Plant Dis. 2024 Nov 6. doi: 10.1094/PDIS-08-24-1691-SC. Online ahead of print.

ABSTRACT

Sunflower is a short-season crop of the Asteraceae family and the Helianthus genus and is the fourth most important oilseed crop in the world. During a field campaign, unusual symptoms (necrosis and longitudinal cracking of the petiole) were observed in a sunflower crop grown in the region of Kavarna (Dobrich district, Bulgaria) and strains of the genus Xanthomonas were isolated. Results based on phylogenetic and phylogenomic analyses showed that they clustered with Xanthomonas euroxanthea CPBF 424T species, a pathogenic strain isolated from walnut buds in Portugal and responsible for causing walnut bacterial blight (WBB). The sunflower strain showed five out of eight X. euroxanthea-specific markers (XEA4-XEA8), a pattern also observed in some strains isolated from Solanum lycopersicum, Phaseolus vulgaris and rainwater sources, reinforcing the emergence of a recent lineage-driven by evolutionary adaptations to new plant hosts. This is the first report of X. euroxanthea in sunflower crops in Bulgaria, which represents a potential threat to production and its distribution should be monitored.

PMID:39504143 | DOI:10.1094/PDIS-08-24-1691-SC

Cell Oncol (Dordr). 2024 Nov 6. doi: 10.1007/s13402-024-01007-8. Online ahead of print.

ABSTRACT

Glioblastoma is the commonest and deadliest primary brain tumor. Glioblastoma is characterized by significant intra- and inter-tumoral heterogeneity, resistance to treatment and dismal prognoses despite decades of research in understanding its biological underpinnings. Encompassed within this heterogeneity and therapy resistance are severely dysregulated programmed cell death pathways. Glioblastomas recapitulate many neurodevelopmental and neural injury responses; in addition, glioblastoma cells are composed of multiple different transformed versions of CNS cell types. To obtain a greater understanding of the features underlying cell death regulation in glioblastoma, it is important to understand the control of cell death within the healthy CNS during homeostatic and neurodegenerative conditions. Herein, we review apoptotic control within neural stem cells, astrocytes, oligodendrocytes and neurons and compare them to glioblastoma apoptotic control. Specific focus is paid to the Inhibitor of Apoptosis proteins, which play key roles in neuroinflammation, CNS cell survival and gliomagenesis. This review will help in understanding glioblastoma as a transformed version of a heterogeneous organ composed of multiple varied cell types performing different functions and possessing different means of apoptotic control. Further, this review will help in developing more glioblastoma-specific treatment approaches and will better inform treatments looking at more direct brain delivery of therapeutic agents.

PMID:39503973 | DOI:10.1007/s13402-024-01007-8

Proc Natl Acad Sci U S A. 2024 Nov 19;121(47):e2414187121. doi: 10.1073/pnas.2414187121. Epub 2024 Nov 6.

ABSTRACT

Mitochondrial biogenesis relies on both the nuclear and mitochondrial genomes, and imbalance in their expression can lead to inborn errors of metabolism, inflammation, and aging. Here, we investigate N6AMT1, a nucleo-cytosolic methyltransferase that exhibits genetic codependency with mitochondria. We determine transcriptional and translational profiles of N6AMT1 and report that it is required for the cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3), two subunits of the mitochondrial RNAse P enzyme. In the absence of N6AMT1, or when its catalytic activity is abolished, RNA processing within mitochondria is impaired, leading to the accumulation of unprocessed and double-stranded RNA, thus preventing mitochondrial protein synthesis and oxidative phosphorylation, and leading to an immune response. Our work sheds light on the function of N6AMT1 in protein synthesis and highlights a cytosolic program required for proper mitochondrial biogenesis.

PMID:39503847 | DOI:10.1073/pnas.2414187121

J Invest Dermatol. 2024 Nov 5:S0022-202X(24)02150-X. doi: 10.1016/j.jid.2024.09.006. Online ahead of print.

