Effect of an Autotaxin Inhibitor, 2-(4-Chlorophenyl)-7-methyl-8-pentylimidazo[1,2-a] Pyrimidin-5(8H)-one (CBT-295), on Bile Duct Ligation-Induced Chronic Liver Disease and Associated Hepatic Encephalopathy in Rats.

The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy. Interestingly, LPA levels were significantly increased in the plasma, liver, and brain of rats following bile duct ligation. Subsequently, we tested the efficacy of an ATX inhibitor, CBT-295, in bile duct-induced biliary cirrhosis and neuropsychiatric symptoms associated with hepatic encephalopathy. CBT-295 showed good oral bioavailability and favorable pharmacokinetic properties. CBT-295 exhibited a significant reduction in inflammatory cytokines like TGF-ß, TNF-α, and IL-6 levels, also reduced bile duct proliferation marker CK-19, and lowered liver fibrosis, as evident from reduced collagen deposition. The reversal of liver fibrosis with CBT-295 led to a reduction in blood and brain ammonia levels. Furthermore, CBT-295 also reduced neuroinflammation induced by ammonia, which is characterized by a significant reduction in brain cytokine levels. It improved neuropsychiatric symptoms such as locomotor activities, cognitive impairment, and clinical grading scores associated with hepatic encephalopathy. The improvement in hepatic encephalopathy observed with the ATX inhibitor could be the result of its hepatoprotective action and its ability to attenuate neuroinflammation. Therefore, inhibition of ATX-LPA signaling can be a multifactorial approach for the treatment of chronic liver diseases.

Palladium-Catalyzed, Site-Selective C(sp2)8-H Halogenation and Nitration of 4-Quinolone Derivatives.

Selective installation of halo and nitro groups in heterocyclic backbone through a transition-metal-catalyzed C-H bond activation strategy is immensely alluring to access high-value scaffolds. Here in, we disclosed N-pyrimidyl-directed assisted palladium(II)-catalyzed C(sp2)8-H halogenation and nitration of substituted 4-quinolone derivatives in the presence of N-halosuccinimide and tert-butyl nitrite, respectively, offering structurally diversified 8-halo/nitro-embedded 4-quinolone frameworks in high yields. Mechanistic studies indicated that the reaction follows an organometallic pathway with a reversible C-H metalation step. This operationally simple protocol is scalable with a broad substrate scope and excellent functional group compatibility. Moreover, the postdiversifications of the synthesized derivatives are also showcased to ensure the synthetic versatility of the methodology.

Revolutionizing Nipah virus vaccinology: insights into subunit vaccine development strategies and immunological advances.

The Nipah virus (NiV), a zoonotic virus in the Henipavirus genus of the Paramyxoviridae family, emerged in Malaysia in 1998 and later spread globally. Diseased patients may have a 40- 70% chance of fatality depending on the severity and early medication. The recent outbreak of NiV was reported in Kerala (India) by a new strain of MCL-19-H-1134 isolate. Currently, no vaccines are available, highlighting the critical need for a conclusive remedy. Our study aims to develop a subunit vaccine against the NiV by analyzing its proteome. NiV genome and proteome sequences were obtained from the NCBI database. A phylogenetic tree was constructed based on genome alignment. T-cell, helper T-cell, and B-cell epitopes were predicted from the protein sequences using NetCTL-1.2, NetMHCIIPan-4.1, and IEDB servers, respectively. High-affinity epitopes for human receptors were selected to construct a multi-epitope vaccine (MEV). These epitopes' antigenicity, toxicity, and allergenicity were evaluated using VaxiJen, AllergenFP-v.1.0, and AllergenFP algorithms. Molecular interactions with specific receptors were analyzed using PyRx and ClusPro. Amino acid interactions were visualized and analyzed using PyMOL and LigPlot. Immuno-simulation was conducted using C-ImmSim to assess the immune response elicited by the MEV. Finally, the vaccine cDNA was inserted into the pET28a(+) expression vector using SnapGene tool for in silico cloning in an E. coli host. The potential for an imminent outbreak cannot be overlooked. A subunit vaccine is more cost-effective and time-efficient. With additional in vitro and in vivo validation, this vaccine could become a superior preventive measure against NiV disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00246-9.

