The research on human gut microbiome, regarded as the black box of the human body, is still at the stage of infancy as the functional properties of the complex gut microbiome have not yet been ...understood. Ongoing metagenomic studies have deciphered that the predominant microbial communities belong to eubacterial phyla
Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria, Cyanobacteria
,
Verrucomicrobia
and archaebacterial phylum
Euryarchaeota
. The indigenous commensal microbial flora prevents opportunistic pathogenic infection and play undeniable roles in digestion, metabolite and signaling molecule production and controlling host’s cellular health, immunity and neuropsychiatric behavior. Besides maintaining intestinal health via short-chain fatty acid (SCFA) production, gut microbes also aid in neuro-immuno-endocrine modulatory molecule production, immune cell differentiation and glucose and lipid metabolism. Interdependence of diet and intestinal microbial diversity suggests the effectiveness of pre- and pro-biotics in maintenance of gut and systemic health. Several companies worldwide have started potentially exploiting the microbial contribution to human health and have translated their use in disease management and therapeutic applications. The present review discusses the vast diversity of microorganisms playing intricate roles in human metabolism. The contribution of the intestinal microbiota to regulate systemic activities including gut–brain–immunity crosstalk has been focused. To the best of our knowledge, this review is the first of its kind to collate and discuss the companies worldwide translating the multi-therapeutic potential of human intestinal microbiota, based on the multi-omics studies, i.e. metagenomics and metabolomics, as ready solutions for several metabolic and systemic disorders.
Graphic abstract
Calcium (Ca2+) is an essential macronutrient as well as a second messenger in diverse biological processes in plants. Plants perceive various stimuli which leads to transient increase in cytosolic ...calcium Ca2+cyt levels, resulting in generation of Ca2+ signatures. These Ca2+ signatures are specific to various stress stimuli and developmental processes and are perceived by Ca2+ sensors. Ca2+ sensors and relay proteins participate in downstream signaling events to decode the Ca2+ signatures. Ca2+ homeostasis involves the synergistic action of transporting elements that regulate Ca2+ influx and efflux. The influx elements help elevate the Ca2+cyt levels during signaling events and efflux elements help in restoring the resting Ca2+cyt levels. These Ca2+ transporters include Cyclic nucleotide gated channels (CNGCs), Glutamate receptor-like (GLRs) channels/Glutamate-like receptor channels, Two pore channels (TPCs), Annexins, Mechanosensitive channels (MSLs), Ca2+-ATPases, Ca2+/H+ exchangers (CAXs), Ca2+/cation exchangers (CCXs). The involvement of these Ca2+ signaling and transporting elements in developmental and physiological processes as well as responses to diverse stress factors accounts for their significance. In this review, we highlight the progress of genomic approaches in dissecting the role of Ca2+ signaling components in mediating stress tolerance in plants, in the context of changing climatic conditions.
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Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancers worldwide. More than half of patients with HNSCC eventually experience disease recurrence and/or metastasis, which ...can threaten their long-term survival. HNSCCs located in the oral cavity and larynx are usually associated with tobacco and/or alcohol use, whereas human papillomavirus (HPV) infection, particularly HPV16 infection, is increasingly recognized as a cause of oropharyngeal HNSCC. Despite clinical, histologic, and molecular differences between HPV-positive and HPV-negative HNSCCs, current treatment approaches are the same. For recurrent disease, these strategies include chemotherapy, immunotherapy with PD-1-inhibitors, or a monoclonal antibody, cetuximab, that targets epidermal growth factor; these therapies can be administered either as single agents or in combination. However, these treatment strategies carry a high risk of toxic side effects; therefore, more effective and less toxic treatments are needed. The landscape of HNSCC therapy is changing significantly; numerous clinical trials are underway to test novel therapeutic options like adaptive cellular therapy, antibody-drug conjugates, new targeted therapy agents, novel immunotherapy combinations, and therapeutic vaccines. This review helps in understanding the various developments in HNSCC therapy and sheds light on the path ahead in terms of further research in this field.
