SpeedFlower: a comprehensive speed breeding protocol for indica and japonica rice.

To increase rice yields and feed billions of people, it is essential to enhance genetic gains. However, the development of new varieties is hindered by longer generation times and seasonal constraints. To address these limitations, a speed breeding facility has been established and a robust speed breeding protocol, SpeedFlower is developed that allows growing 4-5 generations of indica and/or japonica rice in a year. Our findings reveal that a high red-to-blue (2R > 1B) spectrum ratio, followed by green, yellow and far-red (FR) light, along with a 24-h long day (LD) photoperiod for the initial 15 days of the vegetative phase, facilitated early flowering. This is further enhanced by 10-h short day (SD) photoperiod in the later stage and day and night temperatures of 32/30 °C, along with 65% humidity facilitated early flowering ranging from 52 to 60 days at high light intensity (800 µmol m-2 s-1). Additionally, the use of prematurely harvested seeds and gibberellic acid treatment reduced the maturity duration by 50%. Further, SpeedFlower was validated on a diverse subset of 198 rice accessions from 3K RGP panel encompassing all 12 distinct groups of Oryza sativa L. classes. Our results confirmed that using SpeedFlower one generation can be achieved within 58-71 days resulting in 5.1-6.3 generations per year across the 12 sub-groups. This breakthrough enables us to enhance genetic gain, which could feed half of the world's population dependent on rice.

De novo transcriptome sequencing of drought tolerance-associated genes in little millet (Panicum sumatrense L.).

The genome size of the little millet Panicum sumatrense is unknown, although its genome is fairly diploid (2n = 4x = 36). Despite tremendous nutritional value and adaptability to adverse climatic conditions, P. sumatrense use was limited by their low palatability, coarse grain, and lack of variety of culinary preparations. Hence, understanding how to vary their usage to offer food and nutritional security in the continuously changing modern world, the proposed study was aimed to determine potential genes and metabolites implicated in drought resistance. The drought-resistant genotype of tiny millet OLM-203/Tarini was offered in pots under both relaxed and demanding circumstances. The experimental seedlings were 32 days old and had been under water stress for 23 days. A total of 7606 genes were compared between 23 and 32 days for roots and 7264 total genes were compared between 23 and 32 days for leaves, according to a research on differential expression genes (DEGs). Twenty essential genes for drought tolerance were up-or down-regulated in the control and treated roots of the OLM-203 genotype. For instance, the genes RS193 and XB34 were up-regulated in leaves while, WLIM1 was found to be down-regulated. Gene SKI35 was up-regulated in roots, whereas MPK6 and TCMOp1 were down-regulated in root samples. The roots and leaves of the tiny millet OLM-203 genotype expressed 36 up-regulated and 21 down-regulated serine transcripts, respectively. Gene annotations for leaf samples were classified as having "molecular function" (46%), "cellular component" (19%), and "biological process" (35%), while root sample gene annotations were categorized as having "biological process" (573 contigs), "molecular function" (401 contigs), and "cellular components" (166 contigs). Noteworthy, polyamines play a crucial role in drought stress tolerance in the genotype, and it was found that top ten DEGs encoding for polyamines were common in two tissues (leaf and root). Collectively, transcriptomics profiling (RNA-seq) unveiled transcriptional stability drought stress provide a new insight in underlying modus of operandi in little millet genotype "OLM-203/Tarini" in response to heat stress.

Resilience and Mitigation Strategies of Cyanobacteria under Ultraviolet Radiation Stress.

