Intrinsic disorder: A term to define the specific physicochemical characteristic of protein conformational heterogeneity.

In his commentary in this issue of Molecular Cell,1 Struhl reasons that the term "intrinsically disordered regions" represents a vague and confusing concept for protein function. However, the term "intrinsically disordered" highlights the important physicochemical characteristic of conformational heterogeneity. Thus, "intrinsically disordered" is the counterpart to the term "folded, " with neither term having specific functional implications.

Mechanistic insights into the potential role of dietary polyphenols and their nanoformulation in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aß biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.

Peptide-scFv antigen recognition domains effectively confer CAR T cell multiantigen specificity.

The emergence of immune escape is a significant roadblock to developing effective chimeric antigen receptor (CAR) T cell therapies against hematological malignancies, including acute myeloid leukemia (AML). Here, we demonstrate feasibility of targeting two antigens simultaneously by combining a GRP78-specific peptide antigen recognition domain with a CD123-specific scFv to generate a peptide-scFv bispecific antigen recognition domain (78.123). To achieve this, we test linkers with varying length and flexibility and perform immunophenotypic and functional characterization. We demonstrate that bispecific CAR T cells successfully recognize and kill tumor cells that express GRP78, CD123, or both antigens and have improved antitumor activity compared to their monospecific counterparts when both antigens are expressed. Protein structure prediction suggests that linker length and compactness influence the functionality of the generated bispecific CARs. Thus, we present a bispecific CAR design strategy to prevent immune escape in AML that can be extended to other peptide-scFv combinations.

Orchestration and theranostic applications of synthetic genome with Hachimoji bases/building blocks.

Synthetic genomics is a novel field of chemical biology where the chemically modified genetic alphabets have been considered in central dogma of life. Tweaking of chemical compositions of natural nucleotide bases could be developed as novel building blocks of DNA/RNA. The modified bases (dP, dZ, dS, and dB etc.) have been demonstrated to be adaptable for replication, transcription and follow Darwinism law of evolution. With advancement of chemical biology especially nucleotide chemistry, synthetic genetic codes have been discovered and Hachimoji nucleotides are the most important and significant one among them. These additional nucleotide bases can form orthogonal base-pairing, and also follow Darwinian evolution and other structural features. In the Hachimoji base pairing, synthetic building blocks are formed using eight modified nucleotide (DNA/RNA) letters (hence the name "Hachimoji"). Their structural conformations, like polyelectrolyte backbones and stereo-regular building blocks favor thermodynamic stability and confirm Schrodinger aperiodic crystal. From the structural genomics aspect, these synthetic bases could be incorporated into the central dogma of life. Researchers have shown Hachimoji building blocks were transcribed to its RNA counterpart as a functional fluorescent Hachimoji aptamer. Apart from several unnatural nucleotide base pairs maneuvered into its in vitro and in vivo applications, this review describes future perspective towards the development and therapeutic utilization of the genetic codes, a primary objective of synthetic and chemical biology.

Dynamic conformational changes of a tardigrade group-3 late embryogenesis abundant protein modulate membrane biophysical properties.

A number of intrinsically disordered proteins (IDPs) encoded in stress-tolerant organisms, such as tardigrade, can confer fitness advantage and abiotic stress tolerance when heterologously expressed. Tardigrade-specific disordered proteins including the cytosolic-abundant heat-soluble proteins are proposed to confer stress tolerance through vitrification or gelation, whereas evolutionarily conserved IDPs in tardigrades may contribute to stress tolerance through other biophysical mechanisms. In this study, we characterized the mechanism of action of an evolutionarily conserved, tardigrade IDP, HeLEA1, which belongs to the group-3 late embryogenesis abundant (LEA) protein family. HeLEA1 homologs are found across different kingdoms of life. HeLEA1 is intrinsically disordered in solution but shows a propensity for helical structure across its entire sequence. HeLEA1 interacts with negatively charged membranes via dynamic disorder-to-helical transition, mainly driven by electrostatic interactions. Membrane interaction of HeLEA1 is shown to ameliorate excess surface tension and lipid packing defects. HeLEA1 localizes to the mitochondrial matrix when expressed in yeast and interacts with model membranes mimicking inner mitochondrial membrane. Yeast expressing HeLEA1 shows enhanced tolerance to hyperosmotic stress under nonfermentative growth and increased mitochondrial membrane potential. Evolutionary analysis suggests that although HeLEA1 homologs have diverged their sequences to localize to different subcellular organelles, all homologs maintain a weak hydrophobic moment that is characteristic of weak and reversible membrane interaction. We suggest that such dynamic and weak protein-membrane interaction buffering alterations in lipid packing could be a conserved strategy for regulating membrane properties and represent a general biophysical solution for stress tolerance across the domains of life.