Zinc-loaded mesoporous silica nanoparticles mitigate salinity stress in wheat seedlings through silica-zinc uptake, osmotic balance, and ROS detoxification.

Abiotic stresses like salinity and micronutrient deficiency majorly affect wheat productivity. Applying mesoporous silica nanoparticles (MSiNPs) as a smart micronutrient delivery system can facilitate better stress management and nutrient delivery. In this purview, we investigated the potential of MSiNPs and Zn-loaded MSiNPs (Zn-MSiNPs) on the growth and physiology of wheat seedlings exposed to salinity stress (200 mM NaCl). Initially, the FESEM, DLS, and BET analysis portrayed nanoparticles' spherical shape, nano-size, and negatively charged mesoporous surface. A sustained release of Zn+2 from Zn-MSiNPs at 30 °C, diffused light, and pH 7 was perceived with a 96.57% release after 10 days. Further, the mitigation of NaCl stress in the wheat seedlings was evaluated with two different concentrations, each of MSiNPs and Zn-MSiNPs (1 g/L and 5 g/L), respectively. A meticulous improvement in the germination and growth of wheat seedlings was observed when treated with both MSiNPs and Zn-MSiNPs. A considerable increase in chlorophyll, total protein, and sugar content was in consort with a substantial decline in MDA, electrolyte leakage, and ROS accumulation, showcasing the nanomaterials' palliating effects. Most importantly, the K+/Na+ ratio in shoots increased significantly by 3.43 and 4.37 folds after being treated with 5 g/L Zn-MSiNPs, compared to their respective control sets (0 and 200 mM NaCl). Therefore, it can be concluded that the Zn-MSiNPs can effectively restrain the effects of salinity stress on wheat seedlings.

[99mTc]Tc-labeled HYNIC conjugated chlorambucil as a tumor targeting Agent: Synthesis, characterization and ex-vivo evaluation.

Chlorambucil is an alkylating drug that finds application towards chemotherapy of different types of cancers. In order to explore the possibility of utilization of this drug as an imaging agent for early diagnosis of solid tumors, attempt was made to synthesize a 99mTc complex of chlorambucil and evaluate its potential in tumor bearing small animal model. HYNIC-chlorambucil was synthesized by conjugation of HYNIC with chlorambucil via an ethylenediamine linker. All the intermediates and final product were purified and characterized by standard spectroscopic techniques viz. FT-IR, 1H/13C-NMR as well as by mass spectrometry. HYNIC-chlorambucil conjugate was radiolabeled with [99mTc]Tc and found to be formed with > 95 % radiochemical purity via RP-HPLC studies. The partition coefficient (Log10Po/w) of the synthesized complex was found to be -0.78 ± 0.25 which indicated the moderate hydrophilic nature for the complex. Biological behaviour of [99mTc]Tc-HYNIC-chlorambucil, studied in fibrosarcoma bearing Swiss mice, revealed a tumor uptake of about 4.16 ± 1.52 %IA/g at 30 min post-administration, which declined to 1.91 ± 0.13 % IA/g and 1.42 ± 0.14 %IA/g at 1 h and 2 h post-administration, respectively. A comparison of different [99mTc]Tc-chlorambucil derivatives (reported in the contemporary literature) formulated using different methodologies revealed that tumor uptake and pharmacokinetics exhibited by these agents strongly depend on the lipophilicity/hydrophilicity of such agents, which in turn is dependent on the bifunctional chelators used for formulating the radiolabeled chlorambucils.

Evaluation of acute intravenous toxicity of HEPES: Is Good's buffer good and safe enough for clinical utilization in nuclear medicine?

