The Ultimate Resource for Studying the Limb Buds: Ak Dutta Human Anatomy Pdf 134

Abstract: India is a high incidence area for gallbladder cancer (GBC) and contributes to about 10% of the global GBC burden. Within India, the incidence is high in North, North-East, Central and Eastern India, and less common in South and West India. The incidence has been on a steady rise in both genders. The presentation is often with advanced disease and carries dismal prognosis. GBC in India usually affects younger patients in the 5th and 6th decade in contrast to the west. Gallstones are present in 80% of the Indian patients with GBC and its presence increases the vulnerability of the GB to mucosal injury. The incidence of GBC is out of proportion to the prevalence of gallstones in the country. Additional co-factors such as older age, lower socio-economic status, chronic Salmonella typhi (S. typhi) infection, Helicobacter pylori (H. pylori) infection, exposure to pollutants, heavy metals, chemicals, adulterated mustard oil and smoking in patients with gallstones have been identified which promote carcinogenesis. These risk factors act in tandem in an additive manner resulting in higher incidence of GBC as well as hasten the development of GBC. Environmental risk factors such as soil and water contamination by industrial wastes, agricultural effluents and human sewage have been identified as putative risk factors. Combination of a toxic environment, vulnerable GB and a susceptible host play a key role in the pathogenesis of GBC in the country. Large multicentric comprehensive studies are required in India to assess the attributable risk of each of the identified putative risk factors. This will help in formulating cost effective national strategies in preventing GBC related mortality in the country. Meanwhile a high index of suspicion to pick up incidental GBC, and improved access to healthcare facilities to manage GS appropriately will help in reducing GBC related mortality.

The pathogenesis of GBC is poorly understood in its entirety in India even today. It seems to be a multi-step process in which there is accumulation of genetic and epigenetic alterations due to host as well as environmental factors. These cumulative genetic alterations ultimately trigger mutagenesis. It is due to combination of a vulnerable GB interacting with a toxic environment in a susceptible host (Figure 4). The GB is already a physiologically a vulnerable organ of our body due to the following reasons. It an out pouching of the GI tract and has to empty its content against gravity back into the gut lumen. The fundus of the GB is dependent part in biped erect human beings Fundus is the commonest site for GBC possibly due to higher mucosal contact time. The GB is also an excretory organ of the body as the liver flushes all the environmental toxins and their metabolites into the biliary system. The GB tends to concentrate bile which allows increased mucosal contact to the concentrated toxic substances. A diseased GB also tends to be static, enhancing the mucosal exposure time. The GB is also dependent on a fully functional digestive process, intact endocrine signaling pathway with release of CCK by the duodenum to facilitate its emptying. The GB has a weak muscular structure which further disadvantages the emptying process. Moreover, obstruction along the pathway for flow of bile due to CBD stone, stricture, sphincter of Oddi abnormalities can impede the emptying process. Moreover, bacteria once it enters the GB, is difficult for the body to eradicate. These bacteria tend to cause chronic inflammation, deconjugate conjugated bile acids and toxins and thus locally release toxic metabolites. Presence of GS adds to the vulnerability further of the GB since emptying is more often incomplete in those with chronic cholecystitis which is a constant accompaniment of GSD. The presence of stones adds to the surface area for bacterial colonization and these bacteria are difficult eradicate with antibiotic therapy. Stones also result mechanical injury. Thus, stones promote chronic inflammation.

Ak Dutta Human Anatomy Pdf 134

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There are various putative factors which have been proposed to explain partly the differences in the incidence across the country (25-34). The quality of evidence for these factors is limited as they come from small case-controlled studies and requires further larger multi centric studies. The high-risk regions extend from the states of Jammu and Kashmir, Punjab, Haryana, Himachal Pradesh, Uttarakhand, UP, Bihar, Bengal, Assam and Manipur. A large part of these states is based along the major rivers of the country namely Sutlej, Ganges, Yamuna and Brahmaputra (Figure 5). These rivers arise from the glaciers and flow from the northern Himalayas towards west and east and have become polluted due to human waste and industrial pollutants. As the Ganges flows towards east, the pollutants concentration as well as bacterial contamination have been found to steadily rise which may account partially for high incidence in this gangetic region of the country. It is also an agricultural driven community. The Ganges supports a very densely populated human civilization on its banks, especially the poorer sections, which subsist on the river for its daily water needs. Untreated sewage, industrial waste and agricultural effluents unfortunately get added to the water along its course (32). The fecal coliform count steadily rises as the river flows towards the east (30). Salmonella typhi (S. typhi) and Helicobacter pylori (H. pylori) are feco-orally transmitted organisms which have been known to be associated with pathogenesis of GBC and are likely to be increased as the river flows downstream (27,30,35-37). In North, North east and eastern India, mustard oil is the staple cooking oil in contrast to coconut oil, sesame or groundnut oil in south and west India. Mustard oil has irritant property on the gut and is often adulterated with butter yellow which is known carcinogen (33). Individuals belonging to the poorer socioeconomic strata are unable to afford branded safe oils and thus consume loose mustard oils which may be contaminated/adulterated. Higher levels of sanguinarine and diethyl nitrosamine, carcinogenic adulterants in mustard oil, have been found in blood and tissue of GBC patients as compared to patients with cholelithiasis. Diethyl nitrosamine has been reported to induce hepatic carcinogenesis. Mustard oil has pro-inflammatory properties and induces tumors (33).