Ultraviolet radiation (UVR) tends to damage key cellular machinery. Cells may adapt by developing several defence mechanisms as a response to such damage; otherwise, their destiny is cell death. Since cyanobacteria are primary biotic components and also important biomass producers, any drastic effects caused by UVR may imbalance the entire ecosystem. Cyanobacteria are exposed to UVR in their natural habitats. This exposure can cause oxidative stress which affects cellular morphology and vital processes such as cell growth and differentiation, pigmentation, photosynthesis, nitrogen metabolism, and enzyme activity, as well as alterations in the native structure of biomolecules such as proteins and DNA. The high resilience and several mitigation strategies adopted by a cyanobacterial community in the face of UV stress are attributed to the activation of several photo/dark repair mechanisms, avoidance, scavenging, screening, antioxidant systems, and the biosynthesis of UV photoprotectants, such as mycosporine-like amino acids (MAAs), scytonemin (Scy), carotenoids, and polyamines. This knowledge can be used to develop new strategies for protecting other organisms from the harmful effects of UVR. The review critically reports the latest updates on various resilience and defence mechanisms employed by cyanobacteria to withstand UV-stressed environments. In addition, recent developments in the field of the molecular biology of UV-absorbing compounds such as mycosporine-like amino acids and scytonemin and the possible role of programmed cell death, signal perception, and transduction under UVR stress are discussed.

Impact of COVID-19 on cancer care in India: a cohort study.

BACKGROUND: The COVID-19 pandemic has disrupted health-care systems, leading to concerns about its subsequent impact on non-COVID disease conditions. The diagnosis and management of cancer is time sensitive and is likely to be substantially affected by these disruptions. We aimed to assess the impact of the COVID-19 pandemic on cancer care in India. METHODS: We did an ambidirectional cohort study at 41 cancer centres across India that were members of the National Cancer Grid of India to compare provision of oncology services between March 1 and May 31, 2020, with the same time period in 2019. We collected data on new patient registrations, number of patients visiting outpatient clinics, hospital admissions, day care admissions for chemotherapy, minor and major surgeries, patients accessing radiotherapy, diagnostic tests done (pathology reports, CT scans, MRI scans), and palliative care referrals. We also obtained estimates from participating centres on cancer screening, research, and educational activities (teaching of postgraduate students and trainees). We calculated proportional reductions in the provision of oncology services in 2020, compared with 2019. FINDINGS: Between March 1 and May 31, 2020, the number of new patients registered decreased from 112 270 to 51 760 (54% reduction), patients who had follow-up visits decreased from 634 745 to 340 984 (46% reduction), hospital admissions decreased from 88 801 to 56 885 (36% reduction), outpatient chemotherapy decreased from 173634 to 109 107 (37% reduction), the number of major surgeries decreased from 17 120 to 8677 (49% reduction), minor surgeries from 18 004 to 8630 (52% reduction), patients accessing radiotherapy from 51 142 to 39 365 (23% reduction), pathological diagnostic tests from 398 373 to 246 616 (38% reduction), number of radiological diagnostic tests from 93 449 to 53 560 (43% reduction), and palliative care referrals from 19 474 to 13 890 (29% reduction). These reductions were even more marked between April and May, 2020. Cancer screening was stopped completely or was functioning at less than 25% of usual capacity at more than 70% of centres during these months. Reductions in the provision of oncology services were higher for centres in tier 1 cities (larger cities) than tier 2 and 3 cities (smaller cities). INTERPRETATION: The COVID-19 pandemic has had considerable impact on the delivery of oncology services in India. The long-term impact of cessation of cancer screening and delayed hospital visits on cancer stage migration and outcomes are likely to be substantial. FUNDING: None. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Rice breeding for yield under drought has selected for longer flag leaves and lower stomatal density.

Direct selection for yield under drought has resulted in the release of a number of drought-tolerant rice varieties across Asia. In this study, we characterized the physiological traits that have been affected by this strategy in breeding trials across sites in Bangladesh, India, and Nepal. Drought- breeding lines and drought-tolerant varieties showed consistently longer flag leaves and lower stomatal density than our drought-susceptible check variety, IR64. The influence of environmental parameters other than drought treatments on leaf traits was evidenced by close grouping of treatments within a site. Flag-leaf length and width appeared to be regulated by different environmental parameters. In separate trials in the Philippines, the same breeding lines studied in South Asia showed that canopy temperature under drought and harvest index across treatments were most correlated with grain yield. Both atmospheric and soil stress strengthened the relationships between leaf traits and yield. The stable expression of leaf traits among genotypes and the identification of the environmental conditions in which they contribute to yield, as well as the observation that some breeding lines showed longer time to flowering and higher canopy temperature than IR64, suggest that selection for additional physiological traits may result in further improvements of this breeding pool.

