Biology subjects

Shapiro, S.

Publications and source records attributed to Shapiro, S..

5 recordsLinked to original sources

bioRxiv2025

PDLIM2 in Lung Adenocarcinoma Metastasis

Human and mouse studies have established the unique PDZ-LIM domain-containing protein PDLIM2 as a common tumor suppressor that is especially vital for suppressing the tumorigenesis and therapeutic resistance of lung cancer, the leading cause of cancer-related deaths among both men and women. However, the role of PDLIM2 in tumor metastasis, the predominant cause of cancer morbidity and mortality, is yet to be determined. Here, we report that PDLIM2 repression was positively associated with the metastasis of human lung adenocarcinoma, the major type of non-small cell lung cancer that accounts for more than 40% of all cases of human lung cancer. Interestingly, PDLIM2 repression was also correlated with oncogenic KRAS and/or TP53 mutations, two common drivers of human lung adenocarcinoma that often co-occur. In mice, in comparison to concurrently inducing mutant KRAS expression and TP53 deletion, additional co-ablation of PDLIM2 significantly increased the number and size of lung adenocarcinomas in the lung, and more importantly, the distant metastasis of lung tumor cells. The increased metastasis was accompanied by decreased anti-tumor immunity and increased pro-tumor inflammation. These data demonstrate the role of PDLIM2 in suppressing lung adenocarcinoma metastasis, thereby improving our understanding of this crucial tumor suppressor and lung cancer. They also provide a useful model for studying metastasis and testing new lung cancer treatments in vivo.

cancer biology↗

bioRxiv2025

PDLIM2 Repression: A Common Mechanism in Viral Lung Infection

BackgroundPDLIM2, a PDZ-LIM domain-containing protein expressed highest in the lung and immune cells, serves as a unique tumor suppressor and immune modulator, mainly by turning off the activation of the master transcription factors NF-{kappa}B and STAT3. While its role in cancer is established, the involvement of PDLIM2 in viral infection remains unclear. ResultsHere, we analyzed public gene expression data of blood leukocytes, bronchoalveolar lavage cells, and lung tissues from uninfected healthy humans and those infected with the respiratory virus SARS-CoV-2 or influenza. We found that PDLIM2 expression was repressed by viral infection, and notably, this repression correlated with the severity of infectious diseases. Consistently, the expression level of PDLIM2 was negatively associated with NF-{kappa}B and STAT3 activity across a diverse range of cell types, such as macrophages, monocytes, neutrophils, T cells, alveolar type 1 and 2 epithelial cells, airway epithelial cells, and fibroblasts. Accordingly, cells with low PDLIM2 expression exhibited aberrant activation of signaling pathways essential for cellular functions and immune responses. ConclusionsThese findings highlight PDLIM2 repression as a common mechanism underlying human viral infectious diseases and suggest PDLIM2 as a potential biomarker and therapeutic target for disease prognosis, prevention, and treatment.

pathology↗

bioRxiv2025

Mechanistic Basis for Inhibition of the Extended Spectrum Class A b-Lactamase GES-1 by Tazobactam and Enmetazobactam

Expression of {beta}-lactamases is the primary form of {beta}-lactam antibiotic resistance in Gram-negative bacteria. Enmetazobactam is a penicillanic acid sulfone (PAS) that inhibits extended spectrum {beta}-lactamases (ESBLs) by forming an acyl-enzyme complex that eventually breaks down to an irreversible lysinoalanine crosslink. In contrast, enmetazobactam inhibits the class A carbapenemase KPC-2 via an acyl-enzyme that does not lead to lysinoalanine crosslink formation. This difference correlates with greater inhibitory potency of enmetazobactam against class A ESBLs, compared to carbapenemases. The GES enzymes, unlike other class A {beta}-lactamase families, show progression from carbapenem-inhibited to carbapenem-hydrolysing phenotypes through single point mutations. We present crystal structures of GES-1, a globally disseminated ESBL, as the enmetazobactam- and tazobactam-derived acyl-enzymes. The complexes differ in the identities of their respective covalent adducts, with the catalytic Ser70 acylated by a 214 Da enmetazobactam-derived fragment, whereas tazobactam has fragmented to a 70 Da aldehyde. The tautomeric form of the enmetazobactam-derived ligand is verified by high-level QM/MM calculations, revealing the trans-enamine as the most thermodynamically stable tautomer, that adopts an optimised conformation that best matches the experimentally observed electron density appended to the side chain oxygen of Ser70. In contrast to previous findings for the ESBL CTX-M-15, mass spectrometry provides no evidence for lysinoalanine crosslink formation on reaction of GES-1 with (enme)tazobactam, providing further evidence that PAS inhibitors inhibit different class A {beta}-lactamases by different mechanisms. This work reveals new details of the basis for PAS inhibition of diverse {beta}-lactamases, and will guide development of future {beta}-lactamase inhibitors.

biochemistry↗

bioRxiv2023

Abeta*56 is a stable oligomer that correlates with age-related memory loss in Tg2576 mice

Amyloid-{beta} (A{beta}) oligomers consist of fibrillar and non-fibrillar soluble assemblies of the A{beta} peptide. Tg2576 human amyloid precursor protein (APP)-expressing transgenic mice modeling Alzheimers disease produce A{beta}*56, a non-fibrillar A{beta} assembly that has been shown by several groups to relate more closely to memory deficits than plaques. Previous studies did not decipher specific forms of A{beta} present in A{beta}*56. Here, we confirm and extend the biochemical characterization of A{beta}*56. We used anti-A{beta}(1-x), anti-A{beta}(x-40), and A11 anti-oligomer antibodies in conjunction with western blotting, immunoaffinity purification, and size-exclusion chromatography to probe aqueous brain extracts from Tg2576 mice of different ages. We found that A{beta}*56 is a [~]56-kDa, SDS-stable, A11-reactive, non-plaque-related, water-soluble, brain-derived oligomer containing canonical A{beta}(1-40) that correlates with age-related memory loss. The unusual stability of this high molecular-weight oligomer renders it an attractive candidate for studying relationships between molecular structure and effects on brain function.

neuroscience↗

bioRxiv2021

A vaccine targeting the L9 epitope of the malaria circumsporozoite protein confers protection from blood-stage infection in a mouse challenge model

Pre-erythrocytic malaria vaccines that induce high-titer, durable antibody responses can potentially provide protection from infection. Here, we engineered a virus-like particle (VLP)-based vaccine targeting a recently described vulnerable epitope at the N-terminus of the central repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) that is recognized by the potently inhibitory monoclonal antibody L9 and show that immunization with L9 VLPs induces strong antibody responses that provide protection from blood-stage malaria in a mouse infection model.

immunology↗