OBJECTIVE: Good's buffer or HEPES has advantages over other buffers commonly used in radiopharmaceutical preparation as it exhibits significantly lower complexation tendency with metal ions. However, use of HEPES buffer for radiolabeling reactions, meant for clinical applications, has been underrated due to the non-availability of sufficient toxicity data. The objective of the present study is to find the evidences towards safety of intravenous administration of HEPES through systemic toxicological studies in small animal model to support its safe application for clinical exploitation. EXPERIMENTAL: A pilot study was performed to investigate the lethal dose of HEPES in female Sprague Dawley rats by administering seven different doses of HEPES solution (150 to 2000 mg/kg), through intravenous pathway. Similarly, for determining maximum tolerated dose (MTD), gradually increasing doses of HEPES (50 to 950 mg/kg) were administered in the same species via similar pathway. Various hematological and clinical pathological investigations were carried out in order to find out the safe administration dose of HEPES in rats. RESULTS: No mortality was observed up to 2000 mg/kg doses of HEPES. The doses beyond 300 mg/kg resulted few temporary adverse effects, though these were found to disappear within 4-5 days of dosing. CONCLUSION: The amount of HEPES to be administered during clinical intervention is usually much lower (typically 1-2.5 mg per kg of body weight of healthy adult) than the MTD determined in rat model during present report. Hence, the utilization of this buffer for preparation of radiolabeled drugs for human investigation may be safe. However, further detailed investigations may be warranted for supporting the candidature of Good's buffer for regular clinical exploitation.

Nuclear Localization Signal Enhances the Targeting and Therapeutic Efficacy of a Porphyrin-Based Molecular Cargo: A Systemic In Vitro and Ex Vivo Evaluation.

The objective of the present work was to evaluate the potential of a nuclear localization signal (NLS) toward facilitating intracellular delivery and enhancement in the therapeutic efficacy of the molecular cargo. Toward this, an in-house synthesized porphyrin derivative, namely, 5-carboxymethyelene-oxyphenyl-10,15,20-tris(4-methoxyphenyl) porphyrin (UTriMA), was utilized for conjugation with the NLS sequence [PKKKRKV]. The three compounds synthesized during the course of the present work, namely DOTA-Lys-NLS, DOTA-UTriMA-Lys-NLS, and DOTA-Lys-UTriMA, were evaluated for cellular toxicity in cancer cell lines (HT1080), wherein all exhibited minimal dark toxicity. However, during photocytotoxicity studies with DOTA-Lys-UTriMA and DOTA-UTriMA-Lys-NLS conjugates in the same cell line, the latter exhibited significantly higher light-dependent toxicity compared to the former. Furthermore, the photocytotoxicity for DOTA-UTriMA-Lys-NLS in a healthy cell line (WI26VA4) was found to be significantly lower than that observed in the cancer cells. Fluorescence cell imaging studies carried out in HT1080 cancer cells revealed intracellular accumulation for the NLS-conjugated porphyrin (DOTA-UTriMA-Lys-NLS), whereas unconjugated porphyrin (DOTA-Lys-UTriMA) failed to do so. To evaluate the radiotherapeutic effects of the synthesized conjugates, all three compounds were radiolabeled with 177Lu, a well-known therapeutic radionuclide with high radiochemical purity (>95%). During in vitro studies, the [177Lu]Lu-DOTA-UTriMA-Lys-NLS complex exhibited the highest cell binding as well as internalization among the three radiolabeled complexes. Biological distribution studies for the radiolabeled compounds were performed in a fibrosarcoma-bearing small animal model, wherein significantly higher accumulation and prolonged retention of [177Lu]Lu-DOTA-UTriMA-Lys-NLS (9.32 ± 1.27% IA/g at 24 h p.i.) in the tumorous lesion compared to [177Lu]Lu-UTriMA-Lys-DOTA (2.3 ± 0.13% IA/g at 24 h p.i.) and [177Lu]Lu-DOTA-Lys-NLS complexes (0.26 ± 0.17% IA/g at 24 h p.i.) were observed. The results of the biodistribution studies were further corroborated by recording serial SPECT-CT images of fibrosarcoma-bearing Swiss mice administered with [177Lu]Lu-DOTA-UTriMA-Lys-NLS at different time points. Tumor regression studies performed with [177Lu]Lu-DOTA-UTriMA-Lys-NLS in the same animal model with two different doses [250 µCi (9.25 MBq) and 500 µCi (18.5 MBq)] resulted in a significant reduction in tumor mass in the treated group of animals. The above results revealed a definite enhancement in the targeting ability of molecular cargo upon conjugation with NLS and hence indicated that this strategy may be helpful for the preparation of drug-NLS conjugates as multimodal agents.

