Design of high-avidity multivalent ligand structures that target cells with high ligand economy.

Novel cell-targeting ligand structures are constructed with a spikey core scaffold, where multiple copies of coiled-coil peptide nanorods are conjugated on the surface of a peptide nanosheet. Clustering of carbohydrate and aptamer ligands at the end of the coiled coils optimizes ligand accessibility to cell-surface receptors. Display of the ligand-coil conjugates on the nanosheet generates a patchy ligand pattern bearing two levels of multivalency. With the ligand-scaffold system, high-avidity cell targeting is realized using fewer ligands than ever, which facilitates future applications in cell detection and drug delivery.

Assessment of angiogenesis using endoglin in salivary gland tumors - An immunohistochemical study.

Background: Endoglin, a co-receptor of transforming growth factor (TGF)-ß1 and TGF-ß2, is indispensable for endothelial cell proliferation and modulation of tumor promotion activities of TGF-ß1. The assessment of neovascularization using endoglin expression has been considered a potential predictor of prognosis in various solid malignancies. Aims and Objectives: To analyze the expression of endoglin by immunohistochemistry in both benign and malignant salivary gland tumors. Materials and Methods: Fifteen cases of benign salivary gland tumors and seventeen cases of malignant salivary gland tumors were included in the study, and immunohistochemistry was performed using anti-CD105 antibody using standard protocol. Results and Conclusion: The study demonstrated that there is increased endoglin expression in malignant tumors as compared to their benign counterparts which is suggestive of increased angiogenic activity in tumor areas and could be responsible for the aggressive behavior of the malignancies. The highest density of endoglin-positive blood vessels was observed in the inflammatory tumor stromal areas. Furthermore, a significant increase in endoglin expression was evident as the grade of malignant salivary gland tumor increased. The results of the study indicate that the increased expression of endoglin in high-grade malignancies contributes to their aggressive nature.

Large-scale assessment of lepidopteran soybean pests and efficacy of Cry1Ac soybean in Brazil.

The soybean technology MON 87701 × MON 89788, expressing Cry1Ac and conferring tolerance to glyphosate, has been widely adopted in Brazil since 2013. However, pest shifts or resistance evolution could reduce the benefits of this technology. To assess Cry1Ac soybean performance and understand the composition of lepidopteran pest species attacking soybeans, we implemented large-scale sampling of larvae on commercial soybean fields during the 2019 and 2020 crop seasons to compare with data collected prior to the introduction of Cry1Ac soybeans. Chrysodeixis includens was the main lepidopteran pest in non-Bt fields. More than 98% of larvae found in Cry1Ac soybean were Spodoptera spp., although the numbers of Spodoptera were similar between Cry1Ac soybean and non-Bt fields. Cry1Ac soybean provided a high level of protection against Anticarsia gemmatalis, C. includens, Chloridea virescens and Helicoverpa spp. Significant reductions in insecticide sprays for lepidopteran control in soybean were observed from 2012 to 2019. Our study showed that C. includens and A. gemmatalis continue to be primary lepidopteran pests of soybean in Brazil and that Cry1Ac soybean continues to effectively manage the target lepidopteran pests. However, there was an increase in the relative abundance of non-target Spodoptera spp. larvae in both non-Bt and Cry1Ac soybeans.

Fitness Costs of Chlorantraniliprole Resistance Related to the SeNPF Overexpression in the Spodoptera exigua (Lepidoptera: Noctuidae).

