Molecular Receptors Research Articles

Inhibitory Perspective of New Synthesized Compounds against Angiotensin Receptor: Schrodinger-based Induced-Fit Molecular Docking

Angiotensin is a hormone that plays a key role in the development of hypertension. Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) are now the most often prescribed drugs to treat hypertension. The present in silico study involves exploring the antihypertensive potentials of substituted benzimidazoles and indazole compounds ARC 36, ARC 38, ARC 45, ARC 76, and ARC 77 against the most prominent molecular target Angiotensin Receptor (PDB ID: 4YAY, XFEL structure of Human Angiotensin Receptor)using the software Schrodinger Maestro .Based on glide score, ARC 45, ARC 76 and ARC77 were having the docking score of -7.461 Kcal/mol, -7.947 Kcal/mol and -6.683 Kcal/mol which is comparable to the standard drug (Telmisartan) -5.036.The compounds were further screened for Lipinski’s rule for drug-likeliness, and ADME properties. In this study we reported compounds ARC 76 and ARC38had comparable in silico parameters to the standard dug Telmisartan and hence necessitating further in vitro and in vivo studies.

Endangered mountain gorillas and COVID-19: One health lessons for prevention and preparedness during a global pandemic.

The world's 1063 mountain gorillas (Gorilla beringei beringei) live in two subpopulations at the borders of the Democratic Republic of Congo, Rwanda, and Uganda. The majority of mountain gorillas are human-habituated to facilitate tourism and research, which brings mountain gorillas into close proximity of people daily. Wild great apes are proven to be susceptible to human pathogens, including viruses that have caused fatal respiratory disease in mountain gorillas (e.g., human metapneumovirus1 ). This is the result of the close genetic relatedness of humans and gorillas as species, and the structural and genetic similarity in molecular receptors that allow viruses to infect cells2 . At the time of writing, there is no evidence that severe acute respiratory syndrome coronavirus 2, the coronavirus that causes coronavirus disease 19 (COVID-19), has infected a mountain gorilla. However, due to the significant potential for human-to-gorilla transmission, mountain gorilla range States took immediate steps to minimize the COVID-19 threat. These actions included a combination of preventive practice around gorillas and other great apes (e.g., mandatory face mask use, increased "social" minimum distancing from gorillas) as well as human public health measures (e.g., daily health/fever screenings, COVID-19 screening, and quarantines). Minimization of the COVID-19 threat also required socioeconomic decision-making and political will, as all gorilla tourism was suspended by late March 2020 and guidelines developed for tourism reopening. A consortium that collaborates and coordinates on mountain gorilla management and conservation, working within an intergovernmental institutional framework, took a multifaceted One Health approach to address the COVID-19 threat to mountain gorillas by developing a phased contingency plan for prevention and response. The aim of this paper is to describe how range States and partners achieved this collaborative planning effort, with intent that this real-world experience will inform similar actions at other great ape sites.

Optimized TrkB Agonist Ameliorates Alzheimer's Disease Pathologies and Improves Cognitive Functions via Inhibiting Delta-Secretase.

BDNF/TrkB neurotropic pathway, essential for neural synaptic plasticity and survival, is deficient in neurodegenerative diseases including Alzheimer’s disease (AD). Our previous works support that BDNF diminishes AD pathologies by inhibiting delta-secretase, a crucial age-dependent protease that simultaneously cleaves both APP and Tau and promotes AD pathologies, via Akt phosphorylation. Small molecular TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) binds and activates the receptor and its downstream signaling, exerting therapeutic efficacy toward AD. In the current study, we optimize 7,8-DHF pharmacokinetic characteristics via medicinal chemistry to obtain a synthetic derivative CF3CN that interacts with the TrkB LRM/CC2 domain. CF3CN possesses improved druglike features, including oral bioavailability and half-life, compared to those of the lead compound. CF3CN activates TrkB neurotrophic signaling in primary neurons and mouse brains. Oral administration of CF3CN blocks delta-secretase activation, attenuates AD pathologies, and alleviates cognitive dysfunctions in 5xFAD. Notably, chronic treatment of CF3CN reveals no demonstrable toxicity. Hence, CF3CN represents a promising preclinical candidate for treating the devastating neurodegenerative disease.