Resilience as a measure of preparedness for pandemic influenza outbreaks.

The global crisis generated by COVID-19 has heightened awareness of pandemic outbreaks. From a public health preparedness standpoint, it is essential to assess the impact of a pandemic and also the resilience of the affected communities, which is the ability to withstand and recover quickly after a pandemic outbreak. The infection attack rate has been the common metric to assess community response to a pandemic outbreak, while it focuses on the number of infected it does not capture other dimensions such as the recovery time. The aim of this research is to develop community resilience measures and demonstrate their estimation using a simulated pandemic outbreak in a region in the USA. Three scenarios are analysed with different combinations of virus transmissibility rates and non-pharmaceutical interventions. I The inclusion of the resilience framework in the pandemics outbreak analysis will enable decision makers to capture the multi dimensional nature of community response.

Toe brachial index and not ankle brachial index is appropriate in initial evaluation of peripheral arterial disease in type 2 diabetes.

BACKGROUND: Non-invasive clinic-based tools for assessing PAD are not without limitations. Therefore, costly tests like Doppler study, CT angiography and MR angiography are often required to make a diagnosis. Ankle brachial index (ABI), commonly used for assessment of PAD, has high false positivity rates in sclerosed, calcified arteries which render them non-compressible. Toe brachial index (TBI) can be an alternative, as digital arteries are relatively unaffected by these changes. AIM: To compare the reliability of ABI and TBI in diagnosing PAD in type 2 diabetes using CT angiography (CTA) as the reference. METHODS: 175 adults with T2D were selected. ABI &TBI were measured with an automated vascular Doppler XT 6 ports bilaterally for all subjects. For any subject, the limb with lower ABI and TBI was included for analysis. ABI < 0.9 & TBI < 0.6 were taken as evidence of PAD. CTA showing > 50% narrowing was taken as evidence of PAD. RESULTS: 24% of our study subjects had CTA confirmed PAD. ABI has low sensitivity of 35.29% (95% CI 0.21-0.52) compared to TBI being 82.35% (95% CI 0.66-0.92). The specificity however was similar. ABI < 0.9 was able to detect CTA confirmed PAD, but ABI > 0.9, including the so-called normal ABI (0.9-1.3) was unable to detect PAD. ROC showed ABI at 1.005 has sensitivity 64.71% (95% CI 0.48- 0.79) and specificity 61.7% (95% CI 0.53-0.69) and TBI at 0.6 has sensitivity 82.35% (95% CI 0.66-0.92) & specificity 92% (95% CI 0.87-0.96). Utilizing Cohen's Kappa, the reliability of ABI with respect to CTA showed fair agreement (K = 0.225, p = 0.001), whereas the reliability of TBI with respect to CTA showed substantial agreement (K = 0.759, p < 0.0001). CONCLUSION: ABI < 0.9 detects PAD reliably, but presence of PAD in patients with ABI > 9.0 including the normal of ABI (0.9-1.3) can be confirmed with TBI, which correlated strongly with CTA. TBI is also non-inferior for PAD detection, when ABI < 0.9. TBI and not ABI can be utilized for initial assessment of PAD in subjects with T2D.

Formulation of patient dose of [177Lu]Lu-Trastuzumab using in-house developed freeze-dried kit: A path forward for clinical translation.

Trastuzumab is a US-FDA-approved humanized monoclonal antibody used for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The aim of the present work is to optimize a freeze-dried formulation of DOTA-Trastuzumab conjugate for the preparation of patient doses of [177Lu]Lu-Trastuzumab for radioimmunotherapy of breast cancer. The formulation of [177Lu]Lu-Trastuzumab usually takes a long time, and thus, such a process is not suitable for the routine preparation of this agent in hospital radiopharmacies. To circumvent this, a pre-synthesized DOTA-Trastuzumab conjugate as a freeze-dried formulation is proposed. In the present work, DOTA-Trastuzumab conjugate was subjected to a freeze-drying process after the addition of optimized amounts of radioprotectant and cryoprotectant. [177Lu]Lu-DOTA-Trastuzumab was prepared by incubating the lyophilized powder of the kit vial with medium-specific activity 177LuCl3. The final radiochemical purity of [177Lu]Lu-DOTA-Trastuzumab, prepared using freeze-dried kit, was determined to be >95%. To ascertain the reproducibility of the procedure, six consecutive batches of the freeze-dried formulation were prepared, radiolabeled, and evaluated by carrying out both in vitro and ex vivo studies. The consistency of the results of all the six consecutive batches confirmed the robustness and utility of the in-house optimized freeze-dried formulation for the preparation of patient doses of [177Lu]Lu-Trastuzumab at hospital radiopharmacies.