Spodopteraexigua, a multifeeding insect pest, has developed a high level of resistance to chlorantraniliprole, which is a benzoylurea insecticide that targets the ryanodine receptors (RyRs). Herein, the resistant strain (SE-Sel) and sensitive strain (SE-Sus) were obtained by bidirectional screening for six generations. The potential oviposited eggs and oviposition rate of the SE-Sel strain were dramatically lower than those of the SE-Sus strain; on the contrary, the weights of prepupae and preadult were significantly increased. As a post-mating response, the higher number of non-oviposited eggs in the SE-Sel strain was caused by a lower mating rate. In addition, the expression levels of vitellogenin (SeVg) and its receptor (SeVgR) in the SE-Sel strain were consistently lower than those in the SE-Sus strain. An RyRI4743M mutation, contributing to the resistance to chlorantraniliprole, was located in the S3 transmembrane segments and might have affected the release of calcium ions; it led to the upregulated expression of the neuropeptide SeNPF and its receptor SeNPFR, and the mating and oviposition rate were significantly recovered when the SeNPF was knocked down though RNA interference (RNAi) in the male adult of the SE-Sel strain. Moreover, the expression of the juvenile hormone-binding proteins SeJHBWDS3 and SeJHBAN in the male adult of the SE-Sel strain was significantly decreased, which proved the existence of a fitness cost from another angle. Therefore, these results indicate that the fitness cost accompanied by chlorantraniliprole resistance in S. exigua may be related to the decrease in mating desire due to SeNPF overexpression.

Decreased classical monocytes and CD163 expression in TB patients: an indicator of drug resistance.

Tuberculosis (TB) is a disease instigated by Mycobacterium tuberculosis. Peripheral blood monocytes represent highly efficient effector cells of innate immunity against TB. Little is known about monocyte subsets and their potential involvement in the development of M. tuberculosis drug resistance in patients with TB. This study was conducted to investigate alterations in monocyte subsets, CD163 expression on monocytes, and its serum level in patients without and with rifampicin resistance TB (RR-TB) and healthy controls. A total of 164 patients with TB (84 without RR-TB and 80 patients with RR-TB) and 85 healthy controls were enrolled in this study. The percentages of various monocyte subsets and surface expression of CD163 on monocytes were quantitatively determined using flow cytometry. The serum level of CD163 was determined by commercially available ELISA kits. Decreased frequency of classical monocytes was detected in patients with RR-TB. Non-classical monocytes were decreased in patients without RR-TB; however, intermediate monocytes were raised in patients with RR-TB. The serum level of CD163 was decreased in patients of RR-TB that showsed a positive correlation with the frequency of CD14++CD16-CD163+ and CD14++CD16+CD163+ monocytes. It is concluded that decreased classical monocytes and sCD163 in patients with RR-TB could be an indicator of drug resistance.

Understanding the impacts of cellular environments on ligand binding of membrane receptors by computational simulations.

Binding of cell surface receptors with their extracellular ligands initiates various intracellular signaling pathways. However, our understanding of the cellular functions of these receptors is very limited due to the fact that in vivo binding between ligands and receptors has only been successfully measured in a very small number of cases. In living cells, receptors are anchored on surfaces of the plasma membrane, which undergoes thermal undulations. Moreover, it has been observed in various systems that receptors can be organized into oligomers prior to ligand binding. It is not well understood how these cellular factors play roles in regulating the dynamics of ligand-receptor interactions. Here, we tackled these problems by using a coarse-grained kinetic Monte Carlo simulation method. Using this method, we demonstrated that the membrane undulations cause a negative effect on ligand-receptor interactions. We further found that the preassembly of membrane receptors on the cell surface can not only accelerate the kinetics of ligand binding but also reduce the noises during the process. In general, our study highlights the importance of membrane environments in regulating the function of membrane receptors in cells. The simulation method can be potentially applied to specific receptor systems involved in cell signaling.

Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators.

The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of marketed GPCR drugs interact exclusively with the orthosteric binding site, allosteric mechanisms in GPCR biology stay medically underexploited, with only several allosteric ligands currently approved. This review summarizes the current knowledge on the biology of FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), FFAR4 (GPR120), and GPR84, including structural aspects of FFAR1, and discusses the molecular pharmacology of FFAR allosteric ligands as well as the opportunities and challenges in research from the perspective of drug discovery.

Assessment of Adenosine Triphosphatase Phospholipid Transporting 8B1 (ATP8B1) Function in Patients With Cholestasis With ATP8B1 Deficiency by Using Peripheral Blood Monocyte-Derived Macrophages.

Adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) deficiency, an ultrarare autosomal recessive liver disease, includes severe and mild clinical forms, referred to as progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1), respectively. There is currently no practical method for determining PFIC1 or BRIC1 at an early disease course phase. Herein, we assessed the feasibility of developing a diagnostic method for PFIC1 and BRIC1. A nationwide Japanese survey conducted since 2015 identified 25 patients with cholestasis with ATP8B1 mutations, 15 of whom agreed to participate in the study. Patients were divided for analysis into PFIC1 (n = 10) or BRIC1 (n = 5) based on their disease course. An in vitro mutagenesis assay to evaluate pathogenicity of ATP8B1 mutations suggested that residual ATP8B1 function in the patients could be used to identify clinical course. To assess their ATP8B1 function more simply, human peripheral blood monocyte-derived macrophages (HMDMs) were prepared from each patient and elicited into a subset of alternatively activated macrophages (M2c) by interleukin-10 (IL-10). This was based on our previous finding that ATP8B1 contributes to polarization of HMDMs into M2c. Flow cytometric analysis showed that expression of M2c-related surface markers cluster of differentiation (CD)14 and CD163 were 2.3-fold and 2.1-fold lower (95% confidence interval, 2.0-2.5 for CD14 and 1.7-2.4 for CD163), respectively, in patients with IL-10-treated HMDMs from PFIC1 compared with BRIC1. Conclusion: CD14 and CD163 expression levels in IL-10-treated HMDMs may facilitate diagnosis of PFIC1 or BRIC1 in patients with ATP8B1 deficiency.

Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.

Control of Superselectivity by Crowding in Three-Dimensional Hosts.

Motivated by the fine compositional control observed in membraneless droplet organelles in cells, we investigate how a sharp binding-unbinding transition can occur between multivalent client molecules and receptors embedded in a porous three-dimensional structure. In contrast to similar superselective binding previously observed at surfaces, we have identified that a key effect in a three-dimensional environment is that the presence of inert crowding agents can significantly enhance or even introduce superselectivity. In essence, molecular crowding initially suppresses binding via an entropic penalty, but the clients can then more easily form many bonds simultaneously. We demonstrate the robustness of the superselective behavior with respect to client valency, linker length, and binding interactions in Monte Carlo simulations of an archetypal lattice polymer model.

Replication assessment of NUS1 variants in Parkinson's disease.

The NUS1 gene was recently associated with Parkinson's disease (PD) in the Chinese population. Here, as part of the International Parkinson's Disease Genomics Consortium, we have leveraged large-scale PD case-control cohorts to comprehensively assess damaging NUS1 variants in individuals of European descent. Burden analysis of rare nonsynonymous damaging variants across case-control individuals from whole-exome and -genome data sets did not find evidence of NUS1 association with PD. Overall, single-variant tests for rare (minor allele frequency<0.01) and common (minor allele frequency>0.01) variants, including 15 PD-GWAS cohorts and summary statistics from the largest PD GWAS meta-analysis to date, also did not uncover any associations. Our results indicate a lack of evidence for a role of rare damaging nonsynonymous NUS1 variants in PD in unrelated case-control cohorts of European descent, suggesting that the previously observed association could be driven by extremely rare population-specific variants.

Assessment of the association between NUS1 variants and essential tremor.

BACKGROUND: A recent study on early onset Parkinson's disease (PD) revealed that NUS1 is a risk gene for PD. Clinically, essential tremor (ET) is closely related to PD. In this study, we aimed to detect NUS1 variants and assess the effect of those variants on patients with ET. METHODS: The 5 coding regions and the exon-intron boundaries of NUS1 were directly sequenced in 395 patients with ET and an equal number of healthy controls, matched for age and sex. The function of variants was assessed by pathogenic predictive software programs. Genetic analysis of variants was used to evaluate susceptibility to ET. RESULTS: A total of 6 exonic variants were identified, including 3 synonymous and 3 missense variants. The non-synonymous variants were predicted to be tolerable. No variants had significant association with ET (none of the p-values were less than 0.05, using Fisher's exact test). CONCLUSION: Our study suggested that NUS1 variants may not contribute to the risk of ET.

