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Gleicher N, Barad DH
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New insights into the effects of endometriosis on IVF

REPRODUCTIVE BIOMEDICINE ONLINE 2025 FEB; 50(2):? Article 104482
It is not uncommon that a published paper offers unintended insights, unnoticed by its authors. This was to a substantial degree the case with a recent publication addressing the effects of endometriosis on IVF. Using donor-recipient cycles as the study population to isolate recipient effects, the well-executed study demonstrated only mildly adverse outcome effects of endometriosis on IVF cycle outcomes, to a substantial degree laying to rest this still controversial issue. In the process, however, the study also raised some very interesting - but left undiscussed - insights into a host of other issues with considerable relevance to endometriosis and IVF practice in the USA and UK. These are the subject of this communication.
Sampath AJ, Westerkam LL, Blum FR, Alhusayen R, Bechara FG, Caffrey J, Carmon...
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Standardized Protocols for Clinical and Histopathological Characterization of...

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2025 JAN; 145(1):50-55
Methods for describing and reporting the clinical and histologic characteristics of cutaneous tissue samples from patients with hidradenitis suppurativa (HS) are not currently standardized, limiting clinicians' and scientists' ability to uniformly record, report, and communicate about the characteristics of tissue used in translational experiments. A recently published consensus statement outlined morphological definitions of typical HS lesions, but no consensus has been reached regarding clinical characterization and examination of HS tissue samples. In this study, we aimed to establish a protocol for reporting histopathologic and clinical characteristics of HS tissue specimens. This study was conducted from May 2023 to August 2023. Experts in clinical care, dermatopathology, and translational research were recruited, and a modified Delphi technique was used to develop a protocol for histologic reporting and clinical characterization of submitted tissue specimens from patients with HS. A total of 27 experts participated (14 dermatologists, 3 fellowship-trained dermatopathologists, 3 plastic surgeons, 3 general surgeons, and 4 research scientists) in creating and reviewing protocols for the clinical and histopathological examination of HS tissue specimens. The protocols were formatted as a synoptic report and will help to consistently classify specimens in biobanks on the basis of histologic features and more accurately report and select samples used in translational research projects.
Jeong S, Joh CSY, Lee S, Krueger JG, Chae JH, Kim HJ, Jo SJ
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Single-cell transcriptomic analysis of GPP patients treated with IL-12/23 or ...

JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY 2025 2025 MAR 25; ?(?):?
Tlusty T, Libchaber A
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Life sets off a cascade of machines

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2025 JAN 28; 122(4):? Article e2418000122
Life is invasive, occupying all physically accessible scales, stretching between almost nothing (protons, electrons, and photons) and almost everything (the whole biosphere). Motivated by seventeenth-century insights into this infinity, this paper proposes a language to discuss life as an infinite double cascade of machines making machines. Using this simplified language, we first discuss the micro-cascade proposed by Leibniz, which describes how the self-reproducing machine of the cell is built of smaller submachines down to the atomic scale. In the other direction, we propose that a macro-cascade builds from cells larger, organizational machines, up to the scale of the biosphere. The two cascades meet at the critical point of 103 s in time and 1 micron in length, the scales of a microbial cell. We speculate on how this double cascade evolved once a self-replicating machine emerged in the salty water of prebiotic earth.
Kenny TC, Scharenberg S, Abu-Remaileh M, Birsoy K
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Cellular and organismal function of choline metabolism

NATURE METABOLISM 2025 JAN; 7(1):35-52
Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation. Consistent with its pleiotropic role in cellular physiology, choline metabolism contributes to numerous developmental and physiological processes in the brain, liver, kidney, lung and immune system, and both choline deficiency and excess are implicated in human disease. Mutations in the genes encoding choline metabolism proteins lead to inborn errors of metabolism, which manifest in diverse clinical pathologies. While the identities of many enzymes involved in choline metabolism were identified decades ago, only recently has the field begun to understand the diverse mechanisms by which choline availability is regulated and fuelled via metabolite transport/recycling and nutrient acquisition. This review provides a comprehensive overview of choline metabolism, emphasizing emerging concepts and their implications for human health and disease.
Koide E, Pietz HL, Beltran J, Chen J
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Structural basis for the transport and regulation mechanism of the multidrug ...