Renal Dysfunction in Primary Hyperparathyroidism is associated with nephrolithiasis, elevated serum calcium-phosphate product and parathormone levels.

PURPOSE: Baseline renal dysfunction predicts mortality in primary hyperparathyroidism (PHPT). However, it remains controversial whether renal insufficiency in PHPT is due to disease severity alone or other risk factors. This study aimed to explore the association of clinico-biochemical variables with renal dysfunction [estimated glomerular filtration rate (eGFR) < 60 ml/min/m2] in PHPT. METHODS: A total of 112 patients of PHPT were selected and divided into following subgroups: renal dysfunction (n = 28) and normal renal function (n = 84). Demographic characteristics, traditional risk factors, phenotypes of PHPT based on target organ involvement, and biochemical parameters were compared between these subgroups. RESULTS: Patient subgroups of PHPT with and without renal dysfunction had similar age, frequency of diabetes, and hypertension. Renal dysfunction was more prevalent in males (p < 0.05). Compared to normal renal function subgroup, individuals with renal dysfunction had higher serum levels of calcium, phosphate, alkaline phosphatase, intact parathormone (all p < 0.05), while having lower hemoglobin levels (p < 0.05) and higher nephrolithiasis rates (p < 0.05). Multiple regression analysis revealed that nephrolithiasis, serum calcium-phosphorous product (CaxP), parathormone levels were positively associated with baseline renal dysfunction (all p < 0.01). A baseline PTH > 456 pg/mL and CaxP > 30.0 mg2/dl2 could discriminate renal dysfunction from normal renal function with sensitivity and specificity of 75% and 74.5% and 92.6% and 74.4%, respectively. CONCLUSION: Renal dysfunction was associated with presence of nephrolithiasis, elevated serum CaxP and PTH levels in our cohort with predominantly symptomatic PHPT, indicating an association with the underlying disease itself. Serum CaxP may additionally be appraised during risk assessment in PHPT.

Integrated Care for Type 1 Diabetes: The West Bengal Model.

Introduction: A structured dedicated health programme for Type 1 diabetes mellitus (T1DM) has been initiated in the state of West Bengal, India. Aim: The aim is to provide comprehensive healthcare to all children, adolescents and young adults living with T1DM, along with the provision of free supply of insulin, glucose measuring devices, blood glucose test strips, and other logistics. The strategic framework for programme implementation is to utilise the infrastructure and manpower of the already existing non-communicable disease (NCD) clinic under National Health Mission. Methodology: Establishing dedicated T1DM clinics in each district hospital by utilising existing healthcare delivery systems, intensive training and hand-holding of named human resources; providing comprehensive healthcare service and structured diabetes education to all T1DM patients; and building an electronic registry of patients are important components of the programme. T1DM clinics run once a week on the same day throughout the state. All T1DM patients are treated with the correct dose of insulin, both human regular insulin and glargine insulin. Patients are routinely monitored monthly to ensure good glycaemic control and prevent complications of the disease. Routine anthropometric examination and required laboratory investigations are conducted in the set-up of the already existing NCD clinic. Ongoing monitoring and evaluation of the T1DM programme are being conducted in terms of glycated haemoglobin (HbA1c) values, growth and development, complication rates, psychological well-being, quality of life, and direct and indirect expenditure incurred by families. Through this programme, any bottlenecks or gaps in service delivery will be identified and corrective measures will be adopted to ensure better health outcomes for those living with T1DM.

Rice residue promotes mobilisation and plant acquisition of soil phosphorus under wheat (Triticum aestivum)-rice (Oryza sativa) cropping sequence in a semi-arid Inceptisol.