To conclude, India is a high incidence area for GBC. GBC affects patients at a younger age than their western counterparts in developed nations. Within India, north, north east, east and central Indian regions are at higher risk. Environmental risk factors such as soil and water contamination by industrial wastes, agricultural effluents and human sewage have been identified as putative risk factors enhancing carcinogenesis among patients with GS of this region. Selected patients with GS in these regions are easily identifiable targets who may be offered prophylactic cholecystectomy to prevent GBC. Large multicentric comprehensive studies are required in India to assess the attributable risk of each of the identified putative risk factors. This will help in formulating cost effective national strategies in preventing GBC related mortality in the country.

First proteomic analysis: ProteinLynx GlobalServer version 2.4 (Waters Corporation) was used to process all data acquired from the first run as described previously [27]. Protein identifications were obtained by searching UniProt human reference proteome canonical database (June 2016): 1 missed cleavage, 4% false discovery rate and fixed modifications of carboamidomethylation of cysteines and dynamic modifications of oxidation of methionine.

In summary, we provide a detailed and comprehensive assessment of the human PD brain proteome across disease stages to capture the early and common signatures of cells vulnerable to PD pathology. Here, we demonstrate the presence of mitochondrial dysfunction throughout the PD brain, irrespective of the level of pathology (Fig. 9). Critically, we show that this dysfunction occurs prior to, or concomitantly with, the earliest stages of alpha-synuclein aggregation, and certainly prior to neuronal loss, implicating mitochondrial dysfunction as an early driver of the disease, and not just an end-stage phenomenon. Furthermore, we highlight two proteins, sirtuin-2 and metallothionein 2, that significantly change in vulnerable PD regions prior to the appearance of alpha-synuclein pathology, and thus require further investigation as to their pathologic or compensatory role in PD. Together, our use of comparative brain proteomics in carefully selected regions from early stage disease reveals the pathways driving the pathogenesis of sporadic PD. Importantly, our identification of these pathways, rather than those implicated later in the disease, may highlight novel targets for therapeutic intervention that could slow the underlying progression of PD.

Informed consent was given for all cases. Ethical approval was obtained for the use of post-mortem human brain tissue from the Local Research Ethics Committee of the National Hospital for Neurology and Neurosurgery.

Protein- and peptide-based self-assembling responsive biomaterials hold unprecedented promise to facilitate development of functional materials for a variety of applications in human healthcare by preventing, delaying or reversing many disease pathologies based on innovative research. IDPs, in general, play key biological roles including regulation of cellular transcription, translation and signalling. They also play a central role in the ordered assembly of macromolecular machines such as the ribosome, in organization of chromatin, in assembly and disassembly of microfilaments and microtubules28,82. Moreover, IDPs containing low-complexity sequences can promote phase separation to form membrane-less organelles within the cytoplasm or nucleoplasm, thus contributing to their compartmentalization in a regulated manner28,82. Examples of functional IDPs also include HIV-183 and COVID-1984 virus proteins that use the intrinsic disordered region as flexible armour for survival as well as weapon for host invasion. RLPs, being IDPs and displaying multi-stimuli responsiveness including dual-phase behaviour, multiplicity of their conformational ensemble created unmatched new opportunities. The rational protein engineering design with expanding library of peptide domains along with artificial intelligence, machine learning and advanced computational sequence heuristics approach represents unparalleled potential to develop smart RLPs with complex but controlled functionalities. Such advances also offer remarkable opportunity for development of new modular RLP-based biomaterials with desired bioactivity, crosslinking, mechanical property, self-healing, multi-responsive capability and selective biodegradation, which presents a multifunctional platform for increasing the efficacy of RLPs for specific biomedical applications. In this context, indeed, the rational design and development of new modular RLPs comprising several new motifs, such as structural domains from abductin, mussel adhesive protein, etc.85,86, cell-binding domains from collagen, laminin, etc.87, growth factor peptides from bone, platelets, etc.88,89, crosslinking systems like SpyTag-SpyCatcher, nitric oxide-cleavable crosslinker, etc.90,91, can potentially lead us a step closer to clinical and therapeutic realization. Moreover, systematic study of programming molecular self-assembly in modular RLP-based systems by extending the design rules applied for IDPs, such as combining two peptide properties into one sequence by increasing fraction of doping and varying block length, and/or blending at varying volume fractions can provide a new platform for design and application of RLP-based materials for intracellular material manipulation34,92. In addition, introduction of non-canonical amino acids, such as 4S-fluoroproline and thiazolidine carboxylic acid (isostructural analogues of proline)93, and/or post-translational modifications, such as conversion of proline to hydroxyproline, and tyrosine to DOPA94 could also be potentially applied to expand this design space (increase in functional diversity and development of new RLP-based hybrid biomaterials) with useful properties for applications in nanobiotechnology and medicine.

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