ABSTRACT

Molecular pathology, such as high-throughput genomic and proteomic profiling, identifies precise disease targets from biopsies but require tissue dissociation, losing valuable histologic and spatial context. Emerging spatial multi-omic technologies now enable multiplexed visualization of genomic, proteomic, and epigenomic targets within a single tissue slice, eliminating the need for labeling multiple adjacent slices. Although early work focused on RNA (spatial transcriptomics), spatial technologies can now concurrently capture DNA, genome accessibility, histone modifications, and proteins with spatially-resolved single-cell resolution. This review outlines the principles, advantages, limitations, and potential for spatial technologies to advance dermatologic research. By jointly profiling multiple molecular channels, spatial multiomics enables novel studies of copy number variations, clonal heterogeneity, and enhancer dysregulation, replete with spatial context, illuminating the skin's complex heterogeneity.

PMID:39503694 | DOI:10.1016/j.jid.2024.09.006

Adv Sci (Weinh). 2024 Nov 6:e2405818. doi: 10.1002/advs.202405818. Online ahead of print.

ABSTRACT

X-linked retinoschisis (XLRS) is an inherited retinal disorder with severe retinoschisis and visual impairments. Multiomics approaches integrate single-cell RNA-sequencing (scRNA-seq) and spatiotemporal transcriptomics (ST) offering potential for dissecting transcriptional networks and revealing cell-cell interactions involved in biomolecular pathomechanisms. Herein, a multimodal approach is demonstrated combining high-throughput scRNA-seq and ST to elucidate XLRS-specific transcriptomic signatures in two XLRS-like models with retinal splitting phenotypes, including genetically engineered (Rs1emR209C) mice and patient-derived retinal organoids harboring the same patient-specific p.R209C mutation. Through multiomics transcriptomic analysis, the endoplasmic reticulum (ER) stress/eukryotic initiation factor 2 (eIF2) signaling, mTOR pathway, and the regulation of eIF4 and p70S6K pathways are identified as chronically enriched and highly conserved disease pathways between two XLRS-like models. Western blots and proteomics analysis validate the occurrence of unfolded protein responses, chronic eIF2α signaling activation, and chronic ER stress-induced apoptosis. Furthermore, therapeutic targeting of the chronic ER stress/eIF2α pathway activation synergistically enhances the efficacy of AAV-mediated RS1 gene delivery, ultimately improving bipolar cell integrity, postsynaptic transmission, disorganized retinal architecture, and electrophysiological responses. Collectively, the complex transcriptomic signatures obtained from Rs1emR209C mice and patient-derived retinal organoids using the multiomics approach provide opportunities to unravel potential therapeutic targets for incurable retinal diseases, such as XLRS.

PMID:39503290 | DOI:10.1002/advs.202405818

Cereb Cortex. 2024 Nov 5;34(11):bhae438. doi: 10.1093/cercor/bhae438.

ABSTRACT

Mice communicate through high-frequency ultrasonic vocalizations, which are crucial for social interactions such as courtship and aggression. Although ultrasonic vocalization representation has been found in adult brain areas along the auditory pathway, including the auditory cortex, no evidence is available on the neuronal representation of ultrasonic vocalizations early in life. Using in vivo two-photon calcium imaging, we analyzed auditory cortex layer 2/3 neuronal responses to USVs, pure tones (4 to 90 kHz), and high-frequency modulated sweeps from postnatal day 12 (P12) to P21. We found that ACx neurons are tuned to respond to ultrasonic vocalization syllables as early as P12 to P13, with an increasing number of responsive cells as the mouse age. By P14, while pure tone responses showed a frequency preference, no syllable preference was observed. Additionally, at P14, USVs, pure tones, and modulated sweeps activate clusters of largely nonoverlapping responsive neurons. Finally, we show that while cell correlation decreases with increasing processing of peripheral auditory stimuli, neurons responding to the same stimulus maintain highly correlated spontaneous activity after circuits have attained mature organization, forming neuronal subnetworks sharing similar functional properties.

PMID:39503245 | DOI:10.1093/cercor/bhae438

Front Plant Sci. 2024 Oct 22;15:1506089. doi: 10.3389/fpls.2024.1506089. eCollection 2024.

NO ABSTRACT

PMID:39502919 | PMC:PMC11534643 | DOI:10.3389/fpls.2024.1506089

Med Pharm Rep. 2024 Oct;97(4):516-527. doi: 10.15386/mpr-2798. Epub 2024 Oct 30.

