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Nature Communications Jun 2024Accurately building 3D atomic structures from cryo-EM density maps is a crucial step in cryo-EM-based protein structure determination. Converting density maps into 3D...
Accurately building 3D atomic structures from cryo-EM density maps is a crucial step in cryo-EM-based protein structure determination. Converting density maps into 3D atomic structures for proteins lacking accurate homologous or predicted structures as templates remains a significant challenge. Here, we introduce Cryo2Struct, a fully automated de novo cryo-EM structure modeling method. Cryo2Struct utilizes a 3D transformer to identify atoms and amino acid types in cryo-EM density maps, followed by an innovative Hidden Markov Model (HMM) to connect predicted atoms and build protein backbone structures. Cryo2Struct produces substantially more accurate and complete protein structural models than the widely used ab initio method Phenix. Additionally, its performance in building atomic structural models is robust against changes in the resolution of density maps and the size of protein structures.
Topics: Cryoelectron Microscopy; Models, Molecular; Protein Conformation; Proteins; Markov Chains; Algorithms; Software
PubMed: 38951555
DOI: 10.1038/s41467-024-49647-6 -
Nature Communications Jun 2024Like many other viruses, KSHV has two life cycle modes: the latent phase and the lytic phase. The RTA protein from KSHV is essential for lytic reactivation, but how this...
Like many other viruses, KSHV has two life cycle modes: the latent phase and the lytic phase. The RTA protein from KSHV is essential for lytic reactivation, but how this protein's activity is regulated is not fully understood. Here, we report that linear ubiquitination regulates the activity of RTA during KSHV lytic reactivation and de novo infection. Overexpressing OTULIN inhibits KSHV lytic reactivation, whereas knocking down OTULIN or overexpressing HOIP enhances it. Intriguingly, we found that RTA is linearly polyubiquitinated by HOIP at K516 and K518, and these modifications control the RTA's nuclear localization. OTULIN removes linear polyubiquitin chains from cytoplasmic RTA, preventing its nuclear import. The RTA orthologs encoded by the EB and MHV68 viruses are also linearly polyubiquitinated and regulated by OTULIN. Our study establishes that linear polyubiquitination plays a critically regulatory role in herpesvirus infection, adding virus infection to the list of biological processes known to be controlled by linear polyubiquitination.
Topics: Herpesvirus 8, Human; Ubiquitination; Humans; Virus Replication; Immediate-Early Proteins; HEK293 Cells; Trans-Activators; Ubiquitin-Protein Ligases; Virus Activation; Herpesviridae Infections; Cell Nucleus
PubMed: 38951495
DOI: 10.1038/s41467-024-49887-6 -
Journal of Assisted Reproduction and... Jun 2024Retrotransposons play important roles during early development when they are transiently de-repressed during epigenetic reprogramming. Long interspersed element-1 (L1),...
PURPOSE
Retrotransposons play important roles during early development when they are transiently de-repressed during epigenetic reprogramming. Long interspersed element-1 (L1), the only autonomous retrotransposon in humans, comprises 17% of the human genome. We applied the Single Cell Transposon Insertion Profiling by Sequencing (scTIPseq) to characterize and map L1 insertions in human embryos.
METHODS
Sixteen cryopreserved, genetically tested, human blastocysts, were accessed from consenting couples undergoing IVF at NYU Langone Fertility Center. Additionally, four trios (father, mother, and embryos) were also evaluated. scTIPseq was applied to map L1 insertions in all samples, using L1 locations reported in the 1000 Genomes as controls.
RESULTS
Twenty-nine unknown and unique insertions were observed in the sixteen embryos. Most were intergenic; no insertions were located in exons or immediately upstream of genes. The location or number of unknown insertions did not differ between euploid and aneuploid embryos, suggesting they are not merely markers of aneuploidy. Rather, scTIPseq provides novel information about sub-chromosomal structural variation in human embryos. Trio analyses showed a parental origin of all L1 insertions in embryos.
CONCLUSION
Several studies have measured L1 expression at different stages of development in mice, but this study for the first time reports unknown insertions in human embryos that were inherited from one parent, confirming no de novo L1 insertions occurred in parental germline or during embryogenesis. Since one-third of euploid embryo transfers fail, future studies would be useful for understanding whether these sub-chromosomal genetic variants or de novo L1 insertions affect embryo developmental potential.
PubMed: 38951360
DOI: 10.1007/s10815-024-03176-9 -
Acta Diabetologica Jul 2024Cerebrovascular accidents (CVA) represent a major complication in diabetes (DM). Real-life evidence as to whether modern management of CVA and DM have softened this...
BACKGROUND
Cerebrovascular accidents (CVA) represent a major complication in diabetes (DM). Real-life evidence as to whether modern management of CVA and DM have softened this relationship is limited. Therefore, we estimated prevalence and impact of DM on in-hospital survival and complications in a contemporary cohort of subjects with CVA.