Cyclic Dipeptide: A Privileged Molecular Scaffold to Derive Structural Diversity and Functional Utility.

Cyclic dipeptides (CDPs) are the simplest form of cyclic peptides with a wide range of applications from therapeutics to biomaterials. CDP is a versatile molecular platform endowed with unique properties such as conformational rigidity, intermolecular interactions, structural diversification through chemical synthesis, bioavailability and biocompatibility. A variety of natural products with the CDP core exhibit anticancer, antifungal, antibacterial, and antiviral activities. The inherent bioactivities have inspired the development of synthetic analogues as drug candidates and drug delivery systems. CDP plays a crucial role as conformation and molecular assembly directing core in the design of molecular receptors, peptidomimetics and fabrication of functional material architectures. In recent years, CDP has rapidly become a privileged scaffold for the design of advanced drug candidates, drug delivery agents, bioimaging, and biomaterials to mitigate numerous disease conditions. This review describes the structural diversification and multifarious biomedical applications of the CDP scaffold, discusses challenges, and provides future directions for the emerging field.

Dynamics of MHC-I molecules in the antigen processing and presentation pathway.

The endogenous antigen processing and presentation (APP) is a fundamental pathway found in jawed vertebrates, which allows for a set of epitope peptides sampled from the intracellular proteome to be assembled and displayed on class I proteins of the major histocompatibility complex (MHC-I). Peptide/MHC-I antigens enable different aspects of adaptive immunity to emerge, by providing a basis for recognition of self vs. non-self by T cells and Natural Killer (NK) cells. Pioneering studies of pMHC-I molecules and their higher-order protein complexes with molecular chaperones and membrane receptors have gleaned important insights into the peptide loading and antigen recognition mechanisms. While X-ray and cryoEM structures have provided us with static snapshots of different MHC-I assembly stages, complementary biophysical techniques have revealed that MHC-I molecules are highly mobile on a range of biologically relevant timescales, which bears importance for their assembly, peptide repertoire selection, membrane display and turnover. This review summarizes insights gained from experimental and simulation studies aimed at investigating MHC-I dynamics, and their functional implications.

Molecular investigation of brain tumors progressing during pregnancy or postpartum period: the association between tumor type, their receptors, and the timing of presentation

ObjectiveBrain tumors often become clinically evident during pregnancy; however, the mechanism has not been well elucidated. Purpose of this study is to investigate the influence of molecular genetic factors on the progression of brain tumors during pregnancy or the postpartum period. MethodsTwelve cases of brain tumors that presented during pregnancy or postpartum period were included: five gliomas, three meningiomas, two vestibular schwannomas, and two chordomas. Tumor samples were investigated by metaphase comparative genomic hybridization and immunohistochemistry, for chromosomal copy number aberration (CNA) and receptor expression of sex hormones and growth factors. ResultsThe results were correlated with the timing of tumor presentation in relation to the stage of pregnancy. EGFR, VEGFR-1/2, AR, and c-Myc were expressed in gliomas, PgR, ER, HER-2, VEGFR-1, EGF and VEGFR2 in meningiomas, VEGFR-1 in vestibular schwannomas, and EGFR, VEGFR-1/2, and c-Myc in chordomas. The CNAs of the tumors varied. Four of the five gliomas presented in the 2nd trimester, all three meningiomas in the 3rd trimester or postpartum period, and both of the two schwannomas in the late 2nd trimester. Expression of VEGFR-1/2 and EGFR was observed regardless of the timing of tumor presentation, whereas female hormone receptors and HER-2 were exclusively found in meningiomas. Interestingly, one anaplastic astrocytoma (IDH mut, non-codeleted) that progressed from precedent grade 2 tumor harbored amplification of the MYC locus. ConclusionProgression of brain tumors during pregnancy is associated with various growth factors as well as sex hormones. The timing of presentation is likely dependent on molecular receptors specific to each tumor type.

