bioRxiv : the preprint server for biology最新文献

{"title":"Therapeutic assessment of a novel mitochondrial complex I inhibitor in <i>in vitro</i> and <i>in vivo</i> models of Alzheimer's disease.","authors":"Sergey Trushin, Thi Kim Oanh Nguyen, Andrea Stojacovic, Mark Ostroot, J Trey Deason, Su-Youne Chang, Liang Zhang, Slobodan I Macura, Toshihiko Nambara, Wenyan Lu, Takahisa Kanekiyo, Eugenia Trushina","doi":"10.1101/2025.02.12.637918","DOIUrl":"10.1101/2025.02.12.637918","url":null,"abstract":"<p><p>Despite recent approval of monoclonal antibodies that reduce amyloid (Aβ) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimer's disease (AD) is urgently needed. We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signaling, benefiting AD mouse models with Aβ and p-Tau pathologies. Rational design and structure‒activity relationship studies yielded novel mtCI inhibitors profiled in a drug discovery funnel designed to address their safety, selectivity, and efficacy. The new lead compound C458 is highly protective against Aβ toxicity, has favorable pharmacokinetics, and has minimal off-target effects. C458 exhibited excellent brain penetrance, activating neuroprotective pathways with a single dose. Preclinical studies in APP/PS1 mice were conducted via functional tests, metabolic assessment, <i>in vivo</i> ³¹ P- NMR spectroscopy, blood cytokine panels, <i>ex vivo</i> electrophysiology, and Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis, antioxidant signaling, and cellular energetics. These studies provide further evidence that the restoration of mitochondrial function and brain energetics in response to mild energetic stress represents a promising disease- modifying strategy for AD.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metal ion requirement for catalysis by 3'-5' RNA polymerases.","authors":"Brandon W J Iwaniec, Madison M Allegretti, Jane E Jackman","doi":"10.1101/2025.03.21.644660","DOIUrl":"https://doi.org/10.1101/2025.03.21.644660","url":null,"abstract":"<p><p>The two-metal ion mechanism for catalysis of RNA and DNA synthesis by 5'-3' polymerases has been extensively characterized. The 3'-5' polymerase family of enzymes, consisting of tRNA ^His guanylyltransferase (Thg1) and Thg1-like proteins (TLPs), perform a similar nucleotide addition reaction, but in the reverse direction, adding Watson-Crick base paired NTPs to the 5'-ends of RNA substrates, yet the effect of divalent cations beyond magnesium has not been described. Here, we examined the effects of five divalent cations (Mg ²⁺ , Mn ²⁺ , Co ²⁺ , Ni ²⁺ and Ca ²⁺ ) on templated nucleotide addition activity and kinetics of 5'-activation by ATP catalyzed by recombinantly purified, metal-free TLPs from organisms from diverse domains of life. This work revealed that different TLPs exhibit distinct dependencies on the concentration and identity of divalent metal ions that support effective catalysis. The patterns of metal ion usage demonstrated here for TLPs evince features that are characteristic of both canonical 5'-3' polymerases and DNA/RNA ligases. Similar to 5'-3' polymerases, some metals were also seen to be mutagenic in the context of TLP catalysis. Furthermore, we provide the first direct evidence that both ATP and the NTP poised for nucleotidyl transfer are present in the active site during the 5'-adenylylation. These results provide the first in-depth study of the role of the two-metal ion mechanism in TLP catalysis that was first suggested by structures of these enzymes.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic acid signaling guides the efficiency of inner ear organoid-genesis and governs sensory-nonsensory fate specification.","authors":"R Keith Duncan, Liqian Liu, Mo Moyer, Andrew Wylie, Ranya Dano, Luis Cassinotti","doi":"10.1101/2025.03.21.644434","DOIUrl":"https://doi.org/10.1101/2025.03.21.644434","url":null,"abstract":"<p><p>Inner ear organoid development-from germ layer to otocyst formation-relies on timed chemical cues to recapitulate major signals <i>in vivo.