ABSTRACT

BACKGROUND: Polycystic ovary syndrome (PCOS) is commonly associated with obesity and may be exacerbated by the lack of vitamin D3.

AIM: The study aimed to investigate the effects of vitamin D3 administration in female rats with PCOS and prolonged high fat diet (HFD).

METHODS: Forty-four female Wistar rats, 180-200 g, 10 weeks old, were randomly allocated into 2 groups (n=22) that received a single dose intramuscular injection of: sesame oil (group I), or estradiol valerate (5 mg) in sesame oil (group II). After 4 weeks, intraovarian cysts developed in group II, as evidenced by ultrasonography. In the next step, half of rats from each group received standard diet (SD) and the other half high fat diet, through oral gavage, for 17 weeks, the following groups being obtained: Control (SD), HFD, PCOS (PCOS+SD) and PCOS+HFD. Next, all the rats received, for 5 weeks, 500 UI/kg/day vitamin D3, through oral gavage. Lipid peroxidation was assessed through malondialdehyde level in the ovary and periovarian tissue and the inflammation was quantified in ovary by NFkB, pNFkB, NRF2 and SOD1 expressions. Ovaries from all groups were collected for histopathological analysis. Blood samples were taken to evaluate the basal insulin, triglycerides and total cholesterol levels throughout the experiment.

RESULTS: Both groups with PCOS recorded significant increases of malondialdehyde in ovaries (p<0.001) and in periovarian tissue, especially in PCOS+HFD (p<0.05), even after vitamin D3 administration. PCOS+HFD group treated with vitamin D3 showed a high degree of inflammation in ovarian histopathology but with decreased pNFkB expression (p<0.01) while PCOS group recorded an increased SOD1 expression (p<0.05). Additionally, vitamin D3 treatment attenuated the insulin level (p<0.001) in PCOS and in HFD groups and the total cholesterol level in PCOS+HFD group, but triglycerides recordings were without statistical significance (p>0.05). HFD induced inflammation in ovaries, evidenced histologically and through increases of COX2 expressions (p<0.05) without significant influences on oxidative stress and on cholesterol levels.

CONCLUSIONS: Polycystic ovary syndrome is associated with oxidative stress and inflammation in the ovary tissue and in blood with increased levels of insulin, total cholesterol and triglycerides that might be partially mitigated by vitamin D3 oral administration.

PMID:39502756 | PMC:PMC11534383 | DOI:10.15386/mpr-2798

Bioinform Biol Insights. 2024 Nov 4;18:11779322241287120. doi: 10.1177/11779322241287120. eCollection 2024.

ABSTRACT

Gene regulatory networks are powerful tools for modeling genetic interactions that control the expression of genes driving cell differentiation, and single-cell sequencing offers a unique opportunity to build these networks with high-resolution genomic data. There are many proposed computational methods to build these networks using single-cell data, and different approaches are used to benchmark these methods. However, a comprehensive discussion specifically focusing on benchmarking approaches is missing. In this article, we lay the GRN terminology, present an overview of common gold-standard studies and data sets, and define the performance metrics for benchmarking network construction methodologies. We also point out the advantages and limitations of different benchmarking approaches, suggest alternative ground truth data sets that can be used for benchmarking, and specify additional considerations in this context.

PMID:39502448 | PMC:PMC11536393 | DOI:10.1177/11779322241287120

Chronobiol Int. 2024 Nov 6:1-12. doi: 10.1080/07420528.2024.2422867. Online ahead of print.

