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PubMed2025

Genetic basis and role of exotic accessions in cultivated cotton fiber quality improvement.

Exotic Gossypium accessions still harbor QTL‑validated alleles that, combined with CRISPR pyramiding and genomic selection, can break the entrenched fiber length-strength trade‑off. Cotton's four independent domestications twice in diploids and twice in allotetraploids offer a natural experiment in fiber improvement. Synthesizing three decades of data, we chart how polyploidy, selection and modern breeding have repeatedly reshaped the Gossypium genome. More than 15,000 quantitative trait locus (QTL) and genome wide association mapping studies (GWAS) hits converge on a handful of chromosomal "hotspots"; new MAGIC, NAM, NIL and long-read resources now narrow these peaks to < 200 kb, resolving causal genes such as GhHOX3, GhZF14 and GhMYB7. Multi-omics evidence links auxin, ethylene, gibberellin, brassinosteroid and strigolactone signaling to HDZIP IV, MYB, bHLH/HLH and ERF networks that drive fiber initiation, extreme cell elongation and cellulose deposition. Population genomics shows that ~ 40% of favorable fiber alleles are fixed in elite Gossypium hirsutum, yet wild diploids and landraces still harbor variants that could break the length strength trade-off. We propose a three-step roadmap genomic selection, CRISPR gene pyramiding and accelerated introgression to expand cotton's genetic base and deliver fibers suited to sustainable textile demands.

Gossypium↗

PubMed2001

The search for complex disease genes: fault by linkage or fault by association?

With the human DNA sequence nearing completion, the search for complex disease genes is gaining momentum, as is the debate over gene-finding strategies. This overview contrasts two pivotal methods: linkage analysis and association mapping. Linkage analysis has been used successfully to identify the genes underlying rare mendelian disorders. It has also played a role in attempts to map genes for common non-mendelian (also known as 'complex' or 'multifactorial') diseases such as psychiatric disorders. However, despite extensive efforts progress has been slow, marred by inconsistent or ambiguous results. Uncertainties about the utility of the linkage approach for complex genetic traits has spurred interest in association studies with candidate genes, as an alternate strategy. Recently, with the advent of new molecular tools, in particular high-density, single-nucleotide polymorphisms (SNPs) maps, it has been argued that, while linkage analysis may retain some role, genome-wide association studies with SNPs offer a superior strategy for unraveling genetic complexity. In this paper I review these issues, stressing the pros and cons of the various strategies. I propose that: (1) the uncertainties in association studies may have been underestimated; (2) neither method is sufficient or optimal; and (3) a joint linkage and association approach, together with genomic, statistical and computational advances, may have greater promise for understanding the genetic underpinnings of complex disorders in the new millennium.

Genetic Diseases, Inborn↗

PubMed2005

The effect of polymorphisms in the enhancer of split gene complex on bristle number variation in a large wild-caught cohort of Drosophila melanogaster.

The Enhancer of split complex [E(spl)-C] in Drosophila encompasses a variety of functional elements controlling bristle patterning and on the basis of prior work is a strong candidate for harboring alleles having subtle effects on bristle number variation. Here we extend earlier studies identifying associations between complex phenotypes and polymorphisms segregating among inbred laboratory lines of Drosophila and test the influence of E(spl)-C on bristle number variation in a natural cohort. We describe results from an association mapping study using 203 polymorphisms spread throughout the E(spl)-C genotyped in 2000 wild-caught Drosophila melanogaster. Despite power to detect associations accounting for as little as 2% of segregating variation for bristle number, and saturating the region with single-nucleotide polymorphisms (SNPs), we identified no single SNP marker showing a significant (additive over loci) effect after correcting for multiple tests. Using a newly developed test we conservatively identify six regions of the E(spl)-C in which the insertion of transposable elements as a class contributes to variation in bristle number, apparently in a sex- or trait-limited fashion. Finally, we carry out all possible 20,503 two-way tests for epistasis and identify a slight excess of marginally significant interactions, although none survive multiple-testing correction. It may not be straightforward to extend the results of laboratory-based association studies to natural populations.