AlphaFold 2: Why It Works and Its Implications for Understanding the Relationships of Protein Sequence, Structure, and Function.

AlphaFold 2 (AF2) was the star of CASP14, the last biannual structure prediction experiment. Using novel deep learning, AF2 predicted the structures of many difficult protein targets at or near experimental resolution. Here, we present our perspective of why AF2 works and show that it is a very sophisticated fold recognition algorithm that exploits the completeness of the library of single domain PDB structures. It has also learned local side chain packing rearrangements that enable it to refine proteins to high resolution. The benefits and limitations of its ability to predict the structures of many more proteins at or close to atomic detail are discussed.

Genotype × environment interactions for grain iron and zinc content in rice.

BACKGROUND: Nutrient deficiency in humans, especially in children and lactating women, is a major concern. Increasing the micronutrient concentration in staple crops like rice is one way to overcome this. The micronutrient content in rice, especially the iron (Fe) and zinc (Zn) content, is highly variable. The identification of rice genotypes in which there are naturally high Fe and Zn concentrations across environments is an important target towards the production of biofortified rice. RESULTS: Phenotypic correlations between grain Fe and Zn content were positive and significant in all environments but a significant negative association was observed between grain yield and grain Fe and Zn. Promising breeding lines with higher Zn or Fe content, or both, were: IR 82475-110-2-2-1-2 (Zn: 20.24-37.33 mg kg-1 ; Fe: 7.47-14.65 mg kg-1 ); IR 83294-66-2-2-3-2 (Zn: 22-37-41.97 mg kg-1 ; Fe: 9.43-17.16); IR 83668-35-2-2-2 (Zn: 27.15-42.73 mg kg-1 ; Fe: 6.01-14.71); IR 68144-2B-2-2-3-1-166 (Zn: 23.53-40.30 mg kg-1 ; Fe: 10.53-17.80 mg kg-1 ) and RP Bio 5478-185M7 (Zn: 22.60-40.07 mg kg-1 ; Fe: 7.64-14.73 mg kg-1 ). Among these, IR82475-110-2-2-1-2 (Zn: 20.24-37.33 mg kg-1 ; Fe: 7.47-14.65 mg kg-1 ) is also high yielding with 3.75 t ha-1 . Kelhrie Cha (Zn: 17.76-36.45 mg kg-1 ; Fe: 7.17-14.77 mg kg-1 ), Dzuluorhe (Zn: 17.48-39.68 mg kg-1 ; Fe: 7.89-19.90 mg kg-1 ), Nedu (Zn: 18.97-43.55 mg kg-1 Fe: 8.01-19.51 mg kg-1 ), Kuhusoi-Ri-Sareku (Zn: 17.37-44.14 mg kg-1 ; Fe: 8.99-14.30 mg kg-1 ) and Mima (Zn: 17.10-45.64 mg kg-1 ; Fe: 9.97-17.40 mg kg-1 ) were traditional donor genotypes that possessed both high grain Fe and high Zn content. CONCLUSION: Significant genotype × location (G × L) effects were observed in all traits except Fe. Genetic variance was significant and was considerably larger than the variance of G × L for grain Zn and Fe content traits, except grain yield. The G × L × year variance component was significant in all cases. © 2020 Society of Chemical Industry.

Characterization of pond ash-bentonite mixes as landfill liner material.

