From circuits to lifespan: translating mouse and human timelines with neuroimaging based tractography.

Age is a major predictor of developmental processes and disease risk, but humans and model systems (e.g., mice) differ substantially in the pace of development and aging. The timeline of human developmental circuits is well known. It is unclear how such timelines compare to those in mice. We lack age alignments across the lifespan of mice and humans. Here, we build upon our Translating Time resource, which is a tool that equates corresponding ages during development. We collected 477 time points (n=1,132 observations) from age-related changes in body, bone, dental, and brain processes to equate corresponding ages across humans and mice. We acquired high-resolution diffusion MR scans of mouse brains (n=12) at sequential stages of postnatal development (postnatal day 3, 4, 12, 21, 60) to trace the timeline of brain circuit maturation (e.g., olfactory association pathway, corpus callosum). We found heterogeneity in white matter pathway growth. The corpus callosum largely ceases to grow days after birth while the olfactory association pathway grows through P60. We found that a P3 mouse equates to a human at roughly GW24, and a P60 mouse equates to a human in teenage years. Therefore, white matter pathway maturation is extended in mice as it is in humans, but there are species-specific adaptations. For example, olfactory-related wiring is protracted in mice, which is linked to their reliance on olfaction. Our findings underscore the importance of translational tools to map common and species-specific biological processes from model systems to humans.

Diallel analysis, maternal effect and heritability in groundnut for yield components and oil content.

Background: Groundnut is one of the world's major food and oil crops. Being sources of nutrition and vegetable oil, rich in affordable and digestible protein, it is a strategic crop in Burkina Faso for food security, nutrition, and cash income. Understanding the nature of gene effect and genetic variation affecting yield and yield component traits will contribute to designing appropriate breeding methods for groundnut improvement and increase selection efficiency in Burkina Faso. Methods: In 2018, a total of 30 F2 progenies were generated through a 6 x 6 full diallel mating using six different and contrasting varieties. In 2019, parents and progenies were evaluated in a lattice square design in 3 replications at ICRISAT-Mali experimental field to assess the general combining ability (GCA) and specific combining ability (SCA) effects, the inheritance and the maternal and reciprocal effects for yield component traits (YCT) and oil content (OC). Results: Significant variabilities were observed among the parental genotypes and their F2 progenies for DTH, PSR, HPW, PL, PWD, SL, SWD, and OAC. Mean performance of the six parents were HPW (117.05g), HSW (57.24 g), PYH (1914.76), SYH (1312.73), PL (2.52), PWD (1,19), SL (1.38), SWD (0.83), OC (49.43), OAC (50.43) and LAC (33.61). Parent QH243C presented the highest value for SWD (1.02 cm) and OAC (60.76) while the parent ICGV09195 had the highest value of OC (50.36). Chalimbana presented the highest value of HPW (169.61 g), PL (2.98 cm), PWD (1. 41 cm), and SL (1.57 cm) while CG7 presented the highest value for HSW (75. 14 g), and SYH (1639.28 kg). Both YCT and OC are controlled by additive and non-additive gene effects with a predominance of additive gene action for HSW, SL, and SWD, whereas HPW, PL, PWD, and OAC were found to be more controlled by non-additive gene effects. Maternal effects as well as nuclear and cytoplasmic interaction effects were observed for both YCT and OC indicating that YCT and OC are influenced by a combination of genetic factors from both the maternal parent and the nuclear genome, as well as cytoplasmic factors such as mitochondrial DNA. Broad sense heritability ranged from 3.76 % to 91.56 %, and higher broad sense heritability values were recorded for pod length (91.56 %), hundred pod weight (83.71 %) and pod width (80.95 %). Conclusion: The study yields valuable insights into the inheritance of YCT and OC. The parents, Chalimbana and CG7, showed promise as good combiners for both yield component traits and oil content when used as male parents while TE3, Sh470P and QH243C can be used as female for the oil content and its components (oleic and linoleic content).

A Novel NOX Inhibitor Alleviates Parkinson's Disease Pathology in PFF-Injected Mice.