Animal Structures↗

PubMed1989

The specific binding of the microtubule-associated protein 2 (MAP2) to the outer membrane of rat brain mitochondria.

Purified mitochondria from rat brain contain microtubule-associated proteins (MAPs) bound to the outer membrane. Studies of binding in vitro performed with microtubules and with purified microtubule proteins showed that mitochondria preferentially interact with the high-molecular-mass MAPs (and not with Tau protein). Incubation of intact mitochondria with Taxol-stabilized microtubules resulted in the selective trapping of both MAPs 1 and 2 on mitochondria, indicating that an interaction between the two organelles occurred through a site on the arm-like projection of MAPs. Two MAP-binding sites were located on intact mitochondria. The lower-affinity MAP2-binding site (Kd = 2 x 10(-7) M) was preserved and enriched in the outer-membrane fraction, whereas the higher-affinity site (Kd = 1 x 10(-9) M) was destroyed after removing the outer membrane with digitonin. Detergent fractionation of mitochondrial outer membranes saturated with MAP2 bound in vitro showed that MAPs are associated with membrane fragments which contain the pore-forming protein (porin). MAP2 also partially prevents the solubilization of porin from outer membrane, indicating a MAP-induced change in the membrane environment of porin. These observations demonstrate the presence of specific MAP-binding sites on the outer membrane, suggesting an association between porin and the membrane domain involved in the cross-linkage between microtubules and mitochondria.

Animals↗

PubMed2000

Changes in regional vascular resistance in response to microinjection of L-glutamate into different antero-posterior coordinates of the RVLM in awake rats.

Changes in mean arterial pressure (MAP) and in regional vascular resistance (RVR, hindquarter, mesenteric and renal) induced by microinjection of L.-glutamate into three different antero-posterior coordinates of the rostral ventrolateral medulla (RVLM) [1,200-1,600 microm (n=10), 1,601-2,000 microm (n=12) and 2,001-2,500 microm (n=6) rostral to the obex] were investigated in unanesthetized rats. Guide cannulas directed towards the RVLM were implanted 4 days prior to the experiments. Doppler probes were implanted around the superior mesenteric, inferior abdominal aorta and left renal arteries and a catheter was inserted into the femoral artery and vein 1 day prior to the experiments. Insertion of the injector into the RVLM produced an increase in baseline MAP, which was back to control levels 2 min later, when L-glutamate was microinjected. Microinjection of L-glutamate (1 nmol/30 nl) into the three antero-posterior coordinates of the RVLM produced an increase in MAP associated with a similar increase in hindquarter, mesenteric and renal vascular resistance, which were back to control 1 min later. Saline into the RVLM produced negligible effects on MAP and RVR. These findings suggest that the sympathetic vasomotor neurons involved in the regulation of the regional vascular resistance in rats are not topographically distributed in the antero-posterior coordinates of the RVLM. However, the experimental methods used to evaluate the topographic distribution of sympatho-vasomotor neurons in the RVLM and the measurement of the regional blood flow may not be precise enough to detect any possible differences.

Animals↗

PubMed2001

Changes in regional vascular resistance in response to microinjection of L-glutamate into different antero-posterior coordinates of the RVLM in awake rats.

Changes in mean arterial pressure (MAP) and in regional vascular resistance (RVR, hindquarter, mesenteric and renal) induced by microinjection of L-glutamate into three different antero-posterior coordinates of the rostral ventrolateral medulla (RVLM) [1,200-1,600 (microm (n=10), 1,601-2,000 microm (n=12) and 2,001-2,500 microm (n=6) rostral to the obex] were investigated in unanesthetized rats. Guide cannulas directed towards the RVLM were implanted 4 days prior to the experiments. Doppler probes were implanted around the superior mesenteric, inferior abdominal aorta and left renal arteries and a catheter was inserted into the femoral artery and vein 1 day prior to the experiments. Insertion of the injector into the RVLM produced an increase in baseline MAP, which was back to control levels 2 min later, when L-glutamate was microinjected. Microinjection of L-glutamate (1 nmol/30 nl) into the three antero-posterior coordinates of the RVLM produced an increase in MAP associated with a similar increase in hindquarter, mesenteric and renal vascular resistance, which were back to control 1 min later. Saline into the RVLM produced negligible effects on MAP and RVR. These findings suggest that the sympathetic vasomotor neurons involved in the regulation of the regional vascular resistance in rats are not topographically distributed in the antero-posterior coordinates of the RVLM. However, the experimental methods used to evaluate the topographic distribution of sympatho-vasomotor neurons in the RVLM and the measurement of the regional blood flow may not be precise enough to detect any possible differences.

