
Blood biomarkers amyloid beta (Aβ) and tau protein are highly accurate in identifying Alzheimer's disease (AD) in patients with cognitive symptoms, outperforming clinical evaluations by primary care physicians and dementia specialists.


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Blood biomarkers for Alzheimer's disease were highly accurate in identifying Alzheimer's disease in patients with cognitive symptoms attending primary and secondary care clinics.

Blood Biomarkers Highly Accurate in Diagnosing Alzheimer's

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Highly Accurate Blood Biomarkers for Diagnosing Alzheimer's Disease in Primary and Specialty Care Settings


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Urine tests could provide a convenient, pain-free, and cost-effective way to detect and monitor various cancers, offering an "enormous step" in reducing cancer mortality.


Emerging science suggests urine tests could offer a convenient, cost-effective way to spot hard-to-detect cancers.

Urine Tests Could Be 'Enormous Step' in Diagnosing Cancer

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Urine Tests: A Promising Frontier in Early Cancer Detection and Monitoring



DePARylation of S phase pADPr by PARG is essential for cell viability.


Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.

### Competing Interest Statement

The authors have declared no competing interest.

DePARylation is critical for S phase progression and cell survival

deparylation-s-role-in-s-phase-progression-and-cell-survival


DePARylation's Role in S Phase Progression and Cell Survival



ICAM-1 regulates hepatic epithelial cell polarity through actomyosin control, independent of leukocyte adhesion.


Epithelial Intercellular Adhesion Molecule (ICAM)-1 is apically polarized, interacts with and guides leukocytes across epithelial barriers. Polarized hepatic epithelia organize their apical membrane domain into bile canaliculi and ducts, which are not accessible to circulating immune cells but that nevertheless confine most of ICAM-1. Here, by analyzing ICAM-1\_KO human hepatic cells, liver organoids from ICAM-1\_KO mice and rescue-of-function experiments, we show that ICAM-1 regulates epithelial apicobasal polarity in a leukocyte adhesion-independent manner. ICAM-1 signals to an actomyosin network at the base of canalicular microvilli, thereby controlling the dynamics and size of bile canalicular-like structures (BCs). We identified the scaffolding protein EBP50/NHERF1/SLC9A3R1, which connects membrane proteins with the underlying actin cytoskeleton, in the proximity interactome of ICAM-1. EBP50 and ICAM-1 form nano-scale domains that overlap in microvilli, from which ICAM-1 regulates EBP50 nano-organization. Indeed, EBP50 expression is required for ICAM-1-mediated control of BC morphogenesis and actomyosin. Our findings indicate that ICAM-1 regulates the dynamics of epithelial apical membrane domains beyond its role as a heterotypic cell-cell adhesion molecule and reveal potential therapeutic strategies for preserving epithelial architecture during inflammatory stress.

### Competing Interest Statement

The authors have declared no competing interest.

ICAM-1 nanoclusters regulate hepatic epithelial cell polarity by leukocyte adhesion-independent control of apical actomyosin

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ICAM-1 Regulation of Hepatic Epithelial Cell Polarity



Imbalanced expression of eIF3 subunits affects translation efficiency and MAPK signaling pathway.


Protein synthesis plays a major role in homeostasis and when dysregulated leads to various pathologies including cancer. To this end, imbalanced expression of eukaryotic translation initiation factors (eIFs) is not only a consequence but also a driver of neoplastic growth. eIF3 is the largest, multi-subunit translation initiation complex with a modular assembly, where aberrant expression of one subunit generates only partially functional subcomplexes. To comprehensively study the effects of eIF3 remodeling, we contrasted the impact of eIF3d, eIF3e or eIF3h depletion on the translatome of HeLa cells using Ribo-seq. Depletion of eIF3d or eIF3e, but not eIF3h reduced the levels of multiple components of the MAPK signaling pathway. Surprisingly, however, depletion of all three eIF3 subunits increased MAPK pathway activity. Depletion of eIF3e and partially eIF3d also increased translation of TOP mRNAs that encode mainly ribosomal proteins and other components of the translational machinery. Moreover, alterations in eIF3 subunit stoichiometry were often associated with changes in translation of mRNAs containing short uORFs, as in the case of the proto-oncogene MDM2 and the transcription factor ATF4. Collectively, perturbations in eIF3 subunit stoichiometry exert specific effect on the translatome comprising signaling and stress-related transcripts with complex 5’ UTRs that are implicated in homeostatic adaptation to stress and cancer.