ABSTRACT

The potential influence of circadian rhythm, seasonal variations, and alterations in meteorological parameters has been studied across various vascular events. However, there is a lack of evidence on the potential chronobiological impacts on thromboembolic events related to the most common peripheral aneurysm, the popliteal artery aneurysm (PAA). Data was obtained from a German PAA registry and the German Meteorological Service (Deutscher Wetterdienst). In this observational cohort study seasonality and chronobiology as well as associations with meteorological parameters of symptomatic PAA were investigated. In a multivariate logistic regression analysis, it was further analyzed whether meteorological parameters could distinguish asymptomatic from symptomatic patients in the registry. Of 1200 registered PAA, n = 142 PAA presented with acute limb ischemia between February 2011 and September 2022. More symptomatic patients (57.0%) presented to the hospital between January and June than in the second half of the year with a nadir in the fall season. Symptom onset was predominantly in the morning hours (39.5%). Atmospheric pressure and humidity values from the index dates diverged from a normal distribution showing a bimodal ("double-peak") configuration. Most patients developed symptoms after a reduction in temperatures compared to 1 or 2 d prior to the index date. However, we found evidence for an interaction between age and temperature difference, where the effects of a decreasing temperature fade with increasing age. Facing the complexity of individual-environment interactions, further investigations are needed to determine whether meteorological parameters are true risk modifiers or surrogates for seasonal differences and altered behaviors.

PMID:39501891 | DOI:10.1080/07420528.2024.2422867

Chin Med J (Engl). 2024 Nov 6. doi: 10.1097/CM9.0000000000003354. Online ahead of print.

ABSTRACT

Respiratory syncytial virus (RSV) is an enveloped, negative-sense, single-stranded RNA virus of the Orthopneumovirus genus of the Pneumoviridae family in the order Mononegavirales. RSV can cause acute upper and lower respiratory tract infections, sometimes with extrapulmonary complications. The disease burden of RSV infection is enormous, mainly affecting infants and older adults aged 75 years or above. Currently, treatment options for RSV are largely supportive. Prevention strategies remain a critical focus, with efforts centered on vaccine development and the use of prophylactic monoclonal antibodies. To date, three RSV vaccines have been approved for active immunization among individuals aged 60 and above. For children who are not eligible for these vaccines, passive immunization is recommended. A newly approved prophylactic monoclonal antibody, Nirsevimab, which offers enhanced neutralizing activity and an extended half-life, provides exceptional protection for high-risk infants and young children. This review provides a comprehensive and detailed exploration of RSV's virology, immunology, pathogenesis, epidemiology, clinical manifestations, treatment options, and prevention strategies.

PMID:39501814 | DOI:10.1097/CM9.0000000000003354

New Phytol. 2024 Nov 5. doi: 10.1111/nph.20249. Online ahead of print.

ABSTRACT

Genome merging is a common phenomenon causing a wide range of consequences on phenotype, adaptation, and gene expression, yet its broader implications are not well-understood. Two consequences of genome merging on gene expression remain particularly poorly understood: dosage effects and evolution of expression. We employed Chlamydomonas reinhardtii as a model to investigate the effects of asymmetric genome merging by crossing a diploid with a haploid strain to create a novel triploid line. Five independent clonal lineages derived from this triploid line were evolved for 425 asexual generations in a laboratory natural selection experiment. Utilizing fitness assays, flow cytometry, and RNA-Seq, we assessed the immediate consequences of genome merging and subsequent evolution. Our findings reveal substantial alterations in genome size, gene expression, protein homeostasis, and cytonuclear stoichiometry. Gene expression exhibited expression-level dominance and transgressivity (i.e. expression level higher or lower than either parent). Ongoing expression-level dominance and a pattern of 'functional dominance' from the haploid parent was observed. Despite major genomic and nucleo-cytoplasmic disruptions, enhanced fitness was detected in the triploid strain. By comparing gene expression across generations, our results indicate that proteostasis restoration is a critical component of rapid adaptation following genome merging in Chlamydomonas reinhardtii and possibly other systems.

PMID:39501615 | DOI:10.1111/nph.20249

J Chem Inf Model. 2024 Nov 5. doi: 10.1021/acs.jcim.4c01710. Online ahead of print.

ABSTRACT

Alchemical free energy campaigns can be planned using graph theory by building networks that contain nodes representing molecules that are connected by possible transformations as edges. We introduce Konnektor, an open-source Python package, for systematically planning, modifying, and analyzing free energy calculation networks. Konnektor is designed to aid in the drug discovery process by enabling users to easily setup free energy campaigns using complex graph manipulation methods. The package contains functions for network operations including concatenation of networks, deletion of transformations, and clustering of molecules along with a framework for combining these tools with existing network generation algorithms to enable the development of more complex methods for network generation. A comparison of the various network layout features offered is carried out using toy data sets. Additionally, Konnektor contains visualization and analysis tools, making the investigation of network features much simpler. Besides the content of the package, the paper also offers application examples, demonstrating how Konnektor can be used and how the different networks perform from a graph theory perspective. Konnektor is freely available via GitHub at https://github.com/OpenFreeEnergy/konnektor under the permissive MIT License.