Polyether-Cyclodextrin Modified Surfaces for Sensing of Hydrophobic Molecules

Electrochemical Impedance Spectroscopy (EIS) is a broadly used technique to study various surface phenomena in soft matter. For development of cyclodextrin based biosensors, we employ faradaic EIS in the presence of ferri/ferrocyanide to characterize polymer modified surfaces, investigate polymer conformational changes, and evaluate reusability and stability of the biosensors (1).Cyclodextrins consisting of six (αCD), seven (βCD), or eight (γCD) glucose units are composed of a hydrophobic inner cavity and a hydrophilic outer surface. Hydrophobic inner cavity of cyclodextrins have made them promising candidates as molecular receptors for detection of hydrophobic molecules such as trans-resveratrol and cortisol. Health-benefiting effects of trans-resveratrol have been reported in various studies, including those reviewed by Prof. Denis Petters (2). Development of a reusable sensor platform for monitoring hydrophobic species could aid in pharmacokinetics studies and metabolite profiling of trans-resveratrol.To make a reusable resveratrol biosensor, we first modify the gold electrode surface with polyethylene glycol (PEG). The PEG modified surface is then complexed with αCD. The αCD molecules are released from the surface in the presence of trans-resveratrol, which causes PEG molecules to flatten into a bent-over configuration which decreases the electron transfer rate. The surface can be regenerated by αCD reloading, which results in PEG chains forming microcrystalline channel-type domains and increases the electron transfer rate. With the assistance of EIS, we can confirm the charge transfer resistance increase by αCD release and charge transfer resistance increase by αCD reload. Moreover, Nyquist plots of consecutive reloading and release of αCD indicate that the PEG-αCD surface can successfully be regenerated for at least three time.Herein, we will detail our PEG-αCD surface for the detection of resveratrol and our PPG-βCD surface for the detection of cortisol. These surfaces behave similarly in their surface configuration state and EIS analysis. Further investigation in the reusability indicates the modified gold surfaces can be reused for three times but fail when regenerated for more than four times. We assume this limitation is imposed by low stability of gold–thiol bonds, and we will discuss our progress to overcome this issue in studying the formation of more stable covalent bonds through aryl diazonium salts. Acknowledgments: This work was supported by NIH P20 GM113131. References Panahi Z, Merrill MA, Halpern JM. Reusable Cyclodextrin-Based Electrochemical Platform for Detection of trans-Resveratrol. ACS Appl Polym Mater. 2020 Nov 13; 2(11):5086–93. Available from: https://dx.doi.org/10.1021/acsapm.0c00866Rauf A, Imran M, Sulera HAR, Ahmad B, Peters DG, Mubarak MS. A comprehensive review of the health perspectives of resveratrol. Vol. 8, Food and Function. Royal Society of Chemistry; 2017. p. 4284–305. Available from: https://pubs.rsc.org/en/content/articlehtml/2017/fo/c7fo01300k

Design and Electrochemical Investigation of Ureido-Sulfonamidic Receptors for Phosphates