</i> In contrast, later stages of differentiation-from otic vesicle (OV) to organoid formation-are self-guided, even though these stages are modulated by several key morphogens <i>in vivo</i> . We sought to elucidate additional morphogens that might improve culture efficiency and influence cell fate decisions. Using a whole-transcriptomic approach, we identified major differences in native and stem cell-derived OVs related to anterior-posterior patterning and retinoic acid (RA) signaling. Increasing the level of RA during OV formation in these cultures modulated organoid efficiency, increased nonsensory markers, decreased sensory markers, and decreased hair cell production. The organoid culture platform mimics the exquisite RA sensitivity found in normal inner ear development and may help identify RA-responsive genes driving organogenesis and cell fate specification.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex Differences in Cancer Functional Genomics: Gene Dependency and Drug Sensitivity.","authors":"Nicole Zeltser, Chenghao Zhu, Jieun Oh, Constance H Li, Paul C Boutros","doi":"10.1101/2025.02.05.636540","DOIUrl":"10.1101/2025.02.05.636540","url":null,"abstract":"<p><p>Patient sex influences a wide range of cancer phenotypes, including prevalence, response to therapy and survival endpoints. Molecular sex differences have been identified at all levels of the central dogma. It is hypothesized that these molecular differences may drive the observed clinical sex differences. Yet despite a growing catalog of molecular sex differences in a range of cancer types, their specific functional consequences remain unclear. To directly assess how patient sex impacts cancer cell function, we evaluated 1,209 cell lines subjected to CRISPR knockout, RNAi knockdown or drug exposures. Despite limited statistical power, we identified pan- and per-cancer sex differences in gene essentiality in six sex-linked and fourteen autosomal genes, and in drug sensitivity for two compounds. These data fill a gap in our understanding of the link between sex-differential molecular effects and patient phenotypes. They call for much more careful and systematic consideration of sex-specific effects in mechanistic and functional studies.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Satellite 3 DNA encodes megabase-scale transcription factor binding platforms.","authors":"J Matthew Franklin, Danilo Dubocanin, Cy Chittenden, Ashlie Barillas, Rosa Jooyoung Lee, Rajarshi P Ghosh, Jennifer L Gerton, Kun-Liang Guan, Nicolas Altemose","doi":"10.1101/2024.10.22.616524","DOIUrl":"10.1101/2024.10.22.616524","url":null,"abstract":"<p><p>Eukaryotic genomes frequently contain large arrays of tandem repeats, called satellite DNA. While some satellite DNAs participate in centromere function, others do not. For example, Human Satellite 3 (HSat3) forms the largest satellite DNA arrays in the human genome, but these multi-megabase regions were almost fully excluded from genome assemblies until recently, and their potential functions remain understudied and largely unknown. To address this, we performed a systematic screen for HSat3 binding proteins. Our work revealed that HSat3 contains millions of copies of transcription factor (TF) motifs bound by over a dozen TFs from various signaling pathways, including the growth-regulating transcription effector family TEAD1-4 from the Hippo pathway. Imaging experiments show that TEAD recruits the co-activator YAP to HSat3 regions in a cell-state specific manner. Using synthetic reporter assays, targeted repression of HSat3, inducible degradation of YAP, and super-resolution microscopy, we show that HSat3 arrays can localize YAP/TEAD inside the nucleolus, enhancing RNA Polymerase I activity. Beyond discovering a direct relationship between the Hippo pathway and ribosomal DNA regulation, this work demonstrates that satellite DNA can encode multiple transcription factor binding motifs, defining an important functional role for these enormous genomic elements.