Characterization of pond ash-bentonite mixes is made to assess their suitability as liner material for waste disposal facilities by examining the relevant index and engineering properties. Further, a comparative assessment is made between sand-bentonite and pond ash-bentonite mixes for the range of bentonite content varying from 0 to 30% by weight at an interval of 5% to ensure an effective substitution of sand with pond ash. Addition of bentonite to sand or pond ash significantly influences the plasticity, strength and permeability properties. Besides, the shape parameters of the coarser fraction and morphology of compacted mixes also influence the engineering properties. A multiple linear regression equation is suggested to predict the hydraulic conductivity of these mixes by considering the basic material properties such as liquid limit, plasticity index and void ratio as an input variable with a correlation coefficient of 0.92 between the measured and predicted hydraulic conductivity values. At comparable conditions, compacted pond ash-bentonite mixes exhibit higher strength but also higher permeability than sand-bentonite mixes. Pond ash-bentonite and sand-bentonite mixes met the liner requirements when compacted with modified Proctor compaction effort at a minimum bentonite content of 20% and 15%, respectively.

Discovery of Potent Inhibitors of 11ß-Hydroxysteroid Dehydrogenase Type 1 Using a Novel Growth-Based Protocol of in Silico Screening and Optimization in CONTOUR.

With the continuous progress in ultralarge virtual libraries which are readily accessible, it is of great interest to explore this large chemical space for hit identification and lead optimization using reliable structure-based approaches. In this work, a novel growth-based screening protocol has been designed and implemented in the structure-based design platform CONTOUR. The protocol was used to screen the ZINC database in silico and optimize hits to discover 11ß-HSD1 inhibitors. In contrast to molecular docking, the virtual screening process makes significant improvements in computational efficiency without losing chemical equities through partitioning 1.8 million ZINC compounds into fragments, docking fragments to form key hydrogen bonds with anchor residues, reorganizing molecules into molecular fragment trees using matched fragments and common substructures, and then regrowing molecules with the help of developed intelligent growth features inside the protein binding site to find hits. The growth-base screening approach is validated by the high hit rate. A total of 50 compounds have been selected for testing; of these, 15 hits having diverse scaffolds are found to inhibit 11ß-HSD1 with IC50 values of less than 1 µM in a biochemical enzyme assay. The best hit which exhibits an enzyme IC50 of 33 nM is further developed to a novel series of bicyclic 11ß-HSD1 inhibitors with the best inhibition of enzyme IC50 of 3.1 nM. The final lead candidate exhibits IC50 values of 7.2 and 21 nM in enzyme and adipocyte assays, respectively, displayed greater than 1000-fold of selectivity over 11ß-HSD2 and two other related hydroxysteroid dehydrogenases, and can serve as good starting points for further optimization to develop clinical candidates.

In-situ stabilization of sedimented ash deposit by partial penetrating chemical columns.

This paper highlights the efficacy of partial penetrating chemical columns of sodium hydroxide (NaOH) in improving the geo-engineering and leaching characteristics of sedimented ash deposits through a comprehensive laboratory model testing program. Sedimented ash beds were formed in cylindrical tanks and treated with centrally installed chemical columns of either 9M or 18M concentration. After specified curing periods the in-situ moisture content, dry density, unconfined compressive strength (UCS), hydraulic conductivity, pH and concentration of major and trace elements were measured at different locations. Bell-shaped stabilized zones were found to develop around the columns with different magnitudes of strength. A series of sodium based geopolymeric compounds and calcium-based hydration products were identified in the treated ash specimens. Formation of these compounds is primarily responsible for modifying the geo-engineering properties of the sedimented ash deposits. The leaching of different elements from the ash bed is expressed in terms of contamination potential ratio (CPR), which is influenced by the reaction products, the pH of pore fluid and hydraulic conductivity. Test results indicate that chemical columns are quite effective in increasing the strength, reducing the hydraulic conductivity and leachability of elements along with modifying other parameters like in-situ water content and dry density.

Chemical, experimental, and morphological evidence for diagenetically altered melanin in exceptionally preserved fossils.