The role of indigenous bacteria in mobilization of sediment bound arsenic (As) into groundwater is investigated using subsurface sediment from Brahmaputra River Basin (BRB) and the
Bacillus
sp. ...strain IIIJ3-1, an indigenous species to BRB. Anaerobic sediment microcosms with varying organic carbon sources and terminal electron acceptors (TEAs) are used to illustrate the role of the test bacterium in As mobilization. The aquifer sediment shows an asymmetric distribution of As and Fe in its different phases. Among the TEAs added, NO
3
amendment promotes higher cell growth, oxalic acid production and maximum release of sediment bound As. X-ray diffraction analysis further suggests that weathering of As bearing secondary minerals through bacterial action enhances As bioavailability, followed by dissimilatory reduction and thus promotes its mobilization into aqueous phase. Co-release pattern of other elements from the sediment indicates that release of As is decoupled from that of Fe. This study confirms that microbe-mediated mineral weathering followed by respiratory reduction of As facilitates mobilization of sediment hosted As into aqueous phase, and provides a better insight into the catabolic ability of groundwater bacteria in mobilization of sediment hosted As in BRB region.
Graphic abstract
Microbe-mediated redox transformation of arsenic (As) leading to its mobilization has become a serious environmental concern in various subsurface ecosystems especially within the alluvial aquifers. ...However, detailed taxonomic and eco-physiological attributes of indigenous bacteria from As impacted aquifer of Brahmaputra river basin has remained under-studied.
A newly isolated As-resistant and -transforming facultative anaerobic bacterium IIIJ3-1 from As-contaminated groundwater of Jorhat, Assam was characterized. Near complete 16S rRNA gene sequence affiliated the strain IIIJ3-1 to the genus Bacillus and phylogenetically placed within members of B. cereus sensu lato group with B. cereus ATCC 14579(T) as its closest relative with a low DNA-DNA relatedness (49.9%). Presence of iC17:0, iC15:0 fatty acids and menaquinone 7 corroborated its affiliation with B. cereus group, but differential hydroxy-fatty acids, C18:2 and menaquinones 5 & 6 marked its distinctiveness. High As resistance Maximum Tolerable Concentration = 10 mM As
, 350 mM As
, aerobic As
(5 mM) oxidation, and near complete dissimilatory reduction of As
(1 mM) within 15 h of growth designated its physiological novelty. Besides O
, cells were found to reduce As
, Fe
, SO
, NO
, and Se
as alternate terminal electron acceptors (TEAs), sustaining its anaerobic growth. Lactate was the preferred carbon source for anaerobic growth of the bacterium with As
as TEA. Genes encoding As
respiratory reductase (arr A), As
oxidase (aioB), and As
efflux systems (ars B, acr3) were detected. All these As homeostasis genes showed their close phylogenetic lineages to Bacillus spp. Reduction in cell size following As exposure exhibited the strain's morphological response to toxic As, while the formation of As-rich electron opaque dots as evident from SEM-EDX possibly indicated a sequestration based As resistance strategy of strain IIIJ3-1.
This is the first report on molecular, taxonomic, and ecophysiological characterization of a highly As resistant, As
oxidizing, and dissimilatory As
reducing Bacillus sp. IIIJ3-1 from As contaminated sites of Brahmaputra river basin. The strain's ability to resist and transform As along with its capability to sequester As within the cells demonstrate its potential in designing bioremediation strategies for As contaminated groundwater and other ecosystems.
Network theory has become an excellent method of choice through which biological data are smoothly integrated to gain insights into complex biological problems. Understanding protein structure, ...folding, and function has been an important problem, which is being extensively investigated by the network approach. Since the sequence uniquely determines the structure, this review focuses on the networks of non-covalently connected amino acid side chains in proteins. Questions in structural biology are addressed within the framework of such a formalism. While general applications are mentioned in this review, challenging problems which have demanded the attention of scientific community for a long time, such as allostery and protein folding, are considered in greater detail. Our aim has been to explore these important problems through the eyes of networks. Various methods of constructing protein structure networks (PSN) are consolidated. They include the methods based on geometry, edges weighted by different schemes, and also bipartite network of protein-nucleic acid complexes. A number of network metrics that elegantly capture the general features as well as specific features related to phenomena, such as allostery and protein model validation, are described. Additionally, an integration of network theory with ensembles of equilibrium structures of a single protein or that of a large number of structures from the data bank has been presented to perceive complex phenomena from network perspective. Finally, we discuss briefly the capabilities, limitations, and the scope for further explorations of protein structure networks.