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vivo</i> validation of the palmitoylation cycle as a therapeutic target in <i>NRAS</i> -mutant cancer.","authors":"Matthew Decker, Benjamin J Huang, Timothy Ware, Christopher Boone, Michelle Tang, Julia Ybarra, Aishwarya C Ballapuram, Katrine A Taran, Pan-Yu Chen, Marcos Amendáriz, Camille J Leung, Max Harris, Karensa Tjoa, Henry Hongo, Sydney Abelson, Jose Rivera, Nhi Ngo, Dylan M Herbst, Radu M Suciu, Carlos Guijas, Kimia Sedighi, Taylor Andalis, Elysia Roche, Boer Xie, Yunlong Liu, Catherine C Smith, Elliot Stieglitz, Micah J Niphakis, Benjamin F Cravatt, Kevin Shannon","doi":"10.1101/2025.03.20.644389","DOIUrl":"https://doi.org/10.1101/2025.03.20.644389","url":null,"abstract":"<p><p>Normal and oncogenic Ras proteins are functionally dependent on one or more lipid modifications ^1,2 . Whereas K-Ras4b farnesylation is sufficient for stable association with the plasma membrane, farnesylated H-Ras, K-Ras4a, and N-Ras traffic to the Golgi where they must undergo palmitoylation before regulated translocation to cell membranes. N-Ras palmitoylation by the DHHC family of palmitoyl acyl transferases (PATs) and depalmitoylation by ABHD17 serine hydrolases is a dynamic process that is essential for the growth of acute myeloid leukemias (AMLs) harboring oncogenic <i>NRAS</i> mutations ^3-6 . Here, we have tested whether co-targeting ABHD17 enzymes and Ras signal output would cooperatively inhibit the proliferation and survival of <i>NRAS</i> -mutant AMLs while sparing normal tissues that retain K-Ras4b function. We show that ABD778, a potent and selective ABHD17 inhibitor with <i>in vivo</i> activity, selectively reduces the growth of <i>NRAS</i> -mutant AML cells <i>in vitro</i> and is synergistic with the allosteric MEK inhibitor PD0325901 (PD901) ^7,8 . Similarly, ABD778 and PD901 significantly extended the survival of recipient mice transplanted with three independent primary mouse AMLs harboring an oncogenic <i>Nras ^G12D</i> driver mutation. Resistant leukemias that emerged during continuous drug treatment acquired by-pass mutations that confer adaptive drug resistance and increase mitogen activated protein kinase (MAPK) signal output. ABD778 augmented the anti-leukemia activity of the pan-PI3 kinase inhibitor pictilisib ⁹ , the K/N-Ras ^G12C inhibitor sotorasib ¹⁰ , and the FLT3 inhibitor gilteritinib ¹¹ . Co-treatment with ABD778 and gilteritinib restored drug sensitivity in a patient-derived xenograft model of adaptive resistance to FLT3 inhibition. These data validate the palmitoylation cycle as a promising therapeutic target in AML and support exploring it in other <i>NRAS</i> -mutant cancers.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAS mutation-specific signaling dynamics in response to paralog- and state- selective RAS inhibitors.","authors":"Beau Baars, Ana Orive-Ramos, Ziyue Kou, Bijaya Gaire, Mathieu Desaunay, Christos Adamopoulos, Stuart A Aaronson, Shaomeng Wang, Evripidis Gavathiotis, Poulikos I Poulikakos","doi":"10.1101/2025.02.14.638317","DOIUrl":"https://doi.org/10.1101/2025.02.14.638317","url":null,"abstract":"&lt;p&gt;&lt;p&gt;A high therapeutic index (TI), balancing potent oncogenic signaling inhibition in tumor cells with minimal effects on normal cells, is critical for effective cancer therapies. Recent advances have introduced diverse RAS-targeting inhibitors, including mutant-specific inhibitors (e.g., KRAS(G12C) and KRAS(G12D)), as well as paralog- and state-selective inhibitors. Non-mutant-specific RAS inhibition can be accomplished by 1) panRAS-GEF(OFF) inhibitors which inactivate RAS indirectly by inhibiting SHP2 or SOS1, thereby blocking the nucleotide exchange step of RAS activation, 2) direct KRAS(OFF)-selective inhibitors sparing NRAS and HRAS, and 3) panRAS(ON) inhibitors that directly target active RAS, by occluding binding of its effector RAF. However, the signaling inhibition index (SII) - the differential inhibition of oncogenic signaling between RAS-mutant (RAS(MUT)) and normal cells - remains poorly defined for these approaches. In this study, we evaluated the SII of state- and paralog-selective RAS inhibitors across diverse RAS-mutant (RAS(MUT)) and RAS-wild-type (RAS(WT)) models. PanRAS-GEF(OFF) inhibitors exhibited neutral or negative SII, with comparable or reduced MAPK suppression in KRAS(G12X) cells relative to RAS(WT) cells. KRAS(G13D) models showed low sensitivity (negative SII) to panRAS-GEF(OFF) inhibitors, particularly in the context of NF1 loss. Combination treatments with SHP2 and MEK inhibitors resulted in low SII, as pathway suppression was similar