Animals↗

PubMed2000

The Turner syndrome-associated neurocognitive phenotype maps to distal Xp.

Turner syndrome (TS) is associated with a characteristic neurocognitive profile that includes impaired visuospatial/perceptual abilities. We used a molecular approach to identify a critical region of the X chromosome for neurocognitive aspects of TS. Partial deletions of Xp in 34 females were mapped by FISH or by loss of heterozygosity of polymorphic markers. Discriminant function analysis optimally identified the TS-associated neurocognitive phenotype. Only subjects missing approximately 10 Mb of distal Xp manifested the specified neurocognitive profile. The phenotype was seen with either paternally or maternally inherited deletions and with either complete or incomplete skewing of X inactivation. Fine mapping of informative deletions implicated a critical region of <2 Mb within the pseudoautosomal region (PAR1). We conclude that haploinsufficiency of PAR1 gene(s) is the basis for susceptibility to the TS neurocognitive phenotype.

Adolescent↗

PubMed2026

Genomic exploration and in silico prioritization of putative COX-2-targeting metabolites from Streptomyces sp. VITGV156 (MCC 4965).

INTRODUCTION: Streptomyces species represent an important source of bioactive natural products, yet systematic genome-guided prioritization of metabolites targeting cyclooxygenase-2 (COX-2/PTGS2) remains limited. This study aimed to investigate the biosynthetic potential of Streptomyces sp. VITGV156 (MCC 4965) using an integrated genome mining and computational drug discovery pipeline. METHODS: Whole-genome sequencing, functional annotation, antiSMASH v7.0.1-based biosynthetic gene cluster (BGC) prediction, LC-MS/MS metabolomic profiling, SwissADME analysis, target prediction, disease association mapping, molecular docking against PTGS2 (PDB: 5IKR), and PASS bioactivity prediction were performed to prioritize putative bioactive metabolites. RESULTS: Genome analysis identified 29 predicted biosynthetic gene clusters, including clusters associated with geosmin, ectoine, albaflavenone, hopene, coelichelin, and SapB, together with several cryptic clusters exhibiting low similarity to known pathways. LC-MS/MS metabolomic profiling provided experimental support for active secondary metabolite production under the cultivation conditions employed. Computational prioritization identified PTGS2 (COX-2) as a biologically relevant target. Molecular docking demonstrated favorable binding affinities and interaction profiles for several predicted metabolites within the PTGS2 catalytic pocket. PASS analysis further suggested potential anticancer-related biological activities that require experimental validation. DISCUSSION: These findings demonstrate the utility of integrating genome mining, metabolomic profiling, and computational drug discovery for prioritizing natural-product candidates. Streptomyces sp. VITGV156 (MCC 4965) represents a promising source of biosynthetic diversity and provides a genome-guided framework for identifying putative COX-2-targeting natural products for future experimental validation rather than confirming metabolite production or biological activity.

COX-2 (PTGS2)↗

PubMed1996

Nitric oxide synthase inhibition attenuates delayed vasodilation and increases injury after cerebral ischemia in fetal sheep.