Oxidative stress-mediated damage is often a downstream result of Parkinson's disease (PD), which is marked by sharp decline in dopaminergic neurons within the nigrostriatal regions of the brain, accounting for the symptomatic motor deficits in patients. Regulating the level of oxidative stress may present a beneficial approach in preventing PD pathology. Here, we assessed the efficacy of a nicotinamide adenine phosphate (NADPH) oxidase (NOX) inhibitor, an exogenous reactive oxygen species (ROS) regulator synthesized by Aptabio therapeutics with the specificity to NOX-1, 2 and 4. Utilizing N27 rat dopaminergic cells and C57Bl/6 mice, we confirmed that the exposures of alpha-synuclein preformed fibrils (PFF) induced protein aggregation, a hallmark in PD pathology. In vitro assessment of the novel compound revealed an increase in cell viability and decreases in cytotoxicity, ROS, and protein aggregation (Thioflavin-T stain) against PFF exposure at the optimal concentration of 10 nM. Concomitantly, the oral treatment alleviated motor-deficits in behavioral tests, such as hindlimb clasping, rotarod, pole, nesting and grooming test, via reducing protein aggregation, based on rescued dopaminergic neuronal loss. The suppression of NOX-1, 2 and 4 within the striatum and ventral midbrain regions including Substantia Nigra compacta (SNc) contributed to neuroprotective/recovery effects, making it a potential therapeutic option for PD.

Transcription, structure, and organoids translate time across the lifespan of humans and great apes.

How the neural structures supporting human cognition developed and arose in evolution is an enduring question of interest. Yet, we still lack appropriate procedures to align ages across primates, and this lacuna has hindered progress in understanding the evolution of biological programs. We generated a dataset of unprecedented size consisting of 573 time points from abrupt and gradual changes in behavior, anatomy, and transcription across human and 8 nonhuman primate species. We included time points from diverse human populations to capture within-species variation in the generation of cross-species age alignments. We also extracted corresponding ages from organoids. The identification of corresponding ages across the lifespan of 8 primate species, including apes (e.g., orangutans, gorillas) and monkeys (i.e., marmosets, macaques), reveals that some biological pathways are extended in humans compared with some nonhuman primates. Notably, the human lifespan is unusually extended relative to studied nonhuman primates demonstrating that very old age is a phase of life in humans that does not map to other studied primate species. More generally, our work prompts a reevaluation in the choice of a model system to understand aging given very old age in humans is a period of life without a clear counterpart in great apes.

High-density DArTSeq SNP markers revealed wide genetic diversity and structured population in common bean (Phaseolus vulgaris L.) germplasm in Ethiopia.

INTRODUCTION: Common bean is one of the widely consumed food security crop in Africa, Asia, and South America. Understanding genetic diversity and population structure is crucial for designing breeding strategies. MATERIALS: Two hundred and eighty-nine germplasm were recently collected from different regions of Ethiopia and introduced from CIAT to estimate genetic diversity and population structure using 11,480 DArTSeq SNP markers. RESULTS: The overall mean genetic diversity and polymorphic information content (PIC) were 0.38 and 0.30, respectively, suggested the presence of adequate genetic diversity among the genotypes. Among the geographical regions, landraces collected from Oromia showed the highest diversity (0.39) and PIC (0.30). The highest genetic distance was observed between genotypes collected from SNNPR and CIAT (0.49). In addition, genotypes from CIAT were genetically more related to improved varieties than the landraces which could be due to sharing of parents in the improvement process. The analysis of molecular variance revealed that the largest proportion of variation was due to within the population both in geographical region (63.67%) and breeding status (61.3%) based classification. Model-based structure analysis delineated the 289 common bean genotypes into six hypothetical ancestoral populations. CONCLUSIONS: The genotypes were not clustered based on geographical regions and they were not the main drivers for the differentiation. This indicated that selection of the parental lines should be based on systematic assessment of the diversity rather than geographical distance. This article provides new insights into the genetic diversity and population structure of common bean for association studies, designing effective collection and conservation for efficient utilization for the improvement of the crop.