PMID:39501568 | DOI:10.1021/acs.jcim.4c01710

Nat Commun. 2024 Nov 5;15(1):9559. doi: 10.1038/s41467-024-53997-6.

ABSTRACT

RNA methylation is an important regulatory process to determine immune cell function but how it affects the anti-tumor activity of CD8 T cells is not fully understood. Here we show that the N6-methyladenosine (m6A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells. We find that YTHDF2 facilitates nascent RNA synthesis, and m6A recognition is fundamental for this distinctively nuclear function of the protein, which also reinforces its autoregulation at the RNA level. Loss of YTHDF2 in T cells exacerbates tumor progression and confers unresponsiveness to PD-1 blockade in mice and in humans. In addition to initiating RNA decay that is necessary for mitochondrial fitness, YTHDF2 orchestrates chromatin changes that promote T cell polyfunctionality. YTHDF2 interacts with IKZF1/3, which is important for sustained transcription of their target genes. Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of IKZF1/3 inhibitor lenalidomide in a mouse model. Thus, YTHDF2 coordinates epi-transcriptional and transcriptional networks to potentiate T cell immunity, which could inform therapeutic intervention.

PMID:39500904 | DOI:10.1038/s41467-024-53997-6

Nat Commun. 2024 Nov 6;15(1):9568. doi: 10.1038/s41467-024-53634-2.

ABSTRACT

In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10-34, OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P = 7.2 × 10-5), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland (P = 8.82 × 10-28) and Estonia (P = 1.25 × 10-5). The risk allele of rs570516915 alters a conserved binding site for the transcription factor IRF6 within an enhancer (MCS-9.7) upstream of the IRF6 gene and diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level of IRF6, suggesting impaired IRF6 autoregulation as a molecular mechanism underlying the risk for CP.

PMID:39500877 | DOI:10.1038/s41467-024-53634-2

CNS Neurosci Ther. 2024 Nov;30(11):e70109. doi: 10.1111/cns.70109.

ABSTRACT

AIMS: Although the genetic locus of X-linked dystonia parkinsonism (XDP), a neurodegenerative disease endemic in the Philippines, is well-characterized, the exact mechanisms leading to neuronal loss are not yet fully understood. Recently, we demonstrated an increase in myeloperoxidase (MPO) levels in XDP postmortem prefrontal cortex (PFC), suggesting a role for inflammation in XDP pathogenesis. Therefore, we hypothesized that inhibiting MPO could provide a therapeutic strategy for XDP.

METHODS: MPO activity was measured by using an MPO-activatable fluorescent agent (MAFA) in human postmortem PFC. Reactive oxygen species (ROS) and MPO activity were measured in XDP-derived fibroblasts and SH-SY5Y cells following MPO inhibition.

RESULTS: MPO activity was significantly increased in XDP PFC. Additionally, treatment of cell lines with postmortem XDP PFC resulted in a significant increase in ROS levels. To determine whether increases in MPO activity caused increases in ROS, MPO content was immunodepleted from XDP PFC, which resulted in a significant decrease in ROS in SH-SY5Y cells. Consistently, the treatment with verdiperstat, a potent and selective MPO inhibitor, significantly decreased ROS in both XDP-derived fibroblasts and XDP PFC-treated SH-SY5Y cells.

CONCLUSIONS: Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment.

PMID:39500625 | DOI:10.1111/cns.70109

J Neurosci. 2024 Nov 5:e0215242024. doi: 10.1523/JNEUROSCI.0215-24.2024. Online ahead of print.

