previous genomic studies in sugarcane used pseudo-diploid genotyping, grouping all heterozygotes into a single class. In this study, we investigate the use of continuous genotypes as a proxy for allele-dosage in genomic prediction models. The hypothesis is that continuous genotypes could better reflect allele dosage at SNPs linked to mutations affecting target traits, resulting in phenotypic variation. The dataset included genotypes of 1318 clones at 58K SNP markers, with about 26K markers filtered using standard quality controls. Predictions for tonnes of cane per hectare (TCH), commercial cane sugar (CCS), and fiber content (Fiber) were made using parametric, non-parametric, and Bayesian methods. Continuous genotypes increased accuracy by 5%-7% for CCS and Fiber. The pseudo-diploid parametrization performed better for TCH. Reproducing kernel Hilbert spaces model with Gaussian kernel and AK4 (arc-cosine kernel with hidden layer 4) kernel outperformed other methods for TCH and CCS, suggesting that non-additive effects might influence these traits. The prevalence of low-dosage markers in the study may have limited the benefits of approximating allele-dosage information with continuous genotypes in genomic prediction models. Continuous genotypes simplify genomic prediction in polyploid crops, allowing additional markers to be used without adhering to pseudo-diploid inheritance. The approach can particularly benefit high ploidy species or emerging crops with unknown ploidy.

Role of serum eosinophil cationic protein in distinct endotypes of chronic rhinosinusitis.

BACKGROUND: Serum eosinophil cationic protein (ECP) levels affect the surgical outcome of chronic rhinosinusitis (CRS) with nasal polyps. Primary CRS can be classified into type 2 (T2) and non-T2. We aimed to differentiate the role of serum ECP levels in surgical outcomes between the distinct endotypes of primary CRS. METHODS: We prospectively enrolled patients with bilateral primary CRS who underwent surgical treatment with postoperative follow-up for at least 12 months. Endotyping and serum parameter measurements were completed within 1 week before surgery. RESULTS: In total, 113 patients were enrolled, including 65 with T2 CRS and 48 with non-T2 CRS. Patients in the T2 CRS group with uncontrolled CRS had significantly higher serum ECP levels than those in patients in the non-T2 CRS group. An optimal cut-off value was obtained at 17.0 λg/L using the receiver operating characteristic curve, attaining a sensitivity of 91.7% and specificity of 56.6%. Multivariate logistic regression analysis showed that a higher serum ECP level was an independent factor for postoperative uncontrolled disease. The hazard ratio was 11.3 for the T2 group, with serum ECP levels over 17.0 λg/L. In the non-T2 group, no parameters were significantly correlated with postoperative uncontrolled CRS. CONCLUSIONS: Serum ECP levels appear to be a feasible predictor of postoperative uncontrolled disease in patients with T2 CRS as preoperative serum ECP levels >17.0 λg/L in these patients have an approximately 16.7-fold increased risk of postoperative uncontrolled disease and should be closely monitored.

Transfection of Unmodified MicroRNA Using Monolayer-Coated Au Nanoparticles as Gene-Delivery Vehicles.

This article describes a monolayer-coated gold nanoparticle-based transfection system for the delivery of microRNA (miRNA) into human osteosarcoma (HOS) cells. Two distinct ammonium-terminated adsorbates were used in this study, which provided a platform for ionic bonding of the miRNA onto gold nanoparticles (AuNPs). The custom-designed monolayer-coated gold nanoparticles were characterized by dynamic light scattering, gel mobility shift assay, transmission electron microscopy, ultraviolet-visible spectrometry, zeta potential, and X-ray photoelectron spectroscopy. The miRNA-loaded gold nanoparticles were transfected, and the level of intracellular miRNA delivered and taken up by cells was measured by Taqman qPCR. The overall analysis indicated a successful delivery of miRNA into the HOS cells at an ∼11,000-fold increase compared to nontreated cells.

Accurate prediction of quantitative traits with failed SNP calls in canola and maize.

In modern plant breeding, genomic selection is becoming the gold standard to select superior genotypes in large breeding populations that are only partially phenotyped. Many breeding programs commonly rely on single-nucleotide polymorphism (SNP) markers to capture genome-wide data for selection candidates. For this purpose, SNP arrays with moderate to high marker density represent a robust and cost-effective tool to generate reproducible, easy-to-handle, high-throughput genotype data from large-scale breeding populations. However, SNP arrays are prone to technical errors that lead to failed allele calls. To overcome this problem, failed calls are often imputed, based on the assumption that failed SNP calls are purely technical. However, this ignores the biological causes for failed calls-for example: deletions-and there is increasing evidence that gene presence-absence and other kinds of genome structural variants can play a role in phenotypic expression. Because deletions are frequently not in linkage disequilibrium with their flanking SNPs, permutation of missing SNP calls can potentially obscure valuable marker-trait associations. In this study, we analyze published datasets for canola and maize using four parametric and two machine learning models and demonstrate that failed allele calls in genomic prediction are highly predictive for important agronomic traits. We present two statistical pipelines, based on population structure and linkage disequilibrium, that enable the filtering of failed SNP calls that are likely caused by biological reasons. For the population and trait examined, prediction accuracy based on these filtered failed allele calls was competitive to standard SNP-based prediction, underlying the potential value of missing data in genomic prediction approaches. The combination of SNPs with all failed allele calls or the filtered allele calls did not outperform predictions with only SNP-based prediction due to redundancy in genomic relationship estimates.

Does F4TCNQ Adsorption on Cu(111) Form a 2D-MOF?

The results of a quantitative experimental structural investigation of the adsorption phases formed by 2,3,5,6-tetrafluoro-7,7',8,8'-tetracyanoquinodimethane (F4TCNQ) on Cu(111) are reported. A particular objective was to establish whether Cu adatoms are incorporated into the molecular overlayer. A combination of normal incidence X-ray standing waves, low-energy electron diffraction, scanning tunneling microscopy, and X-ray photoelectron spectroscopy measurements, complemented by dispersion-inclusive density functional theory calculations, demonstrates that F4TCNQ on Cu(111) does cause Cu adatoms to be incorporated into the overlayer to form a two-dimensional metal-organic framework (2D-MOF). This conclusion is shown to be consistent with the behavior of F4TCNQ adsorption on other coinage metal surfaces, despite an earlier report concluding that the adsorption structure on Cu(111) is consistent with the absence of any substrate reconstruction.