in RAS(MUT) and RAS(WT) cells. Furthermore, RAS(Q61X) models were resistant to combined SHP2 inhibitor+MEK inhibitor due to dual mechanisms: MEK inhibitor-induced NRAS(Q61X) reactivation and RAS(MUT)-induced SHP2 conformations impairing inhibitor binding. Overall, panRAS-GEF(OFF) inhibitors exhibited the lowest SII. PanKRAS(OFF) inhibitors demonstrated a higher SII, while panRAS(ON) inhibitors displayed broader activity but relatively narrow SII. We observed that tumors that were sensitive to RAS(MUT)-specific inhibitors, were also sensitive to the state-selective RAS inhibitors (OFF, or ON). In fact, all RAS inhibitors (mutant-specific and state- or paralog-selective) were active in the same portion of RAS(MUT) models, while the majority of RAS(MUT) cell lines were insensitive to all of them. These findings reveal significant SII variability among RAS-targeted inhibitors, depending on the specific RAS driver mutation and cell context and underscore the importance of incorporating SII considerations into the design and clinical application of RAS-targeted therapies to improve therapeutic outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main points: &lt;/strong&gt;&lt;b&gt;PanRAS-GEF(OFF) inhibitors have limited SII and effectiveness:&lt;/b&gt; The Signaling Inhibition Index (SII) - i.e. the differential inhibition of oncogenic signaling between tumor and normal cells - was neutral or negative for panRAS-GEF(OFF) inhibitors, with comparable or reduced MAPK suppression in KRAS(G12X) mutant versus RAS(WT) cells. KRAS(G13D) models","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The bacterial chaperone CsgC inhibits functional amyloid CsgA formation by promoting the intrinsically disordered pre-nuclear state.","authors":"Anthony Balistreri, Divya Kolli, Sanduni Wasana Jayaweera, Daniel Lundahl, Yilin Han, Lily Kalcec, Emily Goetzler, Rachel Alessio, Brandon Ruotolo, Anders Olofsson, Matthew R Chapman","doi":"10.1101/2025.03.21.644623","DOIUrl":"https://doi.org/10.1101/2025.03.21.644623","url":null,"abstract":"<p><p><i>E. coli</i> secretes a functional amyloid called curli during biofilm formation. Curli fibers are composed of polymers of the CsgA protein, which adopts a beta-sheet rich fold upon fibrillization. A chaperone-like protein called CsgC inhibits CsgA amyloid formation. Like other amyloidogenic proteins, CsgA undergoes a 3-stage aggregation process: an initial lag phase where a beta-rich nucleus forms, an exponential elongation phase, and a plateau phase. It is currently not known if CsgC inhibits amyloid formation by inhibiting formation of the pre-fibril nucleus, or rather, if CsgC inhibits a later stage of amyloid formation by blocking monomer addition to a growing fiber. Here, CsgC homologs from <i>C. youngae</i> , <i>C. davisae</i> , and <i>H. alvei</i> were purified and characterized for their ability to interrogate CsgA amyloid formation. Each of the CsgC homologs prolonged the lag phase of <i>E. coli</i> CsgA amyloid formation in a similar fashion as <i>E. coli</i> CsgC. Additionally, we found that <i>E. coli</i> CsgC interacted transiently and weakly with a monomeric, pre-nucleus species of CsgA and that this interaction delayed amyloid formation. A transient CsgC-CsgA heterodimer was observed using ion mobility-mass spectrometry. When CsgC was added to actively polymerizing CsgA, exponential growth commonly associated with nucleation-dependent amyloid formation was lost. However, the addition of preformed CsgA seeds did not rescue exponential growth indicating that CsgC also has inhibitory activity during fibril elongation. Indeed, CsgC interacted strongly with CsgA fibers, suggesting that the interaction between CsgC and CsgA fibers can slow new fiber growth. CsgC displays a unique inhibitory activity at multiple stages of amyloid formation. CsgC acts as an energy-independent chaperone that transiently interacts with prefibrillar CsgA as well as an amyloid fiber.