TaNAM-6A is essential for nitrogen remobilisation and regulates grain protein content in wheat (Triticum aestivum L.).

Grain protein content (GPC) is a crucial quality trait in bread wheat, which is influenced by the key transcription factor TaNAM. However, the regulatory mechanisms of TaNAM have remained largely elusive. In this study, a new role of TaNAM was unveiled in regulating nitrogen remobilisation which impacts GPC. The TaNAM knockout mutants generated by clustered regularly interspaced short palindromic repeats/Cas9 exhibited significantly delayed senescence and lower GPC, while overexpression of TaNAM-6A resulted in premature senility and much higher GPC. Further analysis revealed that TaNAM directly activates the genes TaNRT1.1 and TaNPF5.5s, which are involved in nitrogen remobilisation. This activity aids in the transfer of nitrogen from leaves to grains for protein synthesis. In addition, an elite allele of TaNAM-6A, associated with high GPC, was identified as a candidate gene for breeding high-quality wheat. Overall, our work not only elucidates the potential mechanism of TaNAM-6A affecting bread wheat GPC, but also highlights the significance of nitrogen remobilisation from senescent leaves to grains for protein accumulation. Moreover, our research provides a new target and approach for improving the quality traits of wheat, particularly the GPC.

Dissecting the genetic basis of Fusarium crown rot resistance in wheat by genome wide association study.

KEY MESSAGE: A locus conferring Fusarium crown rot resistance was identified on chromosome arm 3DL through genome wide association study and further validated in two recombinant inbred lines populations. Fusarium crown rot (FCR) is a severe soil borne disease in many wheat growing regions of the world. In this study, we attempted to detect loci conferring FCR resistance through a new seedling inoculation assay. A total of 223 wheat accessions from different geography origins were used to assemble an association panel for GWAS analysis. Four genotypes including Heng 4332, Luwanmai, Pingan 998 and Yannong 24 showed stable resistance to FCR. A total of 54 SNPs associated with FCR resistance were identified. Among the 10 putative QTLs represented by these SNPs, seven QTLs on chromosome 2B, 3A, 3D, 4A, 7A and 7B were novel and were consistently detected in at least two of the three trials conducted. Qfcr.cau.3D-3, which was targeted by 38 SNPs clustered within a genomic region of approximately 5.57 Mb (609.12-614.69 Mb) on chromosome arm 3DL, was consistently detected in all the three trials. The effects of Qfcr.cau.3D-3 were further validated in two recombinant inbred line populations. The presence of this locus reduced FCR severity up to 21.55%. Interestingly, the collinear positions of sequences containing the four SNPs associated with two FCR loci (Qfcr.cau.3A and Qfcr.cau.3B) were within the regions of Qfcr.cau.3D-3, suggesting that genes underlying these three loci may be homologous. Our results provide useful information for improving FCR resistance in wheat.

A novel variation of TaGW2-6B increases grain weight without penalty in grain protein content in wheat (Triticum aestivum L.).

Yield and quality are two crucial breeding objects of wheat therein grain weight and grain protein content (GPC) are two key relevant factors correspondingly. Investigations of their genetic mechanisms represent special significance for breeding. In this study, 199 F2 plants and corresponding F2:3 families derived from Nongda3753 (ND3753) and its EMS-generated mutant 564 (M564) were used to investigate the genetic basis of larger grain and higher GPC of M564. QTL analysis identified a total of 33 environmentally stable QTLs related to thousand grain weight (TGW), grain area (GA), grain circle (GC), grain length (GL), grain width (GW), and GPC on chromosomes 1B, 2A, 2B, 4D, 6B, and 7D, respectively, among which QGw.cau-6B.1, QTgw.cau-6B.1, QGa.cau-6B.1, and QGc.cau-6B.1 shared overlap confidence interval on chromosome 6B. This interval contained the TaGW2 gene playing the same role as the QTLs, so TaGW2-6B was cloned and sequenced. Sequence alignment revealed two G/A SNPs between two parents, among which the SNP in the seventh exon led to a premature termination in M564. A KASP marker was developed based on the SNP, and single-marker analysis on biparental populations showed that the mutant allele could significantly increase GW and TGW, but had no effect on GPC. Distribution detection of the mutant allele through KASP marker genotyping and sequence alignment against databases ascertained that no materials harbored this allele within natural populations. This allele was subsequently introduced into three different varieties through molecular marker-assisted backcrossing, and it was revealed that the allele had a significant effect on simultaneously increasing GW, TGW, and even GPC in all of three backgrounds. Summing up the above, it could be concluded that a novel elite allele of TaGW2-6B was artificially created and might play an important role in wheat breeding for high yield and quality. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01455-y.

Modified Botulinum Toxin Type A Injections Improve Symptoms Associated With Interstitial Cystitis/Bladder Pain Syndrome in Women: A Retrospective Cohort Study.

OBJECTIVE: To investigate the efficacy and safety of modified botulinum toxin type A (BoNT-A) injections (with additional periurethral injection [PUI] of BoNT-A) for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: This single-center, retrospective cohort study included 52 adult female patients with IC/BPS, with 24 patients receiving conventional BoNT-A injections and 28 receiving modified BoNT-A injections. The primary outcome measure was patient-reported global response assessment. Secondary outcomes included daytime frequency, nocturia, number of urinary urgency episodes in the voiding diary, pain visual analog score, O'Leary-Sant interstitial cystitis symptom index and interstitial cystitis problem index, pelvic pain and urgency/frequency scores, risk factors for recurrence, and postoperative recurrence-free time. RESULTS: The median duration of follow-up was 16.0 months (interquartile range 11.75-21 months). Patients who underwent modified BoNT-A injections showed significant improvement in postoperative global response assessment, symptom questionnaires, and pain assessment compared with those who underwent conventional surgery. A statistically significant difference was observed between the 2 groups in terms of recurrence-free time (12.5 vs 18.0 months, P = .02). Subgroup analysis suggested that additional PUI of BoNT-A was more effective in patients with combined severe periurethral pain. No serious complications occurred in both groups, and all minor postoperative complications were temporary. CONCLUSION: Modified BoNT-A injection is an effective treatment for IC/BPS that significantly reduces pain and improves voiding symptoms. It is particularly effective in patients with combined periurethral pain. In such patients, PUI of BoNT-A should be added to the routine intravesical injection of BoNT-A.