Anions play an important role in biological systems. At the same time, many of them are the major environmental pollutants and substances endangering living organisms [1]. For these purposes the anion recognition, elimination and sensing would find application in many branches including application in medicine or environmental chemistry. Suitable examples of anion pollutants are phosphates, which could cause eutrophication of water and they are also known for their limited removal from body fluids, which could lead to serious health problems. Therefore, the aim of our research group is the design and preparation of anionic receptors with suitable binding sites to bind these anions.In the first step of our synthesis a series of substituted nosylamidic intermediates (fig. a, b) was prepared. These substances are suitable precursors for the synthesis of novel receptors bearing ureido functions (fig. c). The sulfonamidic motif itself is known as a neutral donor of hydrogen bond. Hence for better understanding of the behaviour of the final urea receptors, the properties of intermediate molecules were studied by various physicochemical techniques including spectroscopic and electrochemical methods.Spectroscopic methods were used to evaluate the binding ability of this motif and to determine its acid-basic properties. Electrochemical methods (represented by polarography and cyclic voltammetry with mercury dropping or hanging electrodes in dimethylformamide with Bu4N PF6 as electrolyte) were chosen because the nitro groups in our intermediate molecules are not only important substituents enabling continuation in synthesis, but also electrochemical "probes" reflecting the properties of the parent molecule. Their reduction in aprotic media is generally known after the first one-electron reversible reduction step where a stable radical anion is formed, a three-electron irreversible process follows resulting in the corresponding hydroxylamine [2]. However, the reduction pattern of the series (b) is totally different: After the first irreversible step (theoretically involving 4/5 of electron) a one-electron reversible reduction takes place followed by a multielectron process. This behaviour can be explained by using autoprotonation mechanism [3] where the acidic hydrogen of the sulfonamidic group is involved.Then our attention focused on final receptors (fig c). It was shown, that sulfonamidic moiety can be utilized as an electron-withdrawing group useful to enhance the anion complexation properties of urea-based receptors. On the other hand, it brings an inherent predisposition for deprotonation in the presence of more basic anions. In order to shift the deprotonation/complexation equilibrium in favour of the complexation, the receptors were derivatized by electron-donating groups like –OCH3 at sulfonamidic moiety. The binding for this receptor was evaluated in a competitive solvent (DMSO) by using NMR titration experiments. The experimental results show a considerable selectivity of our receptor to phosphates compared to another biologically important anions such as Cl-, NO3 - and HSO4 - [4].Based on these results, the prepared receptors appear to be suitable motifs for binding phosphate anions. In order to take advantage of their binding capabilities, these molecules need to be attached to the surface of a suitable molecular carrier. The formation of these functional materials (in our case especially dendrimers) is also associated with the need to design and optimize methods to describe anion binding ability, as well as the possibility to recycle the prepared materials. This was the reason for which it seems to be interesting to consider the presence of an electrochemical “probe” also in the final molecular receptors. The redox transformation of such a probe should fundamentally affect the complexing abilities of the receptor and allow targeted degradation of the complex. Acknowledgements: The work was supported by the grant number 18-12150S and 20-07833S.

Emerging Molecular Receptors for the Specific-Target Delivery of Ruthenium and Gold Complexes into Cancer Cells.

Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.

Biomimetic isolation of affinity peptides for electrochemical detection of influenza virus antigen

In this study, we developed an electrochemical biosensor coated with a peptide that can detect the protein hemagglutinin (HA) present in the envelope of the influenza virus (H5N1). Using phage display, high-affinity peptide-displaying phage particles (GHPHYNNPSLQL) with specific binding abilities for HA were identified, which were evaluated using enzyme-linked immunosorbent assays (ELISAs). Based on the molecular structure identified by the functional studies, six newly designed peptides were chemically synthesized, and their binding interactions with HA proteins were characterized by atomic force microscopy (AFM), scanning electron microscopy (SEM), isothermal titration calorimetry (ITC), and surface plasmon resonance spectroscopy (SPR). Square wave voltammetry (SWV) revealed the presence of a linear relationship between the change in current and concentration of HA protein. From these observations, we selected IFA BP1 peptide as a potential molecular receptor and confirmed that the limit of detection (LOD) was found to be 3.26 nM. In addition, our electrochemical sensor successfully detected HA spiked in human plasma samples. Furthermore, good results for reproducibility and recovery using this biosensor were observed within a range of 31.2–500 nM concentrations and 82.3–111.5%, respectively. Importantly, the levels of HA proteins in the samples of human plasma measured using this sensor system corresponded well with those determined using a commercial ELISA method and also offered advantages such as low cost of fabrication, faster analysis, and use of lower sample volumes, suggesting that it could be applied for rapid and effective detection of the influenza virus antigen.