Psychosocial aspects and life project disruption in young women diagnosed with metastatic hormone-sensitive HER2-negative breast cancer.

Metastatic breast cancer (MBC) diagnosis in young women negatively impacts on quality of life (QoL) and daily activities, disrupting their life project and forcing them to face new psychosocial challenges. The recently published results on the improvement of the overall survival of pre- or perimenopausal women with hormone-receptor-positive, HER2-negative MBC treated with CDK4/6 inhibitors plus endocrine therapy, while preserving, and in some items improving their QoL, will change the landscape of the management of this patient population. Their extended survival and potential improvement in QoL will, therefore, modify their specific needs in terms of psychosocial support. The complexity of the care of young women with MBC is described herein, based on an extensive literature review. Further research about the specific psychosocial requirements of these women and a new multidisciplinary holistic approach is paramount to properly address their concerns and preferences. The communication with and support of their partners, parents and children is an important factor affecting the QoL of these patients. Altogether, a multidisciplinary care, open communication and personalized support is required to address the psychosocial implications of the new prognostic expectations on these patients with the incorporation of new targeted therapies.

Pathologic assessment of tumor-associated macrophages and their histologic localization in invasive breast carcinoma.

BACKGROUND: Tumor-associated macrophages (TAMs) are important in regulating cross-talk between tumor cells and tumor microenvironment. TAMs are involved in multiple steps of tumor progression and invasion. This study aimed to compare CD163 expression with the widely used CD68 pan-macrophage marker in invasive breast carcinoma. Furthermore, it focused on assessing the significance of TAMs localization in relation to clinicopathological parameters. RESULTS: CD68 and CD163 immunohistochemical expressions within TAMs infiltrating both tumor nest (TN) and tumor stroma (TS) were evaluated in 60 specimens with invasive breast carcinoma. High CD68-positive stromal TAMs was significantly related to larger tumor, nodal metastasis and vascular invasion (p = 0.003, 0.037, 0.032, respectively), whereas high CD163-positive stromal TAMs was significantly related to larger tumors, nodal metastasis, stage III tumors, vascular invasion, estrogen receptor (ER) negativity, and triple-negative subtype (p = 0.023, < 0.001, 0.001, 0.022, 0.002, 0.017, respectively). On multivariate analysis, high CD68-positive TAMs infiltrating TS was significantly associated with larger tumor and positive nodal metastasis (p = 0.006 and 0.016, respectively), whereas high CD163 TAMs density within TS was significantly associated with positive vascular invasion, nodal metastasis, and molecular subtypes (p = 0.003, 0.001, and 0.009, respectively). CONCLUSION: TAMs within tumor stroma and tumor nest have different levels of association with poor prognostic parameters. So, it is of great importance to consider the histologic localization of TAMs in addition to the degree of TAMs infiltration.

The importance of FDG-PET/CT parameters for the assessment of the immune status in advanced HNSCC.

OBJECTIVE: Cancer cells secrete large amounts of lactic acid via aerobic glycolysis. We have shown that lactic acid plays an important role as a proinflammatory and immunosuppressive mediator and promotes tumor progression. Fluorine-18 fluorodeoxyglucose (FDG) uptake detected by positron emission tomography/computed tomography (PET/CT) is considered as a good indicator of aerobic glycolysis in cancer. In this study, we examined the relationships between systemic inflammatory parameters and FDG-PET/CT parameters in advanced head and neck squamous cell carcinoma (HNSCC). Furthermore, we investigated the relationships between FDG-PET/CT parameters and M2-macrophage polarization in HNSCC by assessing the ratio of CD163, a M2-macrophage marker, to CD68, a pan-macrophage marker. METHODS: This study included 73 advanced HNSCC patients. We assessed the C-reactive protein (CRP) level, white blood cell (WBC) count, neutrophil count, lymphocyte count, and monocyte count as systemic inflammatory markers. Additionally, we assessed the maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) as FDG-PET/CT parameters. RESULTS: The CRP level, WBC count, and neutrophil count were correlated with whole-body FDG-PET/CT parameters. The CD163/CD68 ratio was correlated with SUVmax and SUVmean. Our results suggest that systemic inflammation, which is associated with neutrophils, develops in patients with HNSCC having tumors with a larger volume and increased glucose uptake and that M2-macrophage polarization is promoted in HNSCC with increased glucose uptake, SUVmax, and SUVmean. FDG-PET/CT has the potential to reflect cancer-related chronic inflammation and immunosuppressive conditions in cancer patients. CONCLUSIONS: FDG-PET/CT parameters appear to be useful in assessing the immune status in HNSCC.