Transient cerebral ischemia in fetal sheep is followed by a period of delayed cerebral injury associated with cerebral vasodilation. As nitric oxide (NO) can mediate both vasodilation and neuronal death, this study investigated whether inhibition of NO synthesis would attenuate the vasodilation and decrease cerebral injury. Eleven late gestation (range 122-133 d) fetal sheep were subjected to 30 min of transient cerebral ischemia in utero. Two hours later, treatment group (n = 5) received a continuous infusion of NG-nitro-L-arginine (L-NNA) at a dose of 50 mg.h-1 for 4 h followed by 20 mg.h-1 for the subsequent study period, a competitive inhibitor of NO synthase (NOS), whereas a control group (n = 6) received PBS. Inhibition of NOS activity was confirmed in the treatment group by 1) suppression of the fall in mean arterial blood pressure (MAP) associated with acetylcholine (p < 0.01), and 2) persistent increase in MAP after commencement of L-NNA (p < 0.05). Changes in cerebral blood volume (CBV) were observed for 3 d by measuring changes in concentration of total cerebral Hb ([tHb]) using near infrared spectroscopy. The delayed increase in CBV commenced at 13.1 +/- 1.0 h postischemia in the control and 12.7 +/- 2.3 h in the treatment group. Maximum increase at 30-36 h was 0.5 +/- 0.1 mL.100 g-1 in the treatment group and 1.2 +/- 0.2 mL.100 g-1 in the control (p < 0.05). Final CBV was depressed below preischemic baseline in the treatment (-0.7 +/- 0.2 mL.100 g-1) but not the control group (-0.1 +/- 0.3 mL.100 g-1) (p < 0.05). Neuronal loss, quantified histologically 3 d postischemia, indicated that cerebral injury was increased in the treatment group (p < 0.05). The results indicate that after transient cerebral ischemia in fetal sheep, NOS inhibition attenuates the delayed rise in CBV but does not decrease the extent of cerebral injury.

Animals↗

PubMed2003

Genetic linkage and association studies in bipolar affective disorder: a time for optimism.

Genetic research on complex diseases is beginning to bear fruit, with the successful identification of candidate susceptibility genes in diabetes, asthma, and other illnesses. Similar success is on the horizon for bipolar affective disorder (BPAD), but significant challenges remain. In this review, we outline the basic concepts of linkage and association mapping for complex phenotypes. We point out important caveats inherent in both approaches, and review guidelines on the interpretation of linkage statistics and significance thresholds. We then apply these concepts to an evaluation of the present status of genetic linkage and association studies in BPAD. The challenges posed by locus heterogeneity, phenotype definition, and sample size requirements are given a detailed treatment. Despite these challenges, we argue that the way ahead remains firmly rooted in linkage studies, complemented by association studies in linked regions. This is the only truly genome-wide approach currently available; it has succeeded in other complex phenotypes, and it is the surest strategy for mapping susceptibility genes in BPAD. Once these genes are identified, genetic mapping methods will yield to the other methods of 21st-century molecular biology as we begin to elucidate the pathophysiology of BPAD.

Bipolar Disorder↗

PubMed1990

Microtubule-associated proteins and the determination of neuronal form.

1. The assembly of microtubules is essential for the maintenance of both the extension and the radial symmetry of axons and dendrites. Microtubule-associated proteins (MAPs) are implicated in this function because they promote tubulin polymerization and because they appear to be involved in cross-linking microtubules in the neuritic cytoplasm. 2. In a variety of species high molecular weight MAP2 is found only in dendrites and MAP tau is found only is axons, indicating that certain MAPs are associated with specific aspects of neuronal morphology. 3. All neuronal MAPs that have been studied are under strong developmental regulation with either their form or abundance changing between developing and adult brain. In both rat and Xenopus the change from "early" to "late" MAP forms occurs concurrently with the cessation of axon and dendrite growth and the maturation of neuronal morphology. 4. In situations where neuronal growth persists in the adult, such as retinal photoreceptor cells and the olfactory system, "early" MAPs continue to be expressed in the adult brain. 5. These results implicate MAPs in neuronal morphogenesis and suggest that "early" MAPs are involved in axon and dendrite growth whereas the "late" MAPs are involved in the stabilization of their mature form.

Animals↗

PubMed1989

Quantitation of microtubule-associated protein MAP-1B in brain and other tissues.