NEW MOLECULAR RECEPTORS FOR DIAGNOSIS AND THERAPY OF PANCREATIC DUCTAL ADENOCARCINOMA

Abstract INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with worst prognosis due to the intense desmoplastic reaction that occurs in this disease, which hinders the action of therapeutic agents and contributes to cancer progression. A possible way to develop new strategies for PDAC diagnosis and therapy is the study of the abnormal components of the tumor stroma. However, new receptors capable of detecting these components are needed. MATERIALS AND METHODS Two types of molecular receptors, monoclonal antibodies and aptamers, were developed in parallel targeting an extracellular matrix protein with potential as a PDAC marker. Antibodies were generated using mice of the DBA/1J strain, while aptamers were obtained by means of an in vitro selection method called SELEX. The analytical characteristics of the developed receptors were studied by ELISA-like assays, as well as cytochemistry on positive and negative cell lines for the protein of interest. RESULTS A total of 44 potential aptamers were identified. After a first bioinformatic screening, 9 candidates were chosen for evaluating their binding affinity in vitro. Two of them showed dissociation constants in the nanomolar range. One of the aptamers also showed specific staining of cells positive for the marker protein, as did one of the generated antibody clones. CONCLUSIONS The newly developed receptors have shown a great potential in the study of PDAC. However, their diagnostic and therapeutic usefulness requires a more in-depth evaluation, currently in progress. ACKNOWLEDGEMENTS This research was funded by the Spanish Government (RTI-2018-095756-B-I00) and Principado de Asturias Government (IDI2018-000217), co-financed by FEDER funds. R.L.G. thanks the Spanish Government for a predoctoral FPU fellowship (FPU16/05670).

Peripheral taste detection in honey bees: What do taste receptors respond to?

Understanding the neural principles governing taste perception in species that bear economic importance or serve as research models for other sensory modalities constitutes a strategic goal. Such is the case of the honey bee (Apis mellifera), which is environmentally and socioeconomically important, given its crucial role as pollinator agent in agricultural landscapes and which has served as a traditional model for visual and olfactory neurosciences and for research on communication, navigation, and learning and memory. Here we review the current knowledge on honey bee gustatory receptors to provide an integrative view of peripheral taste detection in this insect, highlighting specificities and commonalities with other insect species. We describe behavioral and electrophysiological responses to several tastant categories and relate these responses, whenever possible, to known molecular receptor mechanisms. Overall, we adopted an evolutionary and comparative perspective to understand the neural principles of honey bee taste and define key questions that should be answered in future gustatory research centered on this insect.

Neuroendocrine Factors in Melanoma Pathogenesis.

Melanoma is one of the most aggressive skin cancers with a sharp rise in incidence in the last decades, especially in young people. Recognized as a significant public health issue, melanoma is studied with increasing interest as new discoveries in molecular signaling and receptor modulation unlock innovative treatment options. Stress exposure is recognized as an important component in the immune-inflammatory interplay that can alter the progression of melanoma by regulating the release of neuroendocrine factors. Various neurotransmitters, such as catecholamines, glutamate, serotonin, or cannabinoids have also been assessed in experimental studies for their involvement in the biology of melanoma. Alpha-MSH and other neurohormones, as well as neuropeptides including substance P, CGRP, enkephalin, beta-endorphin, and even cellular and molecular agents (mast cells and nitric oxide, respectively), have all been implicated as potential factors in the development, growth, invasion, and dissemination of melanoma in a variety of in vitro and in vivo studies. In this review, we provide an overview of current evidence regarding the intricate effects of neuroendocrine factors in melanoma, including data reported in recent clinical trials, exploring the mechanisms involved, signaling pathways, and the recorded range of effects.

Calcium Dyshomeostasis in Alzheimer's Disease Pathogenesis.

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that is characterized by amyloid β-protein deposition in senile plaques, neurofibrillary tangles consisting of abnormally phosphorylated tau protein, and neuronal loss leading to cognitive decline and dementia. Despite extensive research, the exact mechanisms underlying AD remain unknown and effective treatment is not available. Many hypotheses have been proposed to explain AD pathophysiology; however, there is general consensus that the abnormal aggregation of the amyloid β peptide (Aβ) is the initial event triggering a pathogenic cascade of degenerating events in cholinergic neurons. The dysregulation of calcium homeostasis has been studied considerably to clarify the mechanisms of neurodegeneration induced by Aβ. Intracellular calcium acts as a second messenger and plays a key role in the regulation of neuronal functions, such as neural growth and differentiation, action potential, and synaptic plasticity. The calcium hypothesis of AD posits that activation of the amyloidogenic pathway affects neuronal Ca2+ homeostasis and the mechanisms responsible for learning and memory. Aβ can disrupt Ca2+ signaling through several mechanisms, by increasing the influx of Ca2+ from the extracellular space and by activating its release from intracellular stores. Here, we review the different molecular mechanisms and receptors involved in calcium dysregulation in AD and possible therapeutic strategies for improving the treatment.