### Competing Interest Statement

The authors have declared no competing interest.

Perturbations in eIF3 subunit stoichiometry alter expression of ribosomal proteins and key components of the MAPK signaling pathway

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Impact of eIF3e and eIF3d on Translatome and MAPK Signaling Pathway



Understanding the mechanism behind dimer selectivity and binding cooperativity of BRAF inhibitors is crucial for developing effective cancer treatments.


Aberrant signaling of BRAFV600E is a major cancer driver. Current FDA-approved RAF inhibitors selectively inhibit the monomeric BRAFV600E and suffer from tumor resistance. Recently, dimer-selective and equipotent RAF inhibitors have been developed; however, the mechanism of dimer selectivity is poorly understood. Here, we report extensive molecular dynamics (MD) simulations of the monomeric and dimeric BRAFV600E in the apo form or in complex with one or two dimer-selective (PHI1) or equipotent (LY3009120) inhibitor(s). The simulations uncovered the unprecedented details of the remarkable allostery in BRAFV600E dimerization and inhibitor binding. Specifically, dimerization retrains and shifts the α C helix inward and increases the flexibility of the DFG motif; dimer compatibility is due to the promotion of the α C-in conformation, which is stabilized by a hydrogen bond formation between the inhibitor and the α C Glu501. A more stable hydrogen bond further restrains and shifts the α C helix inward, which incurs a larger entropic penalty that disfavors monomer binding. This mechanism led us to propose an empirical way based on the co-crystal structure to assess the dimer selectivity of a BRAFV600E inhibitor. Simulations also revealed that the positive cooperativity of PHI1 is due to its ability to preorganize the α C and DFG conformation in the opposite protomer, priming it for binding the second inhibitor. The atomically detailed view of the interplay between BRAF dimerization and inhibitor allostery as well as cooperativity has implications for understanding kinase signaling and contributes to the design of protomer selective RAF inhibitors.

### Competing Interest Statement

The authors have declared no competing interest.

Mechanism of Dimer Selectivity and Binding Cooperativity of BRAF inhibitors

mechanism-of-dimer-selectivity-and-binding-cooperativity-of-braf-inhibitors


Mechanism of Dimer Selectivity and Binding Cooperativity of BRAF Inhibitors



Nellie introduces an automated pipeline for organelle segmentation, tracking, and feature extraction in live-cell microscopy.


nellie-automated-organelle-segmentation-and-feature-extraction-in-live-cell-microscopy


Nellie: Automated Organelle Segmentation and Feature Extraction in Live-Cell Microscopy



Cyclophilin A plays a crucial role in DNA repair, impacting genomic stability and influencing homologous recombination repair following replication fork stalling.


We previously reported that non-homologous end-joining (NHEJ)-defective human LIG4 -/- pre-B lymphocytes were unexpectedly sensitive to killing by the cyclic peptide Cyclosporin A (CsA), a common component of bone marrow transplantation conditioning and maintenance regimes. We also found that CsA induced DNA double strand breaks (DSBs) in LIG4 syndrome patient fibroblasts, specifically upon transit through S-phase. The molecular basis underlying these CsA impacts has not been described hitherto. We postulated that CsA-induced genomic instability may reflect a direct role of Cyclophilin A (CYPA) in DNA repair, as CYPA is the primary physiological target interactor of CsA.