Disposal of significant tonnages of rice straw is expensive, but using it to mobilise phosphorus (P) from inorganically fixed pools in the soil may add value. This study was carried out to determine whether the use of rice straw mixed with phosphorus-solubilizing microbes could solubilize a sizable portion fixed soil P and affect P transformation, silicon (Si) concentration, organic acid concentrations, and enzyme activity to increase plant growth. Depending on the soil temperature, the application of rice straw at 12 Mg ha-1 with phosphorus-solubilizing microbes could solubilize 3.4-3.6% of inorganic P, and minimised the hysteresis impact by 6-8%. At plant maturity, application of rice straw at 12 Mg ha-1 with phosphorus-solubilizing microbes and 75% of recommended P application raised the activity of dehydrogenase, alkaline phosphatase activity, cellulase, and peroxidase by 77, 65, 87, and 82% in soil, respectively. It also boosted Si concentration in the soil by 58%. Wheat grain yield was 40% and 18% higher under rice straw at 12 Mg ha-1 with phosphorus-solubilizing microbes with 75% of recommended P application than under no and 100% P application, respectively. Rice grain yield also increased significantly with the same treatment. Additionally, it increased root volume, length, and P uptake by 2.38, 1.74 and 1.62-times above control for wheat and 1.98, 1.67, and 2.06-times above control for rice, respectively. According to path analysis, P solubilisation by Si and organic acids considerably increased (18-32%) P availability in the rhizosphere. Therefore, cultivators could be advised to use rice straw at 12 Mg ha-1 with phosphorus-solubilizing microbes with 75% P of mineral P fertiliser to save 25% P fertiliser without reducing wheat and rice yield.

Myasthenia Gravis Presenting as Bulbar Palsy.

Myasthenia gravis is a rare autoimmune condition that affects postsynaptic cholinergic receptors, resulting in symptoms of muscular fatigue. Clinical signs could be subtle and variable, often leading to many differentials. This leads to inappropriate tests being performed and a delay in diagnosis. Although ocular signs are more common, it may rarely present as bulbar palsy. Our patient, in her 30s, was referred to the emergency department after six months of symptom onset when she was discovered to be at a high risk of silent aspiration. Her presentation was predominantly bulbar palsy, but after appropriate tests, she was eventually diagnosed with generalized myasthenia gravis with a concurrent thymoma. Her treatment included pyridostigmine, corticosteroid, and immunoglobulins, while a thymectomy was scheduled as a planned procedure. Prompt diagnosis and timely management can reduce morbidity and mortality in such cases.

A hydrolyzed lipid blend diet promotes myelination in neonatal piglets in a region and concentration-dependent manner.

The impact of early life nutrition on myelin development is of interest given that cognitive and behavioral function depends on proper myelination. Evidence shows that myelination can be altered by dietary lipid, but most of these studies have been performed in the context of disease or impairment. Here, we assessed the effects of lipid blends containing various levels of a hydrolyzed fat (HF) system on myelination in healthy piglets. Piglets were sow-reared, fed a control diet, or a diet containing 12%, 25%, or 53% HF consisting of cholesterol, fatty acids, monoglycerides, and phospholipid from lecithin. At postnatal day 28/29, magnetic resonance imaging (MRI) was performed to assess changes to brain development, followed by brain collection for microscopic analyses of myelin in targeted regions using CLARITY tissue clearing, immunohistochemistry, and electron microscopy techniques. Sow-reared piglets exhibited the highest overall brain white matter volume by MRI. However, a 25% HF diet resulted in the greatest total myelin density in the prefrontal cortex based on 3D modeling analysis of myelinated filaments. Nodal gap length and g-ratio were inversely correlated with percentage of HF in the corpus callosum, as well as in the PFC and internal capsule for g-ratio, indicating that a 53% HF diet resulted in the thickest myelin per axon and a 0% HF control diet the thinnest in specific brain regions. These findings indicate that HF promoted myelination in the neonatal piglet in a region- and concentration-dependent manner.

Design, synthesis and evaluation of 177Lu-labeled inverso and retro-inverso A9 peptide variants targeting HER2-overexpression.

