Biology subjects

Dey, S. K.

Publications and source records attributed to Dey, S. K..

7 recordsLinked to original sources

bioRxiv2026

ERBB2 establishes the timing of progesterone priming required for uterine receptivity

Progesterone is essential for establishing uterine receptivity and sustaining early pregnancy. However, how the uterus acquires the competence to respond to progesterone at the appropriate time remains poorly understood. Here we show that ERBB2 governs the timing of progesterone responsiveness required for uterine receptivity. In endometrial samples from women with recurrent spontaneous abortion (RSA), ERBB2 is downregulated specifically in the stromal compartment, accompanied by a parallel reduction in stromal progesterone receptor (PGR). Uterine deletion of Erbb2 in mice blunts the rise of stromal PGR at the onset of the receptive window, deferring implantation and impairing decidualization despite normal circulating progesterone and estrogen. Epithelial deletion has no such effect, placing the requirement in the stroma. High-dose progesterone fails to rescue the phenotype; advancing progesterone priming by 24 hours restores stromal PGR, HAND2, Bmp2, and on-time implantation. Collectively, the present study provides evidence that ERBB2 directs the temporal window of stromal progesterone priming by setting the threshold for PGR induction, thereby synchronizing the maternal-fetal interface and safeguarding pregnancy.

developmental biology↗

bioRxiv2025

Uterine stromal Erbb3-Igf1 signaling is critical to functional gland development conducive to implantation

Preimplantation uterine gland differentiation, involving glandular branching, is a prerequisite for secretion of leukemia inhibitory factor (LIF), thereby establishing uterine receptivity to embryo implantation. This differentiation process is disrupted by the absence of FOXA2, a transcription factor specifically present in uterine glands. It remains unclear whether preimplantation glandular differentiation is regulated exclusively by gland-intrinsic mechanisms or is influenced by the surrounding microenvironment through mesenchymal-epithelial interactions. We show here that uterine deletion of Erbb3 leads to impaired gland branching and FOXA2 expression, as well as reduced female fertility. In contrast, females with uterine epithelial-specific deletion of Erbb3 show normal fertility, suggesting a critical role of stromal ERBB3 signaling. A transcriptomic profiling of day 3 stromal cells identified Igf1 as a candidate paracrine factor mediating the stromal-epithelial interaction. Thus, the uterine deletion of Igf1r leads to a reduced gland branching phenotype similar to that observed in Erbb3d/d uteri. These results demonstrate that ERBB3 regulates glandular branching and embryo implantation via the ERBB3-IGF1-IGF1R signaling pathway.

developmental biology↗

bioRxiv2025

Identifying a logical specification and a program for an LLM-based generator of lead molecules

Our interest is in the generation of "lead" molecules in early-stage drug design. Leads are small molecules (ligands) that can bind to a part of pre-specified target and also satisfy multiple physico-chemical constraints. We propose using techniques developed in Inductive Logic Programming (ILP) to identify a logical specification of feasible molecules; and then using this specification to construct a program that uses a large language model (LLM) to generate new molecules. We ensure the program constructed is correct, in the sense that every molecule generated by the program is feasible according the specification. Our focus is on contributing to on-going drug-discovery research on novel inhibitors for Dopamine {beta}-hydroxylase (DBH), an enzyme that plays a pivotal role in several diseases related to the brain and the heart. We find molecules comparable in affinity to the latest generation drugs currently in clinical trials, and chemical assessment of synthesisablity of the molecules generated. For completeness, we also provide results obtained on the classic benchmark datasets used in recent work reported in [1].

bioinformatics↗

bioRxiv2024

The IQGAP1-Claudin Cell Junction Axis in Cisplatin-induced Kidney Damage

Kidney damage resulting from nephrotoxicity is a major side effect of chemotherapy. Cisplatin is an effective antineoplastic agent broadly used in oncology where it interferes with DNA replication in dividing cells, however, its mechanism in kidney damage remains unclear. We tested the hypothesis that cisplatin displaces cell-contact proteins such as IQGAP1-claudin complex in the kidney tubules, causing epithelial cell dissociation and kidney damage. Employing a multifaceted approach, using mutant analyses and optimal cisplatin dose, this hypothesis was tested in cell culture and iqgap1-/- mouse models. Cisplatin inhibited cell proliferation and migration in an IQGAP1-dependent manner, displaced IQGAP1 from cell junctions and altered the expression level of key junctional markers, including claudins 2/4/8 and nephrin. Similar effects were observed in animal models where cisplatin treatment and loss of IQGAP1 had additive effects. These functional outcomes are accounted for by suppression of Akt1/PKB survival and ERK1/2 proliferation signals and activation of JNK-GSK3{beta} stress and inflammatory signal, widely implicated in kidney injury. These findings present IQGAP1-claudin axis as biomarkers and therapeutic targets in kidney damage and pave the way for formulating new analogs that eliminate cisplatin adverse side effects while preserving its antineoplastic efficacy.