RGB-image method enables indirect selection for leaf spot resistance and yield estimation in a groundnut breeding program in Western Africa.

Early Leaf Spot (ELS) caused by the fungus Passalora arachidicola and Late Leaf Spot (LLS) also caused by the fungus Nothopassalora personata, are the two major groundnut (Arachis hypogaea L.) destructive diseases in Ghana. Accurate phenotyping and genotyping to develop groundnut genotypes resistant to Leaf Spot Diseases (LSD) and to increase groundnut production is critically important in Western Africa. Two experiments were conducted at the Council for Scientific and Industrial Research-Savanna Agricultural Research Institute located in Nyankpala, Ghana to explore the effectiveness of using RGB-image method as a high-throughput phenotyping tool to assess groundnut LSD and to estimate yield components. Replicated plots arranged in a rectangular alpha lattice design were conducted during the 2020 growing season using a set of 60 genotypes as the training population and 192 genotypes for validation. Indirect selection models were developed using Red-Green-Blue (RGB) color space indices. Data was collected on conventional LSD ratings, RGB imaging, pod weight per plant and number of pods per plant. Data was analyzed using a mixed linear model with R statistical software version 4.0.2. The results showed differences among the genotypes for the traits evaluated. The RGB-image method traits exhibited comparable or better broad sense heritability to the conventionally measured traits. Significant correlation existed between the RGB-image method traits and the conventionally measured traits. Genotypes 73-33, Gha-GAF 1723, Zam-ICGV-SM 07599, and Oug-ICGV 90099 were among the most resistant genotypes to ELS and LLS, and they represent suitable sources of resistance to LSD for the groundnut breeding programs in Western Africa.

A Novel NOX Inhibitor Treatment Attenuates Parkinson's Disease-Related Pathology in Mouse Models.

Parkinson's disease (PD) is a progressive neurodegenerative motor disorder without an available therapeutic to halt the formation of Lewy bodies for preventing dopaminergic neuronal loss in the nigrostriatal pathway. Since oxidative-stress-mediated damage has been commonly reported as one of the main pathological mechanisms in PD, we assessed the efficacy of a novel NOX inhibitor from AptaBio Therapeutics (C-6) in dopaminergic cells and PD mouse models. The compound reduced the cytotoxicity and enhanced the cell viability at various concentrations against MPP+ and α-synuclein preformed fibrils (PFFs). Further, the levels of ROS and protein aggregation were significantly reduced at the optimal concentration (1 µM). Using two different mouse models, we gavaged C-6 at two different doses to the PD sign-displaying transgenic mice for 2 weeks and stereotaxically PFF-injected mice for 5 weeks. Our results demonstrated that both C-6-treated mouse models showed alleviated motor deficits in pole test, hindlimb clasping, crossbeam, rotarod, grooming, and nesting analyses. We also confirmed that the compound treatment reduced the levels of protein aggregation, along with phosphorylated-α-synuclein, in the striatum and ventral midbrain and further dopaminergic neuronal loss. Taken together, our results strongly suggest that NOX inhibition can be a potential therapeutic target for PD.

Tracing Modification to Cortical Circuits in Human and Nonhuman Primates from High-Resolution Tractography, Transcription, and Temporal Dimensions.

The neural circuits that support human cognition are a topic of enduring interest. Yet, there are limited tools available to map brain circuits in the human and nonhuman primate brain. We harnessed high-resolution diffusion MR tractography, anatomic, and transcriptomic data from individuals of either sex to investigate the evolution and development of frontal cortex circuitry. We applied machine learning to RNA sequencing data to find corresponding ages between humans and macaques and to compare the development of circuits across species. We transcriptionally defined neural circuits by testing for associations between gene expression and white matter maturation. We then considered transcriptional and structural growth to test whether frontal cortex circuit maturation is unusually extended in humans relative to other species. We also considered gene expression and high-resolution diffusion MR tractography of adult brains to test for cross-species variation in frontal cortex circuits. We found that frontal cortex circuitry development is extended in primates, and concomitant with an expansion in corticocortical pathways compared with mice in adulthood. Importantly, we found that these parameters varied relatively little across humans and studied primates. These data identify a surprising collection of conserved features in frontal cortex circuits across humans and Old World monkeys. Our work demonstrates that integrating transcriptional and structural data across temporal dimensions is a robust approach to trace the evolution of brain pathways in primates.SIGNIFICANCE STATEMENT Diffusion MR tractography is an exciting method to explore pathways, but there are uncertainties in the accuracy of reconstructed tracts. We broaden the repertoire of toolkits to enhance our ability to trace human brain pathways from diffusion MR tractography. Our integrative approach finds corresponding ages across species and transcriptionally defines neural circuits. We used this information to test for variation in circuit maturation across species and found a surprising constellation of similar features in frontal cortex neural circuits across humans and primates. Integrating across scales of biological organization expands the repertoire of tools available to study pathways in primates, which opens new avenues to study pathways in health and diseases of the human brain.