METHODS
We retrospectively evaluated the records of 937 patients admitted for CVA at the Stroke Unit of Verona University Hospital during a 3-year period. Pre-existing or de novo DM was ascertained by prior diagnosis, glucose-lowering therapy at admission/discharge or admittance plasma glucose ≥ 200 mg/dL. Multiple regressions were applied to test DM as predictor of in-hospital mortality, complications (composite of infections, cardio- and cerebrovascular complications, major bleeding and pulmonary complications), duration and costs of hospitalization.
RESULTS
Diabetes prevalence was 21%, of which 22% de novo diagnoses. Compared to non-DM, diabetic individuals were older and carried an increased burden of cardiovascular risk factors. Compared to known DM, de novo DM individuals were younger, had higher admittance plasma glucose and poorer cardiovascular comorbidities. Overall, DM versus non-DM individuals did not show significantly increased risk of death (14.0 vs. 9.3%; crude-OR 1.59 95% CI 0.99-2.56). Controlling for confounders did not improve significance. DM resulted independent predictor for in-hospital complications (36.2% vs. 26.9%; adj-OR 1.49, 1.04-2.13), but not for duration and costs of hospitalization.
CONCLUSION
DM frequently occurs in patients admitted for stroke and carries an excess burden of adverse in-hospital complications, urgently calling for strategies to anticipate DM diagnosis and tailored treatment in high-risk individuals.
PubMed: 38951223
DOI: 10.1007/s00592-024-02318-w -
Journal of Human Genetics Jul 2024Heterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of...
Heterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of clinical and imaging findings during childhood. Previous reports have mainly described de novo variants lacking detailed familial cases. Herein, we describe the clinical course of familial cases with a TMEM63A variant. A 5-month-old girl presented with nystagmus, global hypotonia, and difficulty swallowing since birth. Brain magnetic resonance imaging at 1.5 and 5 months revealed diffuse hypomyelination. Her mother, maternal aunt, and grandfather had nystagmus and motor developmental delays in infancy, which resolved spontaneously during childhood. Compared with these cases, the proband's motor developmental delay was profound, and she was the only one with feeding difficulties, necessitating nasogastric tube feeding. Genetic testing revealed a heterozygous TMEM63A variant (NM_014698.3:c.1658G>A, p.(Gly553Asp)) in the proband and her family. This is the first three-generation familial report of a TMEM63A variant that provides insight into its history and heterogeneity.
PubMed: 38951194
DOI: 10.1038/s10038-024-01268-z -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Apr 2024The efficacy and safety of venetoclax combined with reduced dose HAD regimen in the treatment of newly diagnosed acute myeloid leukemia (AML) was investigated. From May...
The efficacy and safety of venetoclax combined with reduced dose HAD regimen in the treatment of newly diagnosed acute myeloid leukemia (AML) was investigated. From May 2022 to January 2023, a total of 25 patients with newly diagnosed AML were treated with venetoclax combined with reduced-dose HAD regimen as induction therapy. Accoding to the 2017 ELN recommendations, 13 (52.0%) in favoable, 3 (12.0%) in intemediate, and 9 (36.0%) in adverse. The ORR (CR rate+PR rate) was 88.0%, and the CR rate was 84.0%. By May 30, 2023, with a median follow-up of 9 months, 1 year overall survival, event-free survival, and relapse-free survival were 100%, 94.7%, and 94.7%, respectively. All patients received 1-5 cycles of consolidation therapy and two median cycles. Treatment with venetoclax and reduced dose of HAD regimen in the treatment of patients with newly diagnosed AML was high effective and safe.
Topics: Humans; Leukemia, Myeloid, Acute; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic; Antineoplastic Combined Chemotherapy Protocols; Induction Chemotherapy; Female; Male; Middle Aged; Adult
PubMed: 38951068
DOI: 10.3760/cma.j.cn121090-20231208-00298 -
Cold Spring Harbor Perspectives in... Jul 2024Lipids have essential functions as structural components of cellular membranes, as efficient energy storage molecules, and as precursors of signaling mediators. While...
Lipids have essential functions as structural components of cellular membranes, as efficient energy storage molecules, and as precursors of signaling mediators. While deregulated glucose and amino acid metabolism in cancer have received substantial attention, the roles of lipids in the metabolic reprogramming of cancer cells are less well understood. However, since the first description of de novo fatty acid biosynthesis in cancer tissues almost 70 years ago, numerous studies have investigated the complex functions of altered lipid metabolism in cancer. Here, we will summarize the mechanisms by which oncogenic signaling pathways regulate fatty acid and cholesterol metabolism to drive rapid proliferation and protect cancer cells from environmental stress. The review also discusses the role of fatty acid metabolism in metabolic plasticity required for the adaptation to changing microenvironments during cancer progression and the connections between fatty acid and cholesterol metabolism and ferroptosis.
PubMed: 38951029
DOI: 10.1101/cshperspect.a041548 -
Regional Anesthesia and Pain Medicine Jun 2024Optic nerve sheath diameter (ONSD) reflects intracranial pressure and is increased in pre-eclampsia. Administrating a significant volume of epidural solution into the...