NATURE COMMUNICATIONS 2025 JAN 8; 16(1):? Article 484
Multidrug resistance-associated protein 2 (MRP2) is an ATP-powered exporter important for maintaining liver homeostasis and a potential contributor to chemotherapeutic resistance. Using cryogenic electron microscopy (cryo-EM), we determine the structures of human MRP2 in three conformational states: an autoinhibited state, a substrate-bound pre-translocation state, and an ATP-bound post-translocation state. In the autoinhibited state, the cytosolic regulatory (R) domain plugs into the transmembrane substrate-binding site and extends into the cytosol to form a composite ATP-binding site at the surface of nucleotide-binding domain 2. Substrate displaces the R domain, permitting conformational changes necessary for transport. These observations suggest that the R domain functions as a selectivity gauge, where only at sufficiently high concentrations can the substrate effectively initiate transport. Comparative structural analyzes of MRP2 bound to various substrates, as determined in this study and others, reveal how MRP2 recognizes a diverse array of compounds, supporting its role in multidrug resistance.
Gong R, Reynolds MJ, Carney KR, Hamilton K, Bidone TC, Alushin GM
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Fascin structural plasticity mediates flexible actin bundle construction

NATURE STRUCTURAL & MOLECULAR BIOLOGY 2025 2025 JAN 20; ?(?):?
Fascin cross-links actin filaments (F-actin) into bundles that support tubular membrane protrusions including filopodia and stereocilia. Fascin dysregulation drives aberrant cell migration during metastasis, and fascin inhibitors are under development as cancer therapeutics. Here, we use cryo-EM, cryo-electron tomography coupled with custom denoising and computational modeling to probe human fascin-1's F-actin cross-linking mechanisms across spatial scales. Our fascin cross-bridge structure reveals an asymmetric F-actin binding conformation that is allosterically blocked by the inhibitor G2. Reconstructions of seven-filament hexagonal bundle elements, variability analysis and simulations show how structural plasticity enables fascin to bridge varied interfilament orientations, accommodating mismatches between F-actin's helical symmetry and bundle hexagonal packing. Tomography of many-filament bundles and modeling uncover geometric rules underlying emergent fascin binding patterns, as well as the accumulation of unfavorable cross-links that limit bundle size. Collectively, this work shows how fascin harnesses fine-tuned nanoscale structural dynamics to build and regulate micron-scale F-actin bundles.
Cuevas-Navarro A, Pourfarjam Y, Hu F, Rodriguez DJ, Vides A, Sang B, Fan SJ, ...
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Pharmacological restoration of GTP hydrolysis by mutant RAS

NATURE 2025 JAN 2; 637(8044):?
Approximately 3.4 million patients worldwide are diagnosed each year with cancers that have pathogenic mutations in one of three RAS proto-oncogenes (KRAS, NRAS and HRAS)1,2. These mutations impair the GTPase activity of RAS, leading to activation of downstream signalling and proliferation3, 4, 5-6. Long-standing efforts to restore the hydrolase activity of RAS mutants have been unsuccessful, extinguishing any consideration towards a viable therapeutic strategy7. Here we show that tri-complex inhibitors-that is, molecular glues with the ability to recruit cyclophilin A (CYPA) to the active state of RAS-have a dual mechanism of action: not only do they prevent activated RAS from binding to its effectors, but they also stimulate GTP hydrolysis. Drug-bound CYPA complexes modulate residues in the switch II motif of RAS to coordinate the nucleophilic attack on the gamma-phosphate of GTP in a mutation-specific manner. RAS mutants that were most sensitive to stimulation of GTPase activity were more susceptible to treatment than mutants in which the hydrolysis could not be enhanced, suggesting that pharmacological stimulation of hydrolysis potentiates the therapeutic effects of tri-complex inhibitors for specific RAS mutants. This study lays the foundation for developing a class of therapeutics that inhibit cancer growth by stimulating mutant GTPase activity.
Torrente D, Su EJ, Citalán-Madrid AF, Schielke GP, Magaoay D, Warnock M, Stev...
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The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegenera...