Prediction of local thermodynamics of water in and around endo-functionalized molecular tube receptors: An approach using grid inhomogeneous solvation theory

Water molecules in and around a receptor play a significant role in the guest/ligand binding process. Here, we discuss the waters’ role in the guest binding process of small miniature receptor endo-functionalized molecular tubes (host-1a and host-1b). We have portrayed this using classical molecular dynamics (MD) simulation and GIST methodology. Trajectories from MD simulation have been utilized in GIST methodology to estimate different localized thermodynamic parameters at different regions of these receptors. These small receptors reveal a surprisingly detailed solvation structure, thermodynamic pattern and offer comprehensive insights. The torus site with high water density is especially relevant within the receptor binding sites in the solvation structure. Water molecules are energetically unstable inside (i.e., torus and cavity regions) of these host molecules. This water instability offers some guest molecules extremely high binding affinities inside these host cavities. Also, we are curious to see the effect of electrostatic on these thermodynamic parameters. For this, we have used a nonpolar version of these host molecules in which all partial charges of the atomic sites of both these receptors are artificially set to zero. Every energetic and entropic solvation parameters are less perturbed for nonpolar host molecules than the corresponding regular host molecules. The water molecules inside the nonpolar host cavity are less strongly bound than the corresponding regular host molecules. Thus, the value of free energy for removing water molecules from a particular region of a purely nonpolar host molecule is more favorable than the corresponding regular host molecule.

Fungal Beta-glucans: Structure and Effect on Host Immune Responses

Fungi are eukaryotic microorganisms that show complex life cycles, including both anamorph and teleomorph stages. Beta-1,3-1,6-glucans (BGs) are major cell wall components in fungi. BGs are also found in a soluble form and are secreted by fungal cells. Studies of fungal BGs extensively expanded from 1960 to 1990 due to their applications in cancer immunotherapy. However, progress in this field slowed down due to the low efficacy of such therapies. In the early 21st century, the discovery of C-type lectin receptors significantly enhanced the molecular understanding of innate immunity. Moreover, pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) were also discovered. Soon, dectin-1 was identified as the PRR of BGs, whereas BGs were established as PAMPs. Then, studies on fungal BGs focused on their participation in the development of deep-seated mycoses and on their role as a source of functional foods. Fungal BGs may have numerous and complex linkages, making it difficult to systematize them even at the primary structure level. Moreover, elucidating the structure of BGs is largely hindered by the multiplicity of genes involved in cell wall biosynthesis, including those for BGs, and by fungal diversity. The present review mainly focused on the characteristics of fungal BGs from the viewpoint of structure and immunological activities.

The Prognostic Value of Retraction Clefts in Chinese Invasive Breast Cancer Patients.

Some studies reported the correlation between retraction clefts (RCs) and the clinicopathological features as well as prognosis in invasive breast carcinoma. However, limited number of investigations have been done and controversial results were reported. Larger population studies around the world might help to provide more accurate and comprehensive information. Thus, we examined the correlation between the extent of RCs and the clinicopathological features as well as the prognosis in 541 invasive breast carcinoma samples from Central China in this study. The statistical analyses were performed with the Pearson χ2 tests and univariate Cox proportional hazards regression assays. Compared with other studies, lower RCs occurrence rate (15.5%) was observed in Chinese breast cancer patients and opposite association between the presence of RCs and lymph nodes metastasis was identified, in which both progression free survival (PFS) and overall survival (OS) were improved with the presence of RCs in our study. Besides, despite some statistically significant associations between RCs and molecular subtypes, RCs and estrogen receptor status, the results were largely depending on the stratification methods. Generally, no convincing association was detected between the extent of RCs and the clinicopathological features or prognosis. In sum, the extent of RCs showed limited value as a prognostic predictor in invasive breast carcinoma patients from Central China.