cell biology↗

bioRxiv2022

Biochemical and structural insights into SARS-CoV-2 polyprotein processing by Mpro

SARS-CoV-2, a human coronavirus, is the causative agent of the COVID-19 pandemic. Its [~]30 kb RNA genome is translated into two large polyproteins subsequently cleaved by viral papain-like protease and main protease (Mpro/nsp5). Polyprotein processing is essential yet incompletely understood. We studied Mpro-mediated processing of the nsp7-10/11 polyprotein, whose mature products are cofactors of the viral replicase, identifying the order of cleavages as: 1) nsp9-10, 2) nsp8-9/nsp10-11, and 3) nsp7-8. Integrative modeling based on mass spectrometry (including hydrogen-deuterium exchange and cross-linking) and X-ray scattering yielded three-dimensional models of the nsp7-10/11 polyprotein. Our data suggest that the nsp7- 10/11 structure in complex with Mpro strongly resembles the unbound polyprotein, and that both polyprotein conformation and junction accessibility determine the preference and order of cleavages. Finally, we used limited proteolysis assays to characterize the effect of a series of inhibitors/binders on Mpro processing of nsp7-11 and Mpro inhibition using a polyprotein substrate. TeaserWe elucidated the structural basis of order of cleavage of SARS-CoV-2 nsp7-11 polyprotein, with implications for Mpro inhibition.

biochemistry↗

bioRxiv2022

Targeted deletion of uterine glandular Foxa2 induces embryonic diapause in mice

Embryonic diapause is a reproductive strategy in which embryo development and growth is temporarily arrested within the uterus to ensure the survival of neonates and mothers during unfavorable conditions. Pregnancy is reinitiated when conditions become favorable for neonatal survival. The mechanism of how the uterus enters diapause remains unclear. Mice with uterine deletion of Foxa2, a transcription factor, are infertile. In this study, we show that dormant blastocysts are recovered from these mice on day 8 of pregnancy with persistent uterine Msx1 expression, a gene critical to maintaining the uterine quiescent state, suggesting that these mice enter embryonic diapause. Leukemia inhibitory factor (LIF) can resume implantation in these mice. Although estrogen is critical for implantation in progesterone (P4)-primed uterus, our current model reveals that FOXA2-independent estrogenic effects are detrimental to sustaining uterine quiescence. Interestingly, P4 and anti-estrogen can prolong uterine quiescence in the absence of FOXA2. While we find that Msx1 expression persists in the uterus deficient in Foxa2, the complex relationship of FOXA2 with Msx genes and estrogen receptors remains to be explored.

developmental biology↗

bioRxiv2020

Pregnancy success in mice requires appropriate cannabinoid receptor signaling for primary decidua formation

An early event after implantation is stromal cell transformation to decidual cells (decidualization) that support embryo development. In mice, this process begins at the antimesometrial (AM) pole with differentiation of stromal cells into epithelial-like cells (epithelioid cells) surrounding the implantation chamber. This is an avascular zone called the primary decidual zone (PDZ), and considered to function as a transient, size-dependent permeable barrier to protect the embryo from maternal circulating harmful agents, including immunoglobulins, immune cells, microorganisms and other noxious agents. This zone forms on day 5 afternoon and becomes fully established on day 6 with the loss of the crypt epithelium. The PDZ gradually degenerates with the appearance of the secondary decidual zone (SDZ) around the PDZ that peaks on day 8 in mice. Decidualization is critical for early pregnancy in mice and humans. We show that cannabinoid/endocannabinoid signaling influences decidualization in early pregnancy. Mice deficient in two major cannabinoid receptors, CB1 and CB2, show compromised PDZ. We found that angiogenic factors are dysregulated in Cnr1-/-Cnr2-/- mice with defective PDZs, resulting in the abnormal presence of blood vessels and macrophages in this zone; disruption of the PDZ compromises pregnancy outcomes. Using an in vitro decidualization model, we found that Cnr1 levels increase in mouse stromal cells and human uterine fibroblast (Huf) cells undergoing decidualization and that limiting CB1 signaling in these cell types suppresses decidualization in vitro. Since endothelial cells express Cnr2 and decidual cells express Cnr1, we hypothesize that angiogenic events driven by CB2 are integrated with CB1 in decidual cells, leading to proper PDZ formation, a critical step for pregnancy success.

developmental biology↗