Assessment of cyclone risk and case study of Gaja cyclone using GIS techniques and machine learning algorithms in coastal zone of Tamil Nadu, India.

Cyclones can cause devastating impacts, including strong winds, heavy rainfall, storm surges, and flooding. The aftermath includes infrastructure damage, loss of life, displacement of communities, and ecological disruptions. Timely response and recovery efforts are crucial to minimize the socio-economic and environmental consequences of cyclones. To accelerate the time-consuming risk assessment process, particularly in geographically diverse regions, a blend of multi-criteria decision-making and machine learning models was utilized. This novel approach swiftly assessed cyclone risk and the impact of the Gaja cyclone in Nagapattinam, India. The method involved assigning weights to distinct criteria, unveiling notable vulnerability aspects like elevation, slope, proximity to the coast, distance from cyclone tracts, Lu/Lc, population density, proximity to cyclone shelters, household density, accessibility to healthcare facilities, NDVI, and levels of awareness. Daddavari, Ettugudi, Kodikarai, Vedharanyam, Velankanni, and Thirupoondi face high/extreme cyclone risk. Nagore, Nagapattinam, Pillai, Enangudi, and Sannanllur have low/no threat. To further enhance the precision of the study, machine learning algorithms like SVM, SAM, and MLC were deployed. These models were instrumental in generating pre- and post-cyclone land use maps. The influence of Gaja cyclones effects shows decreasing of agriculture land from 34% to 30%, aquaculture increase 1%, barren land decrease from 8% to 6%, Built-up land decrease from 15% to 13%, land with scrub and salt pan also decrease from 21% to 17% and 10%-8%. Mostly effect of Gaja cyclone is dramatic increase of water body from 8% to 21%. Conducting cyclone risk zone analysis and pre/post-cyclone Land Use Land Cover (LULC) detection in Nagapattinam offers valuable insights for disaster preparedness, infrastructure planning, and climate resilience. This study can enhance understanding of vulnerability and aid in formulating strategies to mitigate cyclone impacts, ensuring sustainable development in the region.

Antibody-drug conjugates in cancer therapy: innovations, challenges, and future directions.

The emergence of antibody-drug conjugates (ADCs) as a potential therapeutic avenue in cancer treatment has garnered significant attention. By combining the selective specificity of monoclonal antibodies with the cytotoxicity of drug molecules, ADCs aim to increase the therapeutic index, selectively targeting cancer cells while minimizing systemic toxicity. Various ADCs have been licensed for clinical usage, with ongoing research paving the way for additional options. However, the manufacture of ADCs faces several challenges. These include identifying suitable target antigens, enhancing antibodies, linkers, and payloads, and managing resistance mechanisms and side effects. This review focuses on the strategies to overcome these hurdles, such as site-specific conjugation techniques, novel antibody formats, and combination therapy. Our focus lies on current advancements in antibody engineering, linker technology, and cytotoxic payloads while addressing the challenges associated with ADC development. Furthermore, we explore the future potential of personalized medicine, leveraging individual patients' molecular profiles, to propel ADC treatments forward. As our understanding of the molecular mechanisms driving cancer progression continues to expand, we anticipate the development of new ADCs that offer more effective and personalized therapeutic options for cancer patients.