Expanding benzothiadiazole-tetrazole photo-triggered click reaction with chloride ion into reaction-based chloride ion receptor

There is a great increasing need for effective chloride ion receptors due to the widespread distribution and vital role of chloride ion in nature or industrial production. Up to now, most reported molecule receptors (such as chemosensor) reversibly bind chloride ions via specific intermolecular interactions. Although irreversible binding are achieved by a specifically designed reaction that has advantages in terms of high selectivity and sensitivity, the study of reaction-based molecular receptor for chloride ion is currently unexplored. In this work, we designed and synthesized new BTD-tetrazole compounds to study their photo-triggered click reactions with chloride ions. Interestingly, compounds BT1 and BT2 facilely react with chloride ions under UV light irradiation. In the further exploration for the potential application of reaction-based chloride ion molecular receptor, BT1 or BT2 showed obvious absorption and photoluminescence (PL) responses with good selectivity and sensitivity. Moreover, in the response of BT1 or BT2 to chloride ions, the surprising PL changes induced by the hydrogen bonded aggregate of photochemical product (BHc1 or BHc2) provide a new platform to design reaction-based chloride ion receptor.

Ultrahigh molecular recognition specificity of competing DNA oligonucleotide strands in thermal equilibrium: a cooperative transition to order

The specificity of molecular recognition is important for molecular self-organization. A prominent example is the biological cell where a myriad of different molecular receptor pairs recognize their binding partners with astonishing accuracy within a highly crowded molecular environment. In thermal equilibrium it is usually admitted that the affinity of recognizer pairs only depends on the nature of the two binding molecules. Accordingly, Boltzmann factors of binding energy differences relate the molecular affinities among different target molecules that compete for the same probe. Here, we consider the molecular recognition of short DNA oligonucleotide single strands. We show that a better matching oligonucleotide can prevail against a disproportionally more concentrated competitor with reduced affinity due to a mismatch. We investigate the situation using fluorescence-based techniques, among them Förster resonance energy transfer and total internal reflection fluorescence excitation. We find that the affinity of certain strands appears considerably reduced only as long as a better matching competitor is present. Compared to the simple Boltzmann picture above we observe increased specificity, up to several orders of magnitude. We interpret our observations based on an energy-barrier of entropic origin that occurs if two competing oligonucleotide strands occupy the same probe simultaneously. Due to their differences in binding microstate distributions, the barrier affects the binding affinities of the competitors differently. Based on a mean field description, we derive a resulting expression for the free energy landscape, a formal analogue to a Landau description of phase transitions reproducing the observations in quantitative agreement as a result of a cooperative transition. The advantage of improved molecular recognition comes at no energetic cost other than the design of the molecular ensemble and the presence of the competitor. As a possible application, binding assays for the detection of single nucleotide polymorphisms in DNA strands could be improved by adding competing strands. It will be interesting to see if mechanisms along similar lines as exposed here contribute to the molecular synergy that occurs in biological systems.

A multiscale model for multiple platelet aggregation in shear flow.

We developed a multiscale model for simulating aggregation of multiple, free-flowing platelets in low-intermediate shear viscous flow, in which aggregation is mediated by the interaction of αIIbβ3 receptors on the platelet membrane and fibrinogen (Fg). This multiscale model uses coarse grained molecular dynamics (CGMD) for platelets at the microscales and dissipative particle dynamics (DPD) for the shear flow at the macroscales, employing our hybrid aggregation force field for modeling molecular level receptor ligand bonds. We define an aggregation tensor and use it to quantify the molecular level contact characteristics between platelets in an aggregate. We perform numerical studies under different flow conditions for platelet doublets and triplets and evaluate the contact area, detaching force and minimum distance between different pairs of platelets in an aggregate. We also present the dynamics of applied stress and velocity magnitude distributions on the platelet membrane during aggregation and quantify the increase in stress in the contact region under different flow conditions. Integrating the knowledge from our previously validated models, together with new aggregation scenarios, our model can dynamically quantify aggregation characteristics and map stress and velocity distribution on the platelet membrane which are difficult to measure in vitro, thus providing an insight into mechanotransduction bond formation response of platelets to flow-induced shear stresses. This modeling framework, together with the tensor method for quantifying inter-platelet contact, can be extended to simulate and analyze larger aggregates and their adhesive properties.