INTRODUCTION
Optic nerve sheath diameter (ONSD) reflects intracranial pressure and is increased in pre-eclampsia. Administrating a significant volume of epidural solution into the epidural space can potentially increase ONSD. We investigated the impact of epidural local anesthetic injection on ONSD in patients with pre-eclampsia.
METHODS
Patients with pre-eclampsia (n=11) and normotensive pregnant women (n=11) received de novo epidural anesthesia for cesarean delivery. We administered 21 mL of an epidural solution containing 2% lidocaine and 50 μg fentanyl into the lumbar epidural space in incremental doses. ONSD was measured at baseline, 3, 10, and 20 min after completing the epidural injection, after delivery, and at the end of surgery. Primary outcome was the change in ONSD from baseline to 3 min after epidural injection in patients with pre-eclampsia and normotensive pregnant women. Serial changes in the ONSD were analyzed using a linear mixed model.
RESULTS
At baseline and 3 min after epidural drug injection, ONSD was significantly larger in patients with pre-eclampsia than in normotensive mothers (5.7 vs 4.1 mm, p=0.001 and 5.4 vs 4.1 mm, p<0.001, respectively). However, there were no significant changes in ONSD at 3 min after injection from baseline in either group (p>0.999). Linear mixed model demonstrated that ONSD did not change after epidural anesthesia in either group (p=0.279 and p=0.347, respectively).
CONCLUSIONS
Despite a higher baseline ONSD in pre-eclampsia, epidural anesthesia did not further increase ONSD. Our findings indicate that epidural anesthesia can be safely administered in patients with pre-eclampsia at risk of increased intracranial pressure, without other intracranial pathology.
TRIAL REGISTRATION NUMBER
NCT04095832.
PubMed: 38950931
DOI: 10.1136/rapm-2024-105444 -
International Journal of Gynecological... Jun 2024Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique... (Review)
Review
Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique clinical and molecular behaviors. The disease may arise de novo or develop from a serous borderline ovarian tumor. Although it is more indolent than high-grade serous ovarian cancer, most patients have advanced metastatic disease at diagnosis and recurrence is common. Recurrent low-grade serous ovarian cancer is often resistant to standard platinum-taxane chemotherapy, making it difficult to treat with the options currently available. New targeted therapies are needed, but their development is contingent on a deeper understanding of the specific biology of the disease. The known molecular drivers of low-grade tumors are strong hormone receptor expression, mutations in the mitogen-activated protein kinase (MAPK) pathway (, , and ), and in genes related to the MAPK pathway (, and ). However, MAPK inhibitors have shown only modest clinical responses. Based on the discovery of mutations in low-grade serous ovarian cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are now being tested in clinical trials in combination with hormone therapy. Additional mutations seen in a smaller population of low-grade tumors include , and but no specific therapies targeting them have been tested clinically. This review summarizes the clinical, pathologic, and molecular features of low-grade serous ovarian cancer as they are now understood and introduces potential therapeutic targets and new avenues for research.
PubMed: 38950921
DOI: 10.1136/ijgc-2024-005305 -
European Journal of Pharmacology Jun 2024Adiponectin plays key roles in energy metabolism and ameliorates inflammation, oxidative stress, and mitochondrial dysfunction via its primary receptors, adiponectin...
Adiponectin plays key roles in energy metabolism and ameliorates inflammation, oxidative stress, and mitochondrial dysfunction via its primary receptors, adiponectin receptors -1 and 2 (AdipoR1 and AdipoR2). Systemic depletion of adiponectin causes various metabolic disorders, including MASLD; however adiponectin supplementation is not yet achievable owing to its large size and oligomerization-associated complexities. Small-molecule AdipoR agonists, thus, may provide viable therapeutic options against metabolic disorders. Using a novel luciferase reporter-based assay here, we have identified Apigenin-6-C-glucoside (ACG), but not apigenin, as a specific agonist for the liver-rich AdipoR isoform, AdipoR2 (EC: 384 pM) with >10000X preference over AdipoR1. Immunoblot analysis in HEK-293 overexpressing AdipoR2 or HepG2 and PLC/PRF/5 liver cell lines revealed rapid AMPK, p38 activation and induction of typical AdipoR targets PGC-1α and PPARα by ACG at a pharmacologically relevant concentration of 100 nM (reported cMax in mouse; 297 nM). ACG-mediated AdipoR2 activation culminated in a favorable modulation of key metabolic events, including decreased inflammation, oxidative stress, mitochondrial dysfunction, de novo lipogenesis, and increased fatty acid β-oxidation as determined by immunoblotting, QRT-PCR and extracellular flux analysis. AdipoR2 depletion or AMPK/p38 inhibition dampened these effects. The in vitro results were recapitulated in two different murine models of MASLD, where ACG at 10 mg/kg body weight robustly reduced hepatic steatosis, fibrosis, proinflammatory macrophage numbers, and increased hepatic glycogen content. Together, using in vitro experiments and rodent models, we demonstrate a proof-of-concept for AdipoR2 as a therapeutic target for MASLD and provide novel chemicobiological insights for the generation of translation-worthy pharmacological agents.
PubMed: 38950835
DOI: 10.1016/j.ejphar.2024.176800