CYPA is the founding member of the Cyclophilin family of peptidyl-prolyl cis-trans isomerases (PPIs). CsA inhibits the PPI activity of CYPA through occupation of the latter’s enzymatic active site. Using an integrated approach involving CRISPR/Cas9-engineering, siRNA, BioID, co-immunoprecipitation, pathway-specific DNA repair investigations as well as protein expression-interaction analysis, we describe novel impacts of CYPA loss and inhibition of its PPI activity on DNA repair. Prompted by findings from our CYPA-BioID proximity interactome, we validate CYPA interactions with different components of the DNA end resection machinery. Moreover, we characterise a novel and direct CYPA interaction with the NBS1 component of the MRE11-RAD50-NBS1 (MRN) complex, providing evidence that the PPI function of CYPA actively influences DNA repair via direct protein-protein interaction at the level of DNA end resection. Consequently, we demonstrate that CYPA loss or inhibition impairs Homologous Recombination Repair (HRR) following DNA replication fork stalling.

Additionally, we define a set of genetic vulnerabilities associated with CYPA loss and inhibition, identifying DNA replication fork protection as an important determinant of viability herein. Leveraging the novel insights into CYPA biology we have uncovered; we explore examples of how CYPA PPI inhibition may be exploited to selectively kill cells from a variety of different cancers with a shared characteristic genomic instability profile. These findings propose a potential new disease application or repurposing strategy for the non-immunosuppressive CsA analogue class of Cyclophilin inhibitors.

### Competing Interest Statement

The authors have declared no competing interest.

A novel role for the peptidyl-prolyl cis-trans isomerase Cyclophilin A in DNA-repair following replication fork stalling via the MRE11-RAD50-NBS1 complex

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The Role of Cyclophilin A in DNA Repair



The authors propose a transfer learning approach pre-trained on transcriptomic data to control cell behavior, addressing challenges in reprogramming strategies by minimizing transcriptional differences between initial and target states.


cell-reprogramming-design-using-transfer-learning-of-functional-transcriptional-networks


Cell Reprogramming Design Using Transfer Learning of Functional Transcriptional Networks



The author explores the activation mechanism of Polycystin-1 (PC1) signaling through the binding of stalk-derived peptide agonists, shedding light on potential therapeutic targets for autosomal dominant polycystic kidney disease (ADPKD).


Polycystin-1 (PC1) is the membrane protein product of the PKD1 gene whose mutation is responsible for 85% of the cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is primarily characterized by the formation of renal cysts and potential kidney failure. PC1 is an atypical G protein-coupled receptor (GPCR) consisting of 11 transmembrane helices and an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal (NTF) and membrane-embedded C-terminal (CTF) fragments. Recently, signaling activation of the PC1 CTF was shown to be regulated by a stalk tethered agonist (TA), a distinct mechanism observed in the adhesion GPCR family. A novel allosteric activation pathway was elucidated for the PC1 CTF through a combination of Gaussian accelerated molecular dynamics (GaMD), mutagenesis and cellular signaling experiments. Here, we show that synthetic, soluble peptides with 7 to 21 residues derived from the stalk TA, in particular, peptides including the first 9 residues (p9), 17 residues (p17) and 21 residues (p21) exhibited the ability to re-activate signaling by a stalkless PC1 CTF mutant in cellular assays. To reveal molecular mechanisms of stalk peptide-mediated signaling activation, we have applied a novel Peptide GaMD (Pep-GaMD) algorithm to elucidate binding conformations of selected stalk peptide agonists p9, p17 and p21 to the stalkless PC1 CTF. The simulations revealed multiple specific binding regions of the stalk peptide agonists to the PC1 protein including an “intermediate” bound yet inactive state. Our Pep-GaMD simulation findings were consistent with the cellular assay experimental data. Binding of peptide agonists to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of the PC1 CTF signaling activation mechanism. Using sequence covariation analysis of PC1 homologs, we further showed that the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. Therefore, structural dynamic insights into the mechanisms of PC1 activation by stalk-derived peptide agonists have enabled an in-depth understanding of PC1 signaling. They will form a foundation for development of PC1 as a therapeutic target for the treatment of ADPKD.

### Competing Interest Statement

The authors have declared no competing interest.

Activation of Polycystin-1 Signaling by Binding of Stalk-derived Peptide Agonists

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Activation of Polycystin-1 Signaling by Stalk-Derived Peptide Agonists