Molecular determinants of ligand efficacy and potency in GPCR signaling.

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) bind to extracellular ligands and drugs and modulate intracellular responses through conformational changes. Despite their importance as drug targets, the molecular origins of pharmacological properties such as efficacy (maximum signaling response) and potency (the ligand concentration at half-maximal response) remain poorly understood for any ligand-receptor-signaling system. We used the prototypical adrenaline-ß2 adrenergic receptor-G protein system to reveal how specific receptor residues decode and translate the information encoded in a ligand to mediate a signaling response. We present a data science framework to integrate pharmacological and structural data to uncover structural changes and allosteric networks relevant for ligand pharmacology. These methods can be tailored to study any ligand-receptor-signaling system, and the principles open possibilities for designing orthosteric and allosteric compounds with defined signaling properties.

Modular chimeric cytokine receptors with leucine zippers enhance the antitumour activity of CAR T cells via JAK/STAT signalling.

The limited availability of cytokines in solid tumours hinders maintenance of the antitumour activity of chimeric antigen receptor (CAR) T cells. Cytokine receptor signalling pathways in CAR T cells can be activated by transgenic expression or injection of cytokines in the tumour, or by engineering the activation of cognate cytokine receptors. However, these strategies are constrained by toxicity arising from the activation of bystander cells, by the suboptimal biodistribution of the cytokines and by downregulation of the cognate receptor. Here we show that replacement of the extracellular domains of heterodimeric cytokine receptors in T cells with two leucine zipper motifs provides optimal Janus kinase/signal transducer and activator of transcription signalling. Such chimeric cytokine receptors, which can be generated for common γ-chain receptors, interleukin-10 and -12 receptors, enabled T cells to survive cytokine starvation without induction of autonomous cell growth, and augmented the effector function of CAR T cells in vitro in the setting of chronic antigen exposure and in human tumour xenografts in mice. As a modular design, leucine zippers can be used to generate constitutively active cytokine receptors in effector immune cells.

Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

Self-negligence and awareness among oral precancerous and cancer patients - A cross-sectional questionnaire study.

Background: The National Institute of Health and Family Welfare (NIHFW) reports that India has the highest global prevalence of oral cancers. The incidence is significantly more in developing countries when compared to the developed countries. Early detection is key to increasing the survival rate of the patients. Important causes for this late diagnosis could be self-negligence, lack of patient awareness about the causes and asymptomatic and subtle clinical presentation of the lesions. Aim: To assess the causes of self-neglect and awareness levels among oral cancer and pre-cancerous patients. Settings and Design: A cross-sectional questionnaire study was conducted among pre-cancerous and cancerous patients. Methods and Material: A questionnaire with 16 closed-ended questions was framed relating to the causes of self-neglect and awareness of the patients. A total of 45 patients were selected by convenient sampling technique from the Institutional Tumour Board register of which 62 per cent were male patients and 38 per cent were female patients. Statistical Analysis: Data analysis for demographic data, patients' awareness, and causes of self-neglect about precancer and cancer was done using SPSS Version 10. Results and Conclusions: The present study concluded that the patients had adequate awareness that deleterious habits could lead to cancer but had a low level of awareness about the other causes of cancer, symptoms and management options available to treat cancer. The study result emphasizes that the government should plan for more cancer-screening camps in order to prevent the progression of cancer and to increase the awareness. (Reference I.D.: 2015-05006 for funding the project. ICMR).

Defining the condensate landscape of fusion oncoproteins.