Drought Tolerance and Application of Marker-Assisted Selection in Sorghum.

Sorghum is an important staple food crop in drought prone areas of Sub-Saharan Africa, which is characterized by erratic rainfall with poor distribution. Sorghum is a drought-tolerant crop by nature with reasonable yield compared to other cereal crops, but such abiotic stress adversely affects the productivity. Some sorghum varieties maintain green functional leaves under post-anthesis drought stress referred to as stay-green, which makes it an important crop for food and nutritional security. Notwithstanding, it is difficult to maintain consistency of tolerance over time due to climate change, which is caused by human activities. Drought in sorghum is addressed by several approaches, for instance, breeding drought-tolerant sorghum using conventional and molecular technologies. The challenge with conventional methods is that they depend on phenotyping stay-green, which is complex in sorghum, as it is constituted by multiple genes and environmental effects. Marker assisted selection, which involves the use of DNA molecular markers to map QTL associated with stay-green, has been useful to supplement stay-green improvement in sorghum. It involves QTL mapping associated with the stay-green trait for introgression into the senescent sorghum varieties through marker-assisted backcrossing by comparing with phenotypic field data. Therefore, this review discusses mechanisms of drought tolerance in sorghum focusing on physiological, morphological, and biochemical traits. In addition, the review discusses the application of marker-assisted selection techniques, including marker-assisted backcrossing, QTL mapping, and QTL pyramiding for addressing post-flowering drought in sorghum.

Utilization and farmers' knowledge on pigeonpea diversity in Benin, West Africa.

BACKGROUND: Understanding factors driving farmers' uses of crop genetic resources is a key component not only to design appropriate conservation strategies but also to promote sustainable production. However, in Benin, limited information is available on farmers' knowledge related to pigeonpea uses and conservation. This study aimed at i) identifying and investigating the different uses of pigeonpea in relation with socio-cultural factors, namely age, gender, ethnic group and respondents' residence, ii) assessing pigeonpea varieties richness at household level and iii) evaluating the extent and distribution of pigeonpea varieties. METHODS: Three hundred and two farmers were surveyed using structured questionnaire. Direct observation, field visit and focus group discussion were carried out. Association between number of varieties maintained at household level and socio-cultural variables was tested. Mann-Whitney test was used to assess whether the number of varieties held by households headed by men and women were different. Distribution and extent of diversity was assessed through four cells analysis. RESULTS: Farmers in Benin mainly grow pigeonpea for its grains for home consumption. Pigeonpea's stem and leaves are used for medicinal purposes to treat malaria, dizziness, measles, and eye infection. The ethnic group and the locality of residence of farmers influenced on the use of pigeonpea for medicinal purposes (P < 0.01). There was no significant association (P > 0.05) between the number of varieties held by household and the age of the respondent, number of years of experience in pigeonpea cultivation, the size of household, number of family members engaged in agricultural activities and gender. Farmers used criteria including seed colors, seed size, plant height, maturity groups and cooking time to classify their varieties. Varieties with white seed coat color were the most grown while varieties with black, red or mottled seed coat color are being abandoned and deserve to be conserved. CONCLUSION: Knowledge on medicinal uses of pigeonpea is vertically transmitted within community and pigeonpea varieties maintenance at household level does not depend on socio-cultural factors. This study will contribute to raise awareness on the various utilization of pigeonpea. In addition, it provides the basis for designing conservation strategies of pigeonpea genetic resources.