JOURNAL OF NEUROINFLAMMATION 2025 JAN 14; 22(1):? Article 8
The thrombolytic protease tissue plasminogen activator (tPA) is expressed in the CNS, where it regulates diverse functions including neuronal plasticity, neuroinflammation, and blood-brain-barrier integrity. However, its role in different brain regions such as the substantia nigra (SN) is largely unexplored. In this study, we characterize tPA expression, activity, and localization in the SN using a combination of retrograde tracing and beta-galactosidase tPA reporter mice. We further investigate tPA's potential role in SN pathology in an alpha-synuclein mouse model of Parkinson's disease (PD). To characterize the mechanism of tPA action in alpha-synuclein-mediated pathology in the SN and to identify possible therapeutic pathways, we performed RNA-seq analysis of the SN and used multiple transgenic mouse models. These included tPA deficient mice and two newly developed transgenic mice, a knock-in model expressing endogenous levels of proteolytically inactive tPA (tPA Ala-KI) and a second model overexpressing proteolytically inactive tPA (tPA Ala-BAC). Our findings show that striatal GABAergic neurons send tPA+ projections to dopaminergic (DA)-neurons in the SN and that tPA is released from SN-derived synaptosomes upon stimulation. We also found that tPA levels in the SN increased following alpha-synuclein overexpression. Importantly, tPA deficiency protects DA-neurons from degeneration, prevents behavioral deficits, and reduces microglia activation and T-cell infiltration induced by alpha-synuclein overexpression. RNA-seq analysis indicates that tPA in the SN is required for the upregulation of genes involved in the innate and adaptive immune responses induced by alpha-synuclein overexpression. Overexpression of alpha-synuclein in tPA Ala-KI mice, expressing only proteolytically inactive tPA, confirms that tPA-mediated neuroinflammation and neurodegeneration is independent of its proteolytic activity. Moreover, overexpression of proteolytically inactive tPA in tPA Ala-BAC mice leads to increased neuroinflammation and neurodegeneration compared to mice expressing normal levels of tPA, suggesting a tPA dose response. Finally, treatment of mice with glunomab, a neutralizing antibody that selectively blocks tPA binding to the N-methyl-D-aspartate receptor-1 (NMDAR1) without affecting NMDAR1 ion channel function, identifies the tPA interaction with NMDAR1 as necessary for tPA-mediated neuroinflammation and neurodegeneration in response to alpha-synuclein-mediated neurotoxicity. Thus, our data identifies a novel pathway that promotes DA-neuron degeneration and suggests a potential therapeutic intervention for PD targeting the tPA-NMDAR1 interaction.
Brewer JJ, Inlow K, Mooney RA, Bosch B, Olinares PDB, Marcelino LP, Chait BT,...
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RapA opens the RNA polymerase clamp to disrupt post-termination complexes and...

NATURE STRUCTURAL & MOLECULAR BIOLOGY 2025 2025 JAN 8; ?(?):?
Following transcript release during intrinsic termination, Escherichia coli RNA polymerase (RNAP) often remains associated with DNA in a post-termination complex (PTC). RNAPs in PTCs are removed from the DNA by the SWI2/SNF2 adenosine triphosphatase (ATPase) RapA. Here we determined PTC structures on negatively supercoiled DNA and with RapA engaged to dislodge the PTC. We found that core RNAP in the PTC can unwind DNA and initiate RNA synthesis but is prone to producing R-loops. Nucleotide binding to RapA triggers a conformational change that opens the RNAP clamp, allowing DNA in the RNAP cleft to reanneal and dissociate. We show that RapA helps to control cytotoxic R-loop formation in vivo, likely by disrupting PTCs. We suggest that analogous ATPases acting on PTCs to suppress transcriptional noise and R-loop formation may be widespread. These results hold importance for the bacterial transcription cycle and highlight a role for RapA in maintaining genome stability.