1. The presence of microtubule-associated protein MAP-1B in all mammalian tissues tested, as well as in brain, has been demonstrated by immunoblotting using a monospecific polyclonal antibody. 2. The expression of brain MAP-1B is developmentally controlled, as it is less abundant in adult than in newborn rat brain, where it is a major microtubule assembly promoting factor. 3. The level of MAP-1B in tissues other than brain is lower than it is in brain; but the relative ratios of MAP-1B to tubulin are very similar in all tissues, thus differing from the observed for MAP-2 or tau. 4. The amount of MAP-1B in non-nervous tissues seems not to be under developmental control. 5. These results are consistent with a role for MAP-1B in the assembly of microtubules in most cells.

Adrenal Glands↗

PubMed1999

Down-regulation of nitric oxide production by ibuprofen in human volunteers.

Ibuprofen has been shown in vitro to modulate production of nitric oxide (NO), a mediator of sepsis-induced hypotension. We sought to determine whether ibuprofen alters NO production and, thereby, vascular tone, in normal and endotoxin-challenged volunteers. Techniques for detecting NO were validated in 17 subjects infused with sodium nitroprusside, a NO donor. Then, endotoxin (4 ng/kg) or saline (vehicle alone) was administered in a single-blinded, crossover design to 12 other subjects randomized to receive either ibuprofen (2400 mg p.o.) or a placebo. Endotoxin decreased mean arterial pressure (MAP; P =.002) and increased alveolar NO flow rates (P =.04) and urinary excretion of nitrite and nitrate (P =.07). In both endotoxemic and normal subjects, ibuprofen blunted the small fall in MAP associated with bed rest (P =.005) and decreased alveolar NO flow rates (P =.03) and urinary excretion of nitrite and nitrate (P =.02). However, ibuprofen had no effect on the decrease in MAP caused by endotoxin, although it blocked NO production to the point of disrupting the normal relationship between increases in exhaled NO flow rate and decreases in MAP (P =.002). These are the first in vivo data to demonstrate that ibuprofen down-regulates NO in humans. Ibuprofen impaired the NO response to bed rest, producing a small rise in blood pressure. Although ibuprofen also interfered with the ability of endotoxin to induce NO production, it had no effect on the fall in blood pressure, suggesting that the hemodynamic response to endotoxin is not completely dependent on NO under these conditions.

Adult↗

PubMed1995

Genomic structure of human microtubule-associated protein 2 (MAP-2) and characterization of additional MAP-2 isoforms.

We have determined that the gene for human microtubule-associated protein 2 (MAP-2) spans 19 exons, including 6 exons identified in this study, 1-4, 8, and 13; all six of these exons are transcribed. The alternative splicing of coding exons generates a greater diversity of MAP-2 transcripts and isoforms. The first three exons encode alternate 5' untranslated regions that can be spliced to additional untranslated sequences contained in exons 4 and 5. Exons 8 and 13 are transcribed in human fetal spinal cord, adult brain, MSN cells, and rat brain, and each exon maintains an open reading frame with both high and low molecular weight MAP-2 isoforms. Antibodies generated to synthetic peptides of exons 8 and 13 demonstrate that these exons are translated and MAP-2 isoforms containing these exons are generated.

Alternative Splicing↗

PubMed1993

The benefits of business process mapping.

We believe that you should view an organization as an integrated organism. Treating parts of this organism without first understanding the whole and how the parts interrelate leads to suboptimal solutions. "Reinventing" an organization requires fresh, objective, new insights. We believe Business Process Analysis and its associated "mapping" is a superior approach to corporate improvements because of: 1. Its emphasis on business processes. 2. Its organization-wide approach. 3. The discipline of requiring process definitions and building the matrices (mapping) required. 4. The involvement of all decision makers. 5. Its usefulness in so many vital areas of management. We know that, given proper top management support and a proper implementation, valid and acceptable improvements will result.

Decision Making, Organizational↗

PubMed2001

MHC class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy.