Ex vivo assessment of in vivo DC-targeted antibodies in pre-clinical models.

APCs play a key role at initiating adaptive immune responses by presenting antigens to lymphocytes and DCs are professional APCs. It is critical to understand the differential antigen capture and presentation ability of different DC subsets, which is important for DC-targeted immunotherapy. In this section, we give a brief introduction to different antigen presentation pathways and introduce the key concept of cross-presentation, the major antigen presentation pathway used for anti-viral and anti-tumoral immune responses. CD205, a DC restricted receptor, is highly expressed on certain DCs subsets. We find CD205-mediated antigen uptake to be a useful model for studying antigen uptake and defects. These methods provide an introduction to CD205-mediated pre-clinical delivery of antigens to cross-presenting DCs, which can be adapted to the study of targeting to multiple receptors and other C-type lectins. This is a promising strategy to detect the antigen capture capacity and to study the key players orchestrating tolerance and immunity ex vivo.

Receptor variants and the development of centrally acting medications
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The progressive changes in research paradigms observed in the largest pharmaceutical companies and the burgeoning of biotechnology startups over the last 10 years have generated a need for outsourcing research facilities. In parallel, progress made in the fields of genomics, protein expression in recombinant systems, and electrophysiological recording methods have offered new possibilities for the development of contract research organizations (CROs). Successful partnering between pharmaceutical companies and CROs largely depends upon the competences and scientific quality on offer for the discovery of novel active molecules and targets. Thus, it is critical to review the knowledge in the field of neuroscience research, how genetic approaches are augmenting our knowledge, and how they can be applied in the translation from the identification of potential molecules up to the first clinical trials. Taking these together, it is apparent that CROs have an important role to play in the neuroscience of drug discovery.
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Los cambios progresivos en los paradigmas de investigación observados en las principales compañías farmacéuticas y el desarrollo de las nuevas empresas de biotecnología en los últimos 10 años han generado la necesidad de subcontratar las instalaciones de investigación. Paralelamente, el progreso realizado en los campos de la genómica, la expresión de proteínas en sistemas recombinantes y en los métodos de registro electrofisiológico han ofrecido nuevas posibilidades para el desarrollo de organizaciones de investigación por contrato (OIC). La asociación exitosa entre las compañías farmacéuticas y las OIC depende en gran medida de las competencias y la calidad científica que se ofrecen para el descubrimiento de nuevas moléculas activas y sitios de acción. Por lo tanto, es fundamental revisar el conocimiento en el campo de la investigación en neurociencia, cómo las aproximaciones genéticas están aumentando nuestro conocimiento y cómo se pueden aplicar en la traducción desde la identificación de potenciales moléculas hasta los ensayos clínicos iniciales. Tomando esto en conjunto, es evidente que las OIC tienen un papel importante que desempeñar en la neurociencia del descubrimiento de fármacos.

Les modifications observées durant les dix dernières années concernant les modèles organisationnels des grandes industries pharmaceutiques ainsi que la multiplication des entreprises de biotechnologies ont augmentés les besoins de recherches dans des laboratoires privés. En parallèle les progrès en génomique ainsi que dans les systèmes d'expression de protéines recombinantes ont ouvert de nouvelles possibilités pour le développement d'unités indépendantes qui offrent de la recherche sous contrats (CRO). Le succès des recherches distribuées entre partenaires pharmaceutiques et les unités de recherche privées dépend essentiellement des compétences ainsi que des qualités scientifiques qui peuvent être offertes pour la découverte de nouvelles molécules agissant sur une cible définie. Il est important d'examiner, comment les nouvelles découvertes effectuées dans le domaine de la génétique et l'accroissement de nos connaissances, peuvent se traduire dans l'identification de nouvelles molécules à visée thérapeutiques depuis la recherche fondamentale jusqu'aux essais cliniques. D'une manière globale, il apparaît que les unités de recherche contractuelles ont un rôle majeur à jouer dans le domaine de la recherche en neuroscience ainsi que dans la découverte de nouveaux principes actifs.