Mapping the distribution of maize streak virus genotypes across the forest and transition zones of Ghana.

Throughout sub-Saharan Africa, maize streak virus strain A (MSV-A), the causal agent of maize streak disease (MSD), is an important biological constraint on maize production. In November/December 2010, an MSD survey was carried out in the forest and transition zones of Ghana in order to obtain MSV-A virulence sources for the development of MSD-resistant maize genotypes with agronomic properties suitable for these regions. In 79 well-distributed maize fields, the mean MSD incidence was 18.544 % and the symptom severity score was 2.956 (1 = no symptoms and 5 = extremely severe). We detected no correlation between these two variables. Phylogenetic analysis of cloned MSV-A isolates that were fully sequenced from samples collected in 51 of these fields, together with those sampled from various other parts of Africa, indicated that all of the Ghanaian isolates occurred within a broader cluster of West African isolates, all belonging to the highly virulent MSV-A1 subtype. Besides being the first report of a systematic MSV survey in Ghana, this study is the first to characterize the full-genome sequences of Ghanaian MSV isolates. The 51 genome sequences determined here will additionally be a valuable resource for the rational selection of representative MSV-A variant panels for MSD resistance screening.

Diversity in 113 cowpea [Vigna unguiculata (L) Walp] accessions assessed with 458 SNP markers.

Single Nucleotide Polymorphism (SNP) markers were used in characterization of 113 cowpea accessions comprising of 108 from Ghana and 5 from abroad. Leaf tissues from plants cultivated at the University of Ghana were genotyped at KBioscience in the United Kingdom. Data was generated for 477 SNPs, out of which 458 revealed polymorphism. The results were used to analyze genetic dissimilarity among the accessions using Darwin 5 software. The markers discriminated among all of the cowpea accessions and the dissimilarity values which ranged from 0.006 to 0.63 were used for factorial plot. Unexpected high levels of heterozygosity were observed on some of the accessions. Accessions known to be closely related clustered together in a dendrogram drawn with WPGMA method. A maximum length sub-tree which comprised of 48 core accessions was constructed. The software package structure was used to separate accessions into three groups, and the programme correctly identified varieties that were known hybrids. The hybrids were those accessions with numerous heterozygous loci. The structure plot showed closely related accessions with similar genome patterns. The SNP markers were more efficient in discriminating among the cowpea germplasm than morphological, seed protein polymorphism and simple sequence repeat studies reported earlier on the same collection.

Gene expression profiling of bovine bronchial epithelial cells exposed in vitro to bovine herpesvirus 1 and Mannheimia haemolytica.

Bovine respiratory disease (BRD) often occurs when active respiratory virus infections (BHV-1, etc.) impair resistance to Mannheimia haemolytica infection in the lower respiratory tract. The interactions that occur when the respiratory epithelium encounters these viral and bacterial pathogens are poorly understood. We used Agilent bovine gene microarray chips containing 44,000 transcripts to elucidate bovine bronchial epithelial cell (BBEC) responses following in vitro exposure to BHV-1 alone, M. haemolytica alone, or both BHV-1 and M. haemolytica. Microarray analysis revealed differential regulation (>2-fold) of 978 transcripts by BHV-1 alone, 2040 transcripts by M. haemolytica alone, and 2189 genes by BHV-1 and M. haemolytica in combination. M. haemolytica treatment produced significantly greater inductions (>10-fold) of several inflammation associated genes, such as CXCL2, IL-6, IL-1α, e-selectin, and IL-8, than to BHV-1 alone. Functional analysis of the microarray data revealed a significant upregulation of genes involved in important biological processes such as inflammation (TNF-α, IL-8, Tlr-2, IL-1, CXCL2, CSF2), vascular functions (VEGF, EDN2) and leukocyte migration (ICAM1, IL-16) during a co-infection with BHV-1 and M. haemolytica compared to either pathogen alone. This study provides evidence to support that lung epithelial cells are a source of mediators that may promote inflammatory changes observed during bovine respiratory disease.

