Lysine and tryptophan, two essential amino acids, are generally deficient in normal maize but enriched in opaque2 (o2) mutants. However, these o2 mutants are linked to undesirable effects like soft endosperm and yield loss. To circumvent this, researchers introgressed o2 modifiers (Mo2s) into mutant maize and developed Quality Protein Maize (QPM). This study identifies genomic regions linked to Mo2 governing kernel hardness, opacity, and tryptophan content. Two QPM lines (DQL 2104-1 and DQL 2034), contrasting for these traits, were crossed to develop a 138 F2 and 109 F2:3 mapping population. Genotyping with 141 informative SSR markers resulted in 2417.01 cM genetic map with an average marker distance of 20.66 cM between markers. Inclusive composite interval mapping (ICIM) detected 11 QTLs across six different chromosomes: seven QTLs for kernel opacity (chromosomes 1, 2, 4, 7), three for hardness (chromosomes 7, 8, 9), and one for tryptophan (chromosome 9). These QTLs co-localized with candidate genes (opaque1, opaque11, floury1, floury2, floury4, mucronate1, and waxy1). The identified QTLs provide foundational targets for marker-assisted breeding. Few QTLs like qHRD9.1 (PVE = 14.18%) and qTRP9.1 (PVE = 10.69%) are prime candidates for improving hardness and tryptophan. These loci can be pyramided into elite lines using SSR markers; genomic selection could be used to optimize trait stacking. Future fine-mapping and functional studies will refine these regions, accelerating the development of high-yielding QPM with vitreous kernels and enhanced nutritional quality.

Social anxiety disorder (SAD) is a chronic, debilitating, and prevalent neuropsychiatric condition for which an acute, as-needed therapy is an unmet medical need. This Phase 2 study evaluated a potential novel, fast-acting, anxiolytic, BNC210, in SAD patients (NCT05193409). PREVAIL was a placebo-controlled, acute dose study of 225 mg and 675 mg BNC210 in 151 adult participants with SAD. Anxiety was evaluated by self-report efficacy scales during the anticipation and performance phases of a simulated public speaking challenge. Safety data were collected. Least squares mean ± standard error (SE) differences compared to placebo for the Subjective Units of Distress Scale (SUDS) scores for the change from baseline to the average of the performance phase were -6.6 ± 4.75 for 225 mg BNC210 and -4.8 ± 4.73 for 675 mg BNC210 (not significant). A post hoc analysis of SUDS scores evaluating combined BNC210 doses and speaking challenge phases (anticipation and performance) revealed a nominally statistically significant reduction compared to placebo (p = 0.044; effect size 0.36). Both dose levels of BNC210 demonstrated a favorable safety profile. PREVAIL supported further testing of 225 mg BNC210 as a potential safe and effective anxiolytic for acute, as-needed treatment of SAD. A Phase 3 trial is ongoing.

BNC210 is an investigational small molecule selective negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor (α7 nAChR). It is an anxiolytic compound with a novel mechanism of action. In a series of Phase 1 clinical trials in healthy volunteers, psychometric test batteries showed that BNC210 did not cause attention, cognition, or memory impairment, negative effects on mood or emotional stability, sedation, or addiction, ruling out undesirable side effects of known anxiolytic compounds. In healthy volunteers, target engagement at the α7 nAChR was demonstrated in a nicotine shift assay using quantitative electroencephalography, and BNC210 demonstrated improvement in panic-like symptoms in a cholecystokinin tetrapeptide panic model. Initial clinical trials used an aqueous suspension formulation of BNC210 to cover a wide dosage range; however, its pharmacokinetic parameters were consistent with solubility-limited absorption and a significant food effect. A dispersible tablet formulation was then developed with improved bioavailability and is being used in Phases 2 and 3 clinical trials. Collectively, the Phase 1 data demonstrated desired properties of BNC210 supporting proof-of-concept clinical trials. BNC210 is currently being developed for acute, as-needed treatment of social anxiety disorder and chronic treatment of post-traumatic stress disorder.

BACKGROUND:Post-traumatic stress disorder (PTSD) is a serious, debilitating, and prevalent psychiatric condition occurring in people who are traumatized and experience intense, disturbing thoughts and feelings that persist. BNC210 is a novel α7 nicotinic acetylcholine receptor-negative allosteric modulator developed to treat PTSD. METHODS:ATTUNE was a randomized, double-blind, phase 2b, placebo-controlled trial. Patients between 18 and 75 years of age with a current PTSD diagnosis and a Clinician-Administered PTSD Scale for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) (CAPS-5) total symptom severity score of 30 or more were eligible (range: 0 to 80; in all scales used in this trial a higher score indicates a more severe condition). We randomly assigned patients 1:1 to a BNC210 dose of 900 mg twice daily or placebo for 12 weeks. The primary end point was a change from baseline to week 12 in CAPS-5 total score for BNC210 versus placebo. RESULTS:In the modified intent-to-treat population (n=182), an improvement in the CAPS-5 total score was observed with BNC210 compared with placebo (least squares [LS] mean difference: -4.03; Cohen's d effect size: 0.40; P=0.048) at week 12. A LS mean difference in CAPS-5 score of -4.11 was observed as early as week 4. The LS mean difference to week 12 for depressive symptoms measured on the Montgomery-Åsberg Depression Rating Scale (range: 0 to 60; minimal clinically important difference [MCID] ≥2]) was -3.19 and for sleep measured on the Insomnia Severity Index (range: 0 to 28; MCID 6) was -2.19. Treatment-emergent adverse events (AEs) occurred in 70 (66.7%) patients in the BNC210 group and 56 (53.8%) in the placebo group, most commonly headache, nausea, fatigue, and hepatic enzyme elevations. In the BNC210 treatment group, 21 patients withdrew from treatment for AEs, while 10 did so in the placebo group. There were no serious AEs or deaths reported for the BNC210 group. CONCLUSIONS:BNC210 improved PTSD symptom severity at week 12 with indications of effect as early as week 4. Our trial establishes equipoise for additional larger trials that are needed to determine the clinical utility of BNC210 for the treatment of PTSD. (Funded by Bionomics Limited; ClinicalTrials.gov number, NCT04951076.).