Binding constant of membrane-anchored receptors and ligands that induce membrane curvatures.

Cell adhesion is crucial for immune response, tissue formation, and cell locomotion. The adhesion process is mediated by the specific binding of membrane-anchored receptor and ligand proteins. These adhesion proteins are in contact with the membranes and may generate curvature, which has been shown for a number of membrane proteins to play an important role in membrane remodeling. An important question remains of whether the local membrane curvatures induced by the adhesion proteins affect their binding. We've performed Monte Carlo simulations of a mesoscopic model for membrane adhesion via the specific binding of curvature-inducing receptors and ligands. We find that the curvatures induced by the adhesion proteins do affect their binding equilibrium constant. We presented a theory that takes into account the membrane deformations and protein-protein interactions due to the induced curvatures, and agrees quantitatively with our simulation results. Our study suggests that the ability to induce membrane curvatures represents a molecular property of the adhesion proteins and should be carefully considered in experimental characterization of the binding affinity.

A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia.

Individuals of African ancestry in the United States and Europe are at increased risk of developing schizophrenia and have poorer clinical outcomes. The antipsychotic clozapine, the only licensed medication for treatment-resistant schizophrenia, is under-prescribed and has high rates of discontinuation in individuals of African ancestry, due in part to increased rates of neutropenia. The genetic basis of lower neutrophil levels in those of African ancestry has not previously been investigated in the context of clozapine treatment. We sought to identify risk alleles in the first genome-wide association study of neutrophil levels during clozapine treatment, in 552 individuals with treatment-resistant schizophrenia and robustly inferred African genetic ancestry. Two genome-wide significant loci were associated with low neutrophil counts during clozapine treatment. The most significantly associated locus was driven by rs2814778 (ß = -0.9, P = 4.21 × 10-21), a known regulatory variant in the atypical chemokine receptor 1 (ACKR1) gene. Individuals homozygous for the C allele at rs2814778 were significantly more likely to develop neutropenia and have to stop clozapine treatment (OR = 20.4, P = 3.44 × 10-7). This genotype, also termed "Duffy-null", has previously been shown to be associated with lower neutrophil levels in those of African ancestry. Our results indicate the relevance of the rs2814778 genotype for those taking clozapine and its potential as a pharmacogenetic test, dependent on the outcome of additional safety studies, to assist decision making in the initiation and on-going management of clozapine treatment.

Diffusion-Based Molecular Communication Channel in Presence of a Probabilistic Absorber: Single Receptor Model and Congestion Analysis.

In this paper, a diffusion-based molecular communication channel is modeled in presence of a probabilistic absorber. The probabilistic absorber is an absorber which absorbs molecules upon collision with probability q . With random walk analysis, the discrete probability function of particle location in the presence of a probabilistic absorber can be found. Then, a continuous probability function is fitted to this Markov-based results with introducing several fitting parameters to the known probability function of particle location in an unbounded environment without an absorbing barrier. With this approach, a single receptor is modeled as an M/M/1/1 queue in which q represents the complementary blocking probability and the mean service time is the mean trafficking time. Therefore, we are able to model the stochastic nature of ligand-receptor binding, which comes from the incapability of a receptor to receive all molecules in its space; and also known as receptor occupancy. The proper consideration of the absorption effect leads to the accurate calculation of the concentration at the desired site, which is definitely less than the concentration obtained when neglecting it. These findings can have a crucial role in designing drug delivery systems in which determining the optimal rate of the drug transmitting nanomachines is critical to avoid toxicity while maintaining effectiveness.