PI3K mediates stretch-induced COX-2 expression during urinary tract obstruction.

BACKGROUND AND PURPOSE: Stretch-induced cyclooxygenase-2 (COX-2) expression occurs in urothelial cells during urinary tract obstruction (UTO). This increases COX-2-dependent prostanoid synthesis in stretched urothelial cells. These prostanoids then act on afferent neurons and smooth muscle cells in the ureter to amplify nociceptive and contractile responses, respectively. We previously used a unilateral ureteral obstruction (UUO) mouse model and a primary human urothelial cell (HUC) stretch model to describe ureteral COX-2 expression during UTO. The current study was performed to determine whether phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways are necessary for stretch-induced COX-2 expression in urothelial cells. MATERIALS AND METHODS: Adult male CD-1 mice were treated with 25% dimethyl sulfoxide/phosphate buffered saline or PI3K inhibitor LY294002 (3 mg/kg, 30 mg/kg) for 1 hour before performing UUO for up to 4 hours. Obstructed and contralateral mouse ureters were analyzed via immunohistochemistry or Western blotting to assess in vivo stretch-induced COX-2 expression. In addition, HUCs were cyclically stretched (5%-20% displacement, 12 cycles/min) on collagen I-coated stretch plates and assessed for COX-2 expression via Western blotting. RESULTS: Histologic analyses of obstructed ureters show that urothelial cells stretch in response to external obstruction, COX-2 expression increases in the stretched urothelial cells, and no infiltrating immune cells were present under the conditions of the study. PI3K inhibitor LY294002 (30 mg/kg) attenuated in vivo stretch-induced COX-2 expression. LY294002 or RNA-interference also attenuated (HUC) stretch-induced COX-2 expression in vitro. Furthermore, the results also show that LY294002 inhibits stretch-induced protein kinase C (PKCζ) activation previously identified upstream of stretch-induced COX-2 expression in HUCs. CONCLUSIONS: The results indicate that PI3K is a mediator of stretch-induced COX-2 expression in urothelial cells. Identifying molecules that couple urothelial cell stretch to COX-2 expression may provide targets of drug action for effective therapeutics for UTO.

Stretch induction of cyclooxygenase-2 expression in human urothelial cells is calcium- and protein kinase C zeta-dependent.

Prostanoid synthesis via cyclooxygenase (COX)-2 induction during urothelial stretch is central to nociception, inflammation, contractility, and proliferation caused by urinary tract obstruction. We used our primary human urothelial cell stretch model published previously to evaluate the signaling mechanisms responsible for stretch-induced COX-2 expression in urothelial cells. To determine intracytosolic calcium concentrations ([Ca(2+)](i)), primary human urothelial cells were grown on flexible membranes and loaded with Fura-2 acetoxymethyl ester (AM). We determined [Ca(2+)](i) using a fluorescent scope during stretch. Additional cells were treated with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-AM, stretched, and COX-2 mRNA and protein were evaluated by real-time polymerase chain reaction and immunoblotting. To evaluate protein kinase C (PKC) in this system, cells were stretched and fractionated into membrane, cytosol, and nucleus. Fractions were immunoblotted for PKCalpha, beta1, and zeta, the predominant isoforms in urothelial cells. We treated additional cells with increasing concentrations of either bisindolylmaleimide-I or a peptide PKC pseudosubstrate inhibitor, and COX-2 mRNA and protein were evaluated after stretching. Furthermore, we transfected urothelial cells with siRNA against each of the inducible PKC isoforms in these cells and evaluated the stretch-induced COX-2 response. Stretch of urothelial cells activated calcium flux and PKC translocation to membrane and nucleus. Pharmacological inhibition indicated that stretch-induced COX-2 expression is dependent on calcium and PKC, and biochemical knockdown experiments indicated that PKCzeta is the predominant isoform mediating stretch-induced COX-2 expression. Elucidating the signaling mechanism of stretch-induced COX-2 expression may identify therapeutic targets.