Several HER2-specific peptides are being continuously explored to find a candidate with suitable pharmacokinetic properties for development of effective radiopharmaceutical that can find applications for clinical screening of breast cancer patients. In the present work with an aim of preparing a radiopeptide with improved metabolic stability and in vivo pharmacokinetic performance we modified our previously reported [177Lu]DOTA-L-A9 peptide. Here we designed an 'inverso' peptide with all d-amino acids and a 'retro-inverso' peptide where sequence of d-amino acids was reversed. Higher secondary structure stabilization of retro- inverso A9 variant compared to inverso A9 peptide was evident by circular dichroism studies. The two radiopeptides [177Lu]DOTA-D-A9 and [177Lu]DOTA-rD-A9 exhibited significantly improved in vivo metabolic stability over the original l-peptide. The retro-inverso variant, [177Lu]DOTA-rD-A9 demonstrated better pharmacokinetic behavior with significantly higher tumor uptake than the inverso peptide, [177Lu]DOTA-D-A9 and the original peptide, [177Lu]DOTA-L-A9. In the present case of A9 peptide, reversal of the peptide sequence of d-amino acids boosted the uptake and retention of radioactivity in HER2-positive tumor. The present study can thus guide the design and development of newer and improved versions of peptides.

Strategies for identifying stable lentil cultivars (Lens culinaris Medik) for combating hidden hunger, malnourishment, and climate variability.

Iron and zinc malnutrition is a global humanitarian concern that mostly affects newborns, children, and women in low- and middle-income countries where plant-based diets are regularly consumed. This kind of malnutrition has the potential to result in a number of immediate and long-term implications, including stunted growth, an elevated risk of infectious diseases, and poor development, all of which may ultimately cause children to not develop to the fullest extent possible. A determination of the contributions from genotype, environment, and genotype by environment interactions is necessary for the production of nutrient-dense lentil varieties that offer greater availability of iron and zinc with a high level of trait stability. Understanding the genotype and environmental parameters that affect G x E (Genotype x Environment) interactions is essential for plant breeding. We used GGE(Genotype, Genotype x Environment interactions) and AMMI (Additive Main effects and Multiplicative Interaction) models to study genetic stability and GE(Genotype x Environment interactions) for grain Fe, Zn, Al, and anti-nutritional factors like phytic acid content in sixteen commercially produced lentil cultivars over several different six geographical locations across India. Significant genetic variability was evident in the Fe and Zn levels of different genotypes of lentils. The amounts of grain iron, zinc, and phytic acid varied from 114.10 to 49.90 mg/kg, 74.62 to 21.90 mg/kg, and 0.76 to 2.84 g/100g (dw) respectively. The environment and GE (Genotype x Environment interactions) had an impact on the concentration of grain Fe, Zn, and phytic acid (PA). Heritability estimations ranged from low to high (53.18% to 99.48%). The study indicated strong correlation between the contents of Fe and Zn, a strategy for simultaneously increasing Fe and Zn in lentils may be recommended. In addition, our research revealed that the stable and ideal lentil varieties L4076 (Pusa Shivalik) for Fe concentration and L4717 (Pusa Ageti) for Zn content, which have lower phytic acid contents, will not only play an essential role as stable donors in the lentil bio-fortification but will also enable the expansion of the growing area of bio-fortified crops for the security of health and nutrition.

Synthesis and 177Lu Labeling of the First Retro Analog of the HER2-Targeting A9 Peptide: A Superior Variant.

The retro analog of the HER2-targeting A9 peptide was synthesized by coupling amino acids in a reverse fashion and switching the N-terminal in the original sequence of the L-A9 peptide (QDVNTAVAW) to the C-terminal in rL-A9 (WAVATNVDQ). Modification in the backbone resulted in higher conformational stability of the retro peptide as evident from CD spectra. Molecular docking analysis revealed a higher HER2 binding affinity of [177Lu]Lu-DOTA-rL-A9 than the original radiopeptide [177Lu]Lu-DOTA-L-A9. Enormously enhanced metabolic stability of the retro analog led to significant elevation in tumor uptake and retention. SPECT imaging studies corroborated biodistribution results demonstrating a remarkably higher tumor signal for [177Lu]Lu-DOTA-rL-A9. The presently studied retro probe has promising efficiency for clinical screening.