MHC class I chain gene A (MICA) is a non-classical Class I gene which is expressed on the surface of epithelia without beta 2-microglobulin. The gene is found in the major histocompatibility complex (MHC) in tight linkage disequilibrium with human leucocyte antigen-B (HLA-B). Its precise function is unknown, but it interacts with gamma delta T cells of the intestinal immune system. This region of the MHC has been implicated in inflammatory bowel disease (IBD) pathogenesis by recent association mapping studies and this study was performed to examine the prevalence of MICA gene polymorphisms in IBD, in particular in type 2 peripheral arthropathy (PeA), which also has a strong HLA-B association. An assessment of the prevalence of MICA polymorphisms in IBD was made. Blood from 50 ulcerative colitis (UC) and 50 Crohn's disease controls was taken and MICA status determined using allele-specific PCR for 16 known alleles of MICA. A further 91 UC patients were recruited to confirm the results of this stage, and then the polymorphisms were studied in 52 type 1 and 45 type 2 PeA patients. The MICA status of these groups was compared with 118 blood and organ donor controls with appropriate correction for multiple comparisons. UC overall was associated with possession of MICA*007 in 32% compared to 11% of controls (P(c) = 0.017). This association was confirmed in a second cohort of 91 patients (23% versus 11%, P = 0.02). These were independent of HLA class I status. Type 2 IBD PeA was associated with MICA*008 in 98% compared to 73% of controls (P = 0.0001). MICA*007 is associated with susceptibility to UC in our population and MICA*008 with type 2 IBD PeA. Further work is now required to assess the distribution and expression of MICA throughout the gut in health and disease.

Case-Control Studies↗

PubMed2004

Elemental mapping using the Ga 3d and In 4d transitions in the epsilon2 absorption spectra derived from EELS.

It is proposed that by using the valence-band states in electron energy loss spectroscopy, high-spatial resolution maps of quantitative elemental composition may be acquired with high acquisition rates. Further, it is shown that by using the epsilon(2) spectrum instead of single scattering data, the noise in the observed transitions and associated maps is significantly reduced. The epsilon(2) spectra are derived through a Kramers-Kronig transformation from electron energy loss spectra obtained in a scanning transmission electron microscope. Using transitions that occur in the epsilon(2) absorption spectrum (<40eV), quantitative elemental maps for III-V device structures have been produced. An example is provided using the Ga 3d transition to map a GaInNAs/GaAs laser structure. Weaker transitions such as In 4d have also been used to verify the Ga elemental distribution.

Electron Probe Microanalysis↗

PubMed2026

Associations between gut microbiota on carcass traits and meat quality in Neijiang pigs, Yorkshire pigs, and their hybrids.

This study was designed as an exploratory analysis to compare carcass performance, meat quality traits, and gut microbiota of Neijiang pigs (NN), Yorkshire pigs (YY), and Yorkshire × Neijiang hybrid pigs (YN), with the goal of generating testable hypotheses regarding potential links between gut microbial composition and production phenotypes. Compared with NN pigs, YN hybrids exhibited improved carcass performance while inheriting the favorable meat quality characteristics of Neijiang pigs. The results of 16S rRNA sequencing analysis showed that the relative abundance of the microbiota was similar to that of NN pigs. LDA effect size (LEfSe) results showed that Streptococcus, Treponema, probable_genus_10 and Fibrobacter were the differentially enriched taxa in YN pigs (p < 0.05). Correlation analysis was performed on carcass, meat quality and intestinal microbiota screened out by LEfSe. The results showed that Akkermansia tended to positively associate with body length and oblique length in YN pigs; Dialister correlated positively with dressing rate and pH45min; Treponema showed positive trends with a*45min and a*24h (p < 0.05). Finally, the correlation network model preliminarily mapped associations among production traits, gut microbiota, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for exploratory screening. Nine core microbial taxa exhibited close correlations with phenotypic indicators, which implied that these microbes might modulate metabolic pathways to shape pig performance. Overall, hybrids inherited superior parental carcass and meat quality but harbored unique gut microbial communities relative to purebreds-these preliminary correlative observations generate new hypotheses that gut microbiota may contribute to heterosis-associated phenotypic advantages, which require further targeted validation.

Animals↗