Context Amylose is a type of resistant starch with numerous health benefits and industrial applications. Starch from maize (Zea mays L.) usually has an amylose content of ~25%. Aims The aim was to develop high-amylose maize genotypes suitable for human consumption and adapted to Indian conditions. Methods Marker-assisted backcross breeding was used to transfer the mutant ae1 allele from a high-amylose donor from the USA into the three parents (HKI 1344, HKI 1378, HKI 1348-6-2) of two high-yielding white maize hybrids (HM5 and HM12) grown in India. Key results In converted lines, amylose content was 40.40–58.10% of total kernel starch, compared with 22.25–26.39% in parents. The percentage increase in amylose content was 63.70–153.03%. There was a significant amount of background recovery in each backcross generation: 66.80–79% in BC1F1, 72.85–88.60% in BC2F1, and 84.45–93.70% in BC2F2. Overall, the total kernel starch content was reduced (by ~22%) in the ae1-introgressed families. Conclusions The converted lines developed in the study are enriched with kernel amylose while showing significant background recovery. Implications The high-amylose lines developed may be highly beneficial for diabetic patients and in the bioplastics industry, and should be suitable for growing under Indian conditions.

This work describes the characterization of BNC210 (6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(4-morpholinylcarbonyl)-1,8-naphthyridin-4(1H)-one), a selective, small molecule, negative allosteric modulator (NAM) of α7 nicotinic acetylcholine receptors (α7 nAChR). With the aim to discover a non-sedating, anxiolytic compound, BNC210 was identified during phenotypic screening of a focused medicinal chemistry library using the mouse Light Dark (LD) box to evaluate anxiolytic-like activity and the mouse Open Field (OF) (dark) test to detect sedative and/or motor effects. BNC210 exhibited anxiolytic-like activity with no measurable sedative or motor effects. Electrophysiology showed that BNC210 did not induce α7 nAChR currents by itself but inhibited EC80 agonist-evoked currents in recombinant GH4C1 cell lines stably expressing the rat or human α7 nAChR. BNC210 was not active when tested on cell lines expressing other members of the cys-loop ligand-gated ion channel family. Screening over 400 other targets did not reveal any activity for BNC210 confirming its selectivity for α7 nAChR. Oral administration of BNC210 to male mice and rats in several tests of behavior related to anxiety- and stress- related disorders, demonstrated significant reduction of these behaviors over a broad therapeutic range up to 500 times the minimum effective dose. Further testing for potential adverse effects in suitable rat and mouse tests showed that BNC210 did not produce sedation, memory and motor impairment or physical dependence, symptoms associated with current anxiolytic therapeutics. These data suggest that allosteric inhibition of α7 nAChR function may represent a differentiated approach to treating anxiety- and stress- related disorders with an improved safety profile compared to current treatments.

Positive allosteric modulators (PAMs) of α7 nAChRs can have different properties with respect to their effects on channel kinetics. Type I PAMs amplify peak channel response to acetylcholine but do not appear to influence channel desensitization kinetics, whereas Type II PAMs both increase channel response and delay receptor desensitization. Both Type I and Type II PAMs are reported in literature, but there are limited reports describing their structure-kinetic profile relationships. Here, we report a novel class of compounds with either Type I or Type II behavior that can be tuned by the relative stereochemistry around the central cyclopropyl ring: for example, (R,R)-13 (BNC375) and its analogues with RR stereochemistry around the central cyclopropyl ring are Type I PAMs, whereas compounds in the same series with SS stereochemistry (e.g., (S,S)-13) are Type II PAMs as measured using patch-clamp electrophysiology. Further fine control over the kinetics has been achieved by changing the substitutions on the aniline ring: generally the substitution of aniline with strong electron withdrawing groups reduces the Type II character of these compounds. Our structure-activity optimization efforts have led to the discovery of BNC375, a small molecule with good CNS-drug like properties and clinical candidate potential.

Sitophilus oryzae L is the most destructive insect pest of stored maize and is widely distributed in tropical regions. In the present study, eighteen maize genotypes were screened for several susceptibility parameters against S. oryzae by using "No Choice method". Biophysical traits (test weight, thousand kernel weight, kernel hardness), anatomical fractions (tip cap, germ, pericarp, endosperm), biochemical variants (starch, protein, oil, sugar) were correlated with insect susceptibility parameters. There is significant relationship among test weight, kernel hardness, and insect susceptibility parameters. Pericarp was positively correlated while endosperm, starch content were negatively correlated with median development period but were non-significant. Majority of the maize genotypes containing harder kernels and thick pericarp showed less susceptibility to S. oryzae. The results indicated that the biophysical, anatomical and biochemical traits are responsible for varying levels of resistance to S. oryzae.