Implementation of antibody-drug conjugates in HER2-positive solid cancers: Recent advances and future directions.

In recent decades, there has been a surge in the approval of monoclonal antibodies for treating a wide range of hematological and solid malignancies. These antibodies exhibit exceptional precision in targeting the surface antigens of tumors, heralding a groundbreaking approach to cancer therapy. Nevertheless, monoclonal antibodies alone do not show sufficient lethality against cancerous cells compared to chemotherapy. Consequently, a new class of anti-tumor medications, known as antibody-drug conjugates (ADCs), has been developed to bridge the divide between monoclonal antibodies and cytotoxic drugs, enhancing their therapeutic potential. ADCs are chemically synthesized by binding tumor-targeting monoclonal antibodies with cytotoxic payloads through linkers that are susceptible to cleavage by intracellular proteases. They combined the accurate targeting of monoclonal antibodies with the potent efficacy of cytotoxic chemotherapy drugs while circumventing systemic toxicity and boasting superior lethality over standalone targeted drugs. The human epidermal growth factor receptor (HER) family, which encompasses HER1 (also known as EGFR), HER2, HER3, and HER4, plays a key role in regulating cellular proliferation, survival, differentiation, and migration. HER2 overexpression in various tumors is one of the most frequently targeted antigens for ADC therapy in HER2-positive cancers. HER2-directed ADCs have emerged as highly promising treatment modalities for patients with HER2-positive cancers. This review focuses on three approved anti-HER2 ADCs (T-DM1, DS-8201a, and RC48) and reviews ongoing clinical trials and failed trials based on anti-HER2 ADCs. Finally, we address the notable challenges linked to ADC development and underscore potential future avenues for tackling these hurdles.

Genome-wide association study identifies loci and candidate genes for RVA parameters in wheat (Triticum aestivum L.).

The gelatinization and retrogradation characteristics of wheat starch affect the eating quality of Chinese-style food. Rapid Visco Analyzer (RVA) parameters have been widely used as important indicators to evaluate and improve the quality of wheat starch. However, the genetic basis of RVA parameters remains to be further explored. In the present study, a natural population was genotyped using 90K single nucleotide polymorphism (SNP) arrays, and the RVA parameters of this population grown in five environments were evaluated. The results showed that 22,068 high-quality SNP markers were identified and distributed unequally on the chromosomes. According to the genetic distance, 214 wheat materials were divided into four groups. Except for the pasting temperature (PTT), six parameters followed a normal distribution. Based on the general linear model, 969 significant association SNPs were detected by genome-wide association studies (GWAS), and chromosomes 7A and 2B had the most associated SNPs. Breakdown viscosity (BV) was associated with the most SNPs (n = 238), followed by PTT (n = 186), peak viscosity (PV; n = 156), trough viscosity (TV; n = 127), and final viscosity (FV; n = 126). According to the average linkage disequilibrium (LD), 33 stable quantitative trait loci (QTLs) were identified for single parameters in multiple environments, of which 12 were associated with BV, followed by peak time (PT; n = 8) and PTT (n = 7). On the other hand, 67 pleiotropic QTLs were identified for multiple parameters. Three candidate genes-TasbeIIa, TasbeI, and TassIIa-were screened for phenotyping analysis. The grain width and the weight of the TasbeIIa and TaSSIIa knockout (KO) lines were significantly lower than those of the TasbeI KO lines and the control (CK). The KO lines had smaller endosperm cells, smaller A-type starch granules, and higher amylose content. The TasbeI KO lines showed normal RVA curves, while the TasbeIIa KO lines showed flat curves. However, the TaSSIIa lines failed to paste under the RVA temperatures. Conclusively, the SNPs/QTLs significantly associated with the RVA parameters and genetic resources with novel haplotypes could be used to improve the quality of wheat starch.

Grain albumin content is affected by 1BL/1RS translocation and alters the processing quality of wheat (Triticum aestivum L.).

Grain albumin is highly nutritious and closely related to the processing quality of wheat. However, few studies have explored the grain albumin content (GAC) in wheat. This study aims to uncover quantitative trait loci (QTLs) linked to wheat GAC by analyzing a doubled haploid (DH) population derived from common wheat cultivars ShanNong23 and ZhouMai17. We detected six QTLs controlling GAC on chromosomes 1B, 5A, and 6D, with individual QTL explaining 5.78% to 22.29% of the GAC variation. The effect of QGac.cau-1B.1 on GAC is attributed to the presence of the 1BL/1RS translocation, indicating that the 1BL/1RS translocation increase of GAC compared with the non-1BL/1RS translocation lines. The higher GAC observed in 1BL/1RS lines could be primarily attributed to the increased accumulation of omega-secalin, omega-gliadin, low molecular weight glutenin subunit and ribosomal protein content. Additionally, we also found that the SDS-sedimentation value of whole wheat flour was decreased by adding albumin solution. These results advance our understanding of the genetic basis of GAC and offer novel perspectives for enhancing wheat quality through genetic enhancements.