Fusion oncoproteins (FOs) arise from chromosomal translocations in ~17% of cancers and are often oncogenic drivers. Although some FOs can promote oncogenesis by undergoing liquid-liquid phase separation (LLPS) to form aberrant biomolecular condensates, the generality of this phenomenon is unknown. We explored this question by testing 166 FOs in HeLa cells and found that 58% formed condensates. The condensate-forming FOs displayed physicochemical features distinct from those of condensate-negative FOs and segregated into distinct feature-based groups that aligned with their sub-cellular localization and biological function. Using Machine Learning, we developed a predictor of FO condensation behavior, and discovered that 67% of ~3000 additional FOs likely form condensates, with 35% of those predicted to function by altering gene expression. 47% of the predicted condensate-negative FOs were associated with cell signaling functions, suggesting a functional dichotomy between condensate-positive and -negative FOs. Our Datasets and reagents are rich resources to interrogate FO condensation in the future.

Predicting evolutionary outcomes through the probability of accessing sequence variants.

Natural selection can only operate on available genetic variation. Thus, determining the probability of accessing different sequence variants from a starting sequence can help predict evolutionary trajectories and outcomes. We define the concept of "variant accessibility" as the probability that a set of genotypes encoding a particular protein function will arise through mutations before subject to natural selection. This probability is shaped by the mutational biases of nucleotides and the structure of the genetic code. Using the influenza A virus as a model, we discuss how a more accessible but less fit variant can emerge as an adaptation rather than a more fit variant. We describe a genotype-accessibility landscape, complementary to the genotype-fitness landscape, that informs the likelihood of a starting sequence reaching different parts of genotype space. The proposed framework lays the foundation for predicting the emergence of adaptive genotypes in evolving systems such as viruses and tumors.

Single-cell biology: what does the future hold?

In this Editorial, our Chief Editor and members of our Advisory Editorial Board discuss recent breakthroughs, current challenges, and emerging opportunities in single-cell biology and share their vision of "where the field is headed."

Recent breakthroughs in computational structural biology harnessing the power of sequences and structures.

Recent advances in computational approaches and their integration into structural biology enable tackling increasingly complex questions. Here, we discuss several key areas, highlighting breakthroughs and remaining challenges. Theoretical modeling has provided tools to accurately predict and design protein structures on a scale currently difficult to achieve using experimental approaches. Molecular Dynamics simulations have become faster and more precise, delivering actionable information inaccessible by current experimental methods. Virtual screening workflows allow a high-throughput approach to discover ligands that bind and modulate protein function, while Machine Learning methods enable the design of proteins with new functionalities. Integrative structural biology combines several of these approaches, pushing the frontiers of structural and functional characterization to ever larger systems, advancing towards a complete understanding of the living cell. These breakthroughs will accelerate and significantly impact diverse areas of science.

Infantile Tubercular Endobronchial Polypoid Obstructive Lesion.

Endobronchial tuberculosis is reported in 18% of adults and 30%-60% of children with primary pulmonary tuberculosis. We are reporting two infants who presented with nonspecific respiratory symptoms due to an obstructive tubercular polypoid mass which was detected on computed tomography. Bronchoscopy showed a pale friable polypoid lesion in the bronchus causing a luminal obstruction. The biopsy of the lesion was suggestive of tuberculosis. On treatment with antitubercular medications, both the babies improved and remained asymptomatic on long-term follow-up.

A novel ultrasonic non-destructive testing methodology to monitor fatigue crack growth in compact tension specimens.

Detection and evaluation of fatigue cracks in structural materials are extremely important for life prediction analysis as part of the structural integrity procedure. In this article, we present a novel ultrasonic measurement methodology, based on the diffraction of elastic waves at the crack tips, to monitor the fatigue crack growth near the threshold regime in compact tension specimens at different load ratios. The diffraction phenomenon of ultrasonic waves from the crack tip is demonstrated using a finite element 2D wave propagation simulation. The applicability of this methodology has also been contrasted with that of the conventional direct current potential drop method. In addition, the crack morphology obtained in the ultrasonic c-scan imaging showed a variation in the crack propagation plane as a function of the cyclic loading parameters. The results suggest that this novel methodology is sensitive to fatigue cracks and can form the basis of in situ ultrasonic-based crack measurements in metallic and non-metallic materials.