ABSTRACT

Huntington's disease (HD) is a progressive neurodegenerative disorder with no cure, characterized by significant neurodegeneration of striatal GABAergic medium spiny neurons (MSNs). Early stages of the disease are characterized by the loss of dopamine 2 receptor-expressing MSNs (D2 MSNs) followed by degeneration of dopamine 1 receptor-expressing MSNs (D1 MSNs), leading to aberrant basal ganglia signaling. While the early degeneration of D2 MSNs and impaired GABAergic transmission are well-documented, potassium chloride cotransporter 2 (KCC2), a key regulator of intracellular chloride (Cl-), and therefore GABAergic signaling, has not been characterized in D1 and D2 MSNs in HD. We aimed to investigate whether Cl- regulation was differentially altered in D1 and D2 MSNs and may contribute to the early degeneration of D2 MSNs in male and female symptomatic R6/2 mice. We used electrophysiology to record the reversal potential for GABAA receptors (EGABA), a read-out for the efficacy of Cl- regulation, in striatal D1 and D2 MSNs and their corresponding output structures. During the early symptomatic phase (P55-P65), Cl- impairments were observed in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl- regulation was also dysfunctional in the globus pallidus externa, resulting in GABA-mediated excitation. When we overexpressed KCC2 in D2 MSNs using AAV-mediated delivery, we delayed the onset of motor impairments in R6/2 mice. We demonstrate that Cl- homeostasis is differentially altered in D1 and D2 MSNs and may contribute to the enhanced susceptibility of D2 MSNs during HD progression.Significance Statement Huntington's Disease is an inherited neurodegenerative disease caused by a repeat expansion in the Huntingtin gene and characterized by the sequential loss of dopamine 2 and dopamine 1 receptor-expressing medium spiny neurons (D2 and D1 MSNs) of the striatum. MSNs release GABA, which depends on proper Cl- regulation for inhibition. We asked whether Cl- homeostasis is differentially altered in D1 and D2 MSNs and their output structures, and whether this altered expression contributes to the pattern of degeneration between these two principal striatal cell types. Using electrophysiology, biochemistry, and fluorescence imaging, we determined that Cl- regulation was impaired in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl- was also dysregulated in the globus pallidus externa resulting in excitatory GABA.

PMID:39500579 | DOI:10.1523/JNEUROSCI.0215-24.2024

J Agric Food Chem. 2024 Nov 5. doi: 10.1021/acs.jafc.4c07688. Online ahead of print.

ABSTRACT

Wheat lipids are a minor constituent of wheat, with an important influence on its processing properties. While breeding aimed to improve the protein composition of wheat flour, its influence on the lipid composition remains unknown. We therefore analyzed the lipidome of 60 different common wheat (Triticum aestivum) flours representing cultivars registered and grown in Germany from 1891 to 2010. Four different extraction techniques were tested before the application of a semiquantitative, untargeted UHPLC-MS/MS method. The measurements included 16 different lipid classes and 102 different lipid species. Based on the lipid profile, discrimination between old (registered between 1891 to 1950) and modern (1951 to 2010) cultivars was possible. While the lipid class composition remained constant, differences were due to variations within the class of triacylglycerols, with modern cultivars containing less unsaturated fatty acids than the older ones. Our results imply that improving the lipid class composition of common wheat is a promising target for further breeding.

PMID:39500489 | DOI:10.1021/acs.jafc.4c07688

J Am Chem Soc. 2024 Nov 5. doi: 10.1021/jacs.4c06127. Online ahead of print.

ABSTRACT

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

PMID:39499896 | DOI:10.1021/jacs.4c06127

STAR Protoc. 2024 Nov 4;5(4):103438. doi: 10.1016/j.xpro.2024.103438. Online ahead of print.

ABSTRACT

Drosophila and its parasitoids provide an ecologically relevant model for studying host-parasitoid biology, focusing on the behavioral and physiological responses involved in host defensive strategies and parasitoid countermeasures. Here, we outline a protocol for rearing Pachycrepoideus, a pupal parasitoid wasp, and a behavioral assay to assess the long-term impact of parasitoid exposure on adult Drosophila. We detail the steps for preparing and cohabiting Drosophila with the wasps, documenting egg-laying, and analyzing reproductive responses and eclosion in fruit flies. For complete details on the use and execution of this protocol, please refer to Sadanandappa et al.1.

PMID:39499614 | DOI:10.1016/j.xpro.2024.103438