In living organisms, color patterns, behavior, and ecology are closely linked. Thus, detection of fossil pigments may permit inferences about important aspects of ancient animal ecology and evolution. Melanin-bearing melanosomes were suggested to preserve as organic residues in exceptionally preserved fossils, retaining distinct morphology that is associated with aspects of original color patterns. Nevertheless, these oblong and spherical structures have also been identified as fossilized bacteria. To date, chemical studies have not directly considered the effects of diagenesis on melanin preservation, and how this may influence its identification. Here we use time-of-flight secondary ion mass spectrometry to identify and chemically characterize melanin in a diverse sample of previously unstudied extant and fossil taxa, including fossils with notably different diagenetic histories and geologic ages. We document signatures consistent with melanin preservation in fossils ranging from feathers, to mammals, to amphibians. Using principal component analyses, we characterize putative mixtures of eumelanin and phaeomelanin in both fossil and extant samples. Surprisingly, both extant and fossil amphibians generally exhibit melanosomes with a mixed eumelanin/phaeomelanin composition rather than pure eumelanin, as assumed previously. We argue that experimental maturation of modern melanin samples replicates diagenetic chemical alteration of melanin observed in fossils. This refutes the hypothesis that such fossil microbodies could be bacteria, and demonstrates that melanin is widely responsible for the organic soft tissue outlines in vertebrates found at exceptional fossil localities, thus allowing for the reconstruction of certain aspects of original pigment patterns.

Conformational control in structure-based drug design.

In structure-based drug design, the basic goal is to design molecules that fit complementarily to a given binding pocket. Since such computationally modeled molecules may not adopt the intended bound conformation outside the binding pocket, one challenge is to ensure that the designed ligands adopt similar low energy conformations both inside and outside of the binding pocket. Computational chemistry methods and conformational preferences of small molecules from PDB and Cambridge Structural Database (CSD) can be used to predict the bound structures of the designed molecules. Herein, we review applications of conformational control in structure-based drug design using selected examples from the recent medicinal chemistry literature. The main purpose is to highlight some intriguing conformational features that can be applied to other drug discovery programs.

Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11ß hydroxysteroid dehydrogenase type 1 inhibitor.

A potent, in vivo efficacious 11ß hydroxysteroid dehydrogenase type 1 (11ß HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11ß HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11ß HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.

Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core.

Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aß) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aß levels was detected.

Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists.

Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.

The use of spirocyclic scaffolds in drug discovery.

Owing to their inherent three-dimensionality and structural novelty, spiro scaffolds have been increasingly utilized in drug discovery. In this brief review, we highlight selected examples from the primary medicinal chemistry literature during the last three years to demonstrate the versatility of spiro scaffolds. With recent progress in synthetic methods providing access to spiro building blocks, spiro scaffolds are likely to be used more frequently in drug discovery.

Long-Term Complete Response with Single-Agent Capecitabine in Her-2-neu-Positive Metastatic Breast Cancer-A Rare Case Report.

The standard treatment approach for metastatic breast cancer with HR- and Her-2-neu + disease is trastuzumab with systemic therapy. But in patients having severe cardiac dysfunction, trastuzumab is avoided. Various combination regimens are available in that setting, but no study has shown better efficacy of capecitabine monotherapy in this setting. We hereby present a case report of using capecitabine monotherapy in first-line setting, and the patient had complete resolution of lung metastasis from the last 2 years. A 64-year-old postmenopausal lady with a known case of breast carcinoma in the left side diagnosed in the year 2016 with hormone receptor-positive, Her2-negative disease completed chemoradiation and on is aromatase inhibitor from the last 5 years. She complained of breathlessness and fatigue lasting for 1 month in July 2021. On evaluation, chest CT scan revealed multiple bilateral lung metastases along with 3×3 cm right-sided breast lump with no metastasis elsewhere in the body. Core needle biopsy of breast lump and CT-guided left lung nodule biopsy were performed which revealed infiltrating carcinoma with immunohistochemical markers showing tumor cells positive for Her-2-neu with hormone receptor-negative disease. PET-CT scan was done which revealed FDG avidity in bilateral lung fields and right breast lump with no disease elsewhere. Her echocardiography showed ejection fraction of 40% owing to which injection trastuzumab was deferred and the plan to start tablet capecitabine 1000 mg twice BD days 1-14 cycles every 21 days was made. She showed improvement in symptoms with PET-CT scan revealing resolution of lung metastasis from the last 2 years. Trastuzumab in combination with pertuzumab and taxane is the standard of care for metastatic breast carcinoma with hormone receptor-negative and Her2-positive disease. But in patients who are elderly, frail with severe cardiac dysfunction, trastuzumab-based regimen is contraindicated. No study demonstrated efficacy of capecitabine monotherapy in this subset of disease. More prospective studies are required to identify patients who can benefit from capecitabine monotherapy in first-line setting in this subset of disease. Also capecitabine usage has several advantages mainly low cost and availability in oral form, and patients can be followed up on OPD basis.