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gyral crowns contribute to the cortical infrastructure of human face processing.","authors":"Ethan H Willbrand, Joseph P Kelly, Xiayu Chen, Zonglei Zhen, Guo Jiahui, Brad Duchaine, Kevin S Weiner","doi":"10.1101/2025.03.20.644439","DOIUrl":"https://doi.org/10.1101/2025.03.20.644439","url":null,"abstract":"<p><p>Neuroanatomical features across spatial scales contribute to functional specialization and individual differences in behavior across species. Among species with gyrencephalic brains, gyral crown height, which measures a key aspect of the morphology of cortical folding, may represent an anatomical characteristic that importantly shapes neural function. Nevertheless, little is known about the relationship between functional selectivity and gyral crowns-especially in clinical populations. Here, we investigated this relationship and found that the size and gyral crown height of the middle, but not posterior, face-selective region on the fusiform gyrus (FG) was smaller in individuals with developmental prosopagnosia (DPs; <i>N</i> = 22, 68% female, aged 25-62) compared to neurotypical controls (NTs; <i>N =</i> 25, 60% females, aged 21-55), and this difference was related to face perception. Additional analyses replicated the relationship between gyral crowns and face selectivity in 1,053 NTs (55% females, aged 22-36). These results inform theoretical models of face processing while also providing a novel neuroanatomical feature contributing to the cortical infrastructure supporting face processing.</p><p><strong>Significance statement: </strong>Understanding how brain structure supports specialized brain functions is a central goal of neuroscience. Here, we identified a role of gyral crown height-an understudied cortical feature-in shaping the cortical infrastructure underlying face processing. By examining face-selective regions of the fusiform gyrus in both neurotypical individuals and those with developmental prosopagnosia, we demonstrate that reduced gyral crown height is associated with diminished face-selective region surface area and impaired face recognition ability. Furthermore, this structural-functional relationship extends to a large neurotypical sample of over 1,000 individuals, highlighting a generalizable link between cortical anatomy and functional specialization. These findings introduce a new neuroanatomical factor to theoretical models of face perception, which could extend to additional neurodevelopmental disorders and other cognitive tasks.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of housing conditions and social behavior on methamphetamine self-administration in male and female rats.","authors":"Ivette L Gonzalez, Ammar F Chauhdri, Reily J Nessen, Kristin Lee, Jill B Becker","doi":"10.1101/2025.02.21.639469","DOIUrl":"10.1101/2025.02.21.639469","url":null,"abstract":"<p><p>Social support is a potentially protective factor against substance use disorders (SUDs). Previous studies in animal models for SUDs have shown that when females are pair housed, they have lower motivation for cocaine and methamphetamine (METH) than females who are single housed. In males, however, social housing has not had the same beneficial effect. This study investigates effects of social housing on METH self-administration in females or males when both cage mates are self-administering METH. The study also investigated how the quality of the relationships changed after METH self-administration. The results show that singly housed females self-administered more METH than socially housed females, while males in both social housing conditions self-administered METH at the same rate. The social behavior data showed that females given saline spent more time apart, however the females given METH spent more time together, suggesting that their social behavior may play a role in the attenuation of METH self-administration. Males' social behavior remained unchanged after METH and the dominant male in a pair self-administered more METH than the non-dominant male. Females' self-administration was not affected by dominance. The results of this study show that social housing provides some protective benefits to females, but not males, for METH self-administration. Further, the type of relationship between cage mates affects males' self-administration and may explain why social housing with a same sex mate is not beneficial for males.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}