Virulence mechanisms typically evolve through the continual interaction of a pathogen with its host. In contrast, it is poorly understood how environmentally acquired pathogens are able to cause ...disease without prior interaction with humans. Here, we provide experimental evidence for the model that Legionella pathogenesis in humans results from the cumulative selective pressures of multiple amoebal hosts in the environment. Using transposon sequencing, we identify Legionella pneumophila genes required for growth in four diverse amoebae, defining universal virulence factors commonly required in all host cell types and amoeba-specific auxiliary genes that determine host range. By comparing genes that promote growth in amoebae and macrophages, we show that adaptation of L. pneumophila to each amoeba causes the accumulation of distinct virulence genes that collectively allow replication in macrophages and, in some cases, leads to redundancy in this host cell type. In contrast, some bacterial proteins that promote replication in amoebae restrict growth in macrophages. Thus, amoebae-imposed selection is a double-edged sword, having both positive and negative impacts on disease. Comparing the genome composition and host range of multiple Legionella species, we demonstrate that their distinct evolutionary trajectories in the environment have led to the convergent evolution of compensatory virulence mechanisms.
Because of emergence of resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), no targeted treatments are available for patients with lung cancer who lose sensitivity due ...to new mutations or bypass mechanisms. We examined in animals and
an alternative therapeutic approach making use of antibodies.
An osimertinib-sensitive animal model of lung cancer, which rapidly develops drug resistance, has been employed. To overcome compensatory hyperactivation of ERK, which we previously reported, an anti-EGFR antibody (cetuximab) was combined with other antibodies, as well as with a subtherapeutic dose of osimertinib, and cancer cell apoptosis was assayed.
Our animal studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 mAb), and osimertinib (low dose), as an effective and long-lasting treatment that is able to prevent onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and for prevention of relapses. Studies employing cultured cells and analyses of tumor extracts indicated that the combination of two mAbs and a subtherapeutic TKI dose sorted EGFR and HER2 for degradation; cooperatively enhanced apoptosis; inhibited activation of ERK; and reduced abundance of several bypass proteins, namely MET, AXL, and HER3.
Our
assays and animal studies identified an effective combination of clinically approved drugs that might overcome resistance to irreversible TKIs in clinical settings. The results we present attribute the long-lasting effect of the drug combination to simultaneous blockade of several well-characterized mechanisms of drug resistance.
.
Calcium ion (Ca
2+
) is a multifaceted signaling molecule that acts as an important second messenger. During the course of evolution, plants and animals have developed Ca
2+
signaling in order to ...respond against diverse stimuli, to regulate a large number of physiological and developmental pathways. Our understanding of Ca
2+
signaling and its components in physiological phenomena ranging from lower to higher organisms, and from single cell to multiple tissues has grown exponentially. The generation of Ca
2+
transients or signatures for various stress factor is a well-known mechanism adopted in plant and animal systems. However, the decoding of such remarkable signatures is an uphill task and is always an interesting goal for the scientific community. In the past few decades, studies on the concentration and dynamics of intracellular Ca
2+
are significantly increasing and have become a trend in modern biology. The advancement in approaches from Ca
2+
binding dyes to in vivo Ca
2+
imaging through the use of Ca
2+
biosensors to achieve spatio-temporal resolution in micro and milliseconds range, provide us phenomenal opportunities to study live cell Ca
2+
imaging or dynamics. Here, we describe the usage, improvement and advancement of Ca
2+
based dyes, genetically encoded probes and sensors to achieve extraordinary Ca
2+
imaging in plants and animals.
Graphical abstract
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