Management of a Rare Challenging Case of Duodenal Ampullary Lipoma.

Duodenal lipoma is a very rare entity with limited case reports present in literature. But duodenal ampullary lipomas are even more rare in nature. Owing to the recent advances in endoscopy and modern imaging techniques, more cases are being diagnosed and treated. However, challenge lies in performing a less invasive and least morbid procedures to treat them surgically in such complex location of tumour. To study the diagnosis and treatment of duodenal ampullary lipoma in a young male patient and challenges faced during surgical management. A 15-year-old young boy presented to us with complaints of intermittent upper gastrointestinal bleed and jaundice since last 2 months. At admission, his serum haemoglobin was 3 g% for which he was transfused 3 units of packed blood cells for optimization. On further evaluation, CT scan abdomen revealed 71 × 49 mm large heterogeneous mass in D3 segment of duodenum causing duodeno-duodenal intussusception involving D1 and D2 segment along with ampullary region with mass being the lead point. There was compression of CBD with dilatation measuring 11 mm in diameter and mild IHBR dilatation. UGIE revealed narrowing at D1-D2 junction due to polypoidal lesion with overlying smooth mucosa with no active bleeding point identified. His blood parameters were normal except for low haemoglobin (before blood transfusion) and total serum bilirubin of 2.3 mg/dl.He was optimized for surgery and underwent exploratory laparotomy with duodenotomy at D2 with mass excision of 7 × 5 cm sessile polyp with base over ampulla followed by plastic repair of sphincter of Oddi (pancreas preserving procedure). He was started on oral liquids on POD 3 and was discharged on normal diet by POD 7 with an uneventful recovery. Result of histopathological report revealed, on gross cut section, the presence of mass of 7 × 5 × 3 cm size with smooth mucosa and fibrofatty tissue. On microscopic examination, diagnosis of submucosal lipomatous polyp was made. Our case report indicated duodenal ampullary lipoma is extremely rare entity. The symptoms are nonspecific and CT scan abdomen is the first investigation of choice for diagnosis. The treatment depends on the patient's condition as well as the size and position of the tumour. In our case report, the tumour base was exactly at the level of ampulla where we performed complex procedure of local excision of mass with sphincteroplasty avoiding major Whipple procedure for such benign condition. It provided rapid postoperative recovery to the patient.

Maxillary Fibromatosis: A Rare Clinical Report and Its Review of Literature.

Fibromatosis is a rare locally aggressive benign tumour which arises from the musculoaponeurotic structures throughout the body. In the oral and maxillofacial region, It has been described under a variety of synonyms, including 'extra articular desmoids', 'desmoids tumours', 'grade-1 fibrosarcomas','non metastasizing fibrosarcoma'and 'aggressive fibromatosis'. The pecularity of this entity in paranasal sinuses is that it is rare in this location and are locally aggressive with higher rates of recurrence in a relatively restricted area.The purpose of this study is to present a rare case report and reviewing the literature of this entity.