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Gene expression programs underlying memory are not well understood in Drosophila. Here, authors use mushroom body-specific RNA sequencing to characterize the transcriptional trace of long-term memory and key TFs that may regulate it.

LINE-1 activity was quantified in a large, pan-cancer dataset, finding locus-specific heterogeneity and new associations using a computational pipeline. A mathematical mediation model of p53 and L1 interactions was inferred. Somatic retrotransposition was seen in Li-Fraumeni Syndrome with heritable TP53 mutations.

Ewing sarcoma (ES) is characterized by EWSR1/ETS gene rearrangements with unknown cellular origin. Here, authors show that expressing the EWS::FLI1 oncogene in human embryonic mesenchymal stem cells induces an Ewing sarcoma-like transcriptome and forms tumors in mice.

Arp2/3 complex forms branched actin networks that drive cell and organelle motility. Here, authors show that Coro7 targets branch junctions by binding Arp2/3 complex and actin filaments, promoting debranching, and supporting ER–Golgi transport.

Here the authors describe that the human origin recognition complex subunit 1 (ORC1) binds to RNAs transcribed from genes with origins of replication at their TSS impacting origin activation.

Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCRS regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCRS alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-Δ32 and CCR2-64I polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-64I allele were found in African Americans but not in Caucasians, and the SDF1-3′A/3′A genotype was associated with an accelerated progression to death. In contrast, the CCR5-Δ32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.

Whether intermittent strategies of delivering drugs can improve cancer patients survival is still unclear. Here, the authors reports the results of a randomized phase II clinical trial aimed to compare the efficacy and safety of two dosing regimens (continuous and intermittent) of vemurafenib and cobimetinib combination as first-line treatment of patients with unresectable or metastatic advanced melanoma with BRAFV600 mutation

T cells undergo age-related changes that impair their organismal functions. Here Soto-Heredero et al. show that regulatory T cells characterized by the expression of KLRG1 accumulate with age in both mice and humans and exhibit features including mitochondrial decline and an inflammatory phenotype.

Use of a longitudinal study design allows for more precise analysis of the interplay between clonal hematopoiesis and atherosclerotic disease, finding that whereas clonal hematopoiesis confers an increased risk of atherosclerosis, the reverse is not the case, arguing for a unidirectional effect of clonal hematopoiesis on atherosclerosis.

Zhang et al. identify unimodal neural representations in the spinal cord of cutaneous mechanical and heat stimuli gated by a shared feed-forward local inhibitory neuron type and a neural transition during neuropathy, with increased excitatory drive.

The intensity of UVA light, in addition to the photoperiod, is shown to determine seasonal change in the marine mass spawning annelid Platynereis dumerilii.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Llorente, Blasco, Espuny and colleagues show that MAF regulates the genomic distribution of ERα and modulates the expression of metastasis genes via KDM1A, thereby driving metastatic spread in breast cancer.

Pathological cardiac fibrosis is a hallmark of diseases leading to heart failure. Here, the authors used systems genetics to identify a pro-fibrotic gene network regulated by WWP2, a E3 ubiquitin ligase, which orchestrates the nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in the diseased heart.

Actin cables affect lifespan by supporting movement and inheritance of fitter mitochondria to daughter cells in yeast. Here the authors show that branched-chain amino acid (BCAA) levels affect actin cable stability and a role for YKL075C/AAN1 in control of BCAA metabolism and actin cable stability and function.

Enhanced IL-1β signaling pathway causes hematopoietic stem cell (HSC) to differentiate into myeloid cells and contributes to malignant hematopoiesis. Here the authors reveal that HSC differentiation is controlled by balanced levels of IL-1 receptor antagonist (IL-1rn) and IL-1β under steady-state, and that IL-1rn protects against pre-leukemic myelopoiesis by repressing IL-1β signaling.

Steroid-refractory acute graft-versus-host disease (aGVHD) is associated with a low one-year survival rate. Here, the authors show that ROCK1 is upregulated in leukocytes from patients with steroid-refractory aGVHD and that ROCK1/2 inhibition reduces the severity of aGVHD in mice by interfering with activation of multiple immune cell types.

Here, the authors apply positron emission tomography (PET) imaging to visualize HIV tissue-wide burden in infected individuals using a radiolabeled broadly neutralizing antibody, ⁸⁹Zr-VRC01, and show that PET tracer lymph node uptake positively correlates with HIV protein levels measured directly from cells obtained from these tissues. This strategy may allow non-invasive characterization of residual HIV infection in the setting of therapeutic interventions.

Soochit et al. report that the residence time of CTCF on chromatin is controlled by its zinc finger 8 domain and determines chromatin organization, DNA methylation and transcriptional robustness in mouse embryonic stem cells.

The success of targeting KRAS for cancer therapy is limited by resistance due to compensatory mechanism, making combinatorial approaches attractive. Here, the authors use a KRAS signature drug repurposing screen and identify the multityrosine kinase PKC inhibitor Midostaurin as synergistic with MEK and KRAS inhibitors in KRAS-mutated lung adenocarcinoma.

Examination of allele-specific expression identifies 71 genes with excess somatic cis-regulatory effects in colorectal cancer (CRC), and 1,693 and 948 expression quantitative trait loci (eQTLs) in normal samples and tumours, respectively (with 36% of tumour eQTLs exclusive to CRC); tumour-specific eQTLs are more enriched for low CRC genome-wide association study P values and accumulate more somatic mutations than shared eQTLs, suggesting a role as germline-derived cancer regulatory drivers.

Schwann cells associated with most sensory receptors in the skin actively participate in the transduction of mechanical stimuli. Here the authors show that silencing these sensory Schwann cells is sufficient to reduce touch perception and can inhibit mechanical pain in mice.

Using a spatial reasoning task in mice, the authors show that retrosplenial cortex encodes spatial hypotheses with well-behaved recurrent dynamics, which can combine these hypotheses with incoming information to resolve ambiguities.

A strategy for protecting redox-active ortho-quinones, which show promise as anticancer agents but suffer from redox-cycling behaviour and systemic toxicity, has been developed. The ortho-quinones are derivatized to redox-inactive para-aminobenzyl ketols. Upon amine deprotection, an acid-promoted, self-immolative C–C bond-cleaving 1,6-elimination releases the redox-active hydroquinone. The strategy also enables conjugation to a carrier for targeted delivery of ortho-quinone species.

Receptor activator of nuclear factor-κB (RANK)/RANK-ligand (RANKL) signaling regulates the tumor-immune crosstalk. Here the authors show that systemic RANKL inhibition promotes CD8 + T cell infiltration in patients with early breast cancer and that loss of RANK signaling in tumor cells drives a T cell-dependent anti-tumor response in preclinical models.

Deregulation of lipid metabolism in cancer cells is critical to the maintenance of certain malignant features. Here, the authors show that the proliferation of breast cancer cells depends upon the extracellular activity of the endothelial lipase enzyme LIPG whose expression is regulated by the FoxA family of transcription factors.

Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour. 

Replication stress represents a major threat to genome integrity of normal and cancer cells. Here, the authors find that the long non-coding RNA lncREST affects the replication stress response through interaction with nucleolin. This interaction bridges the recruitment of replication factors to stressed chromatin.

Both A/B compartments and TADs are thought to be absent from the inactive X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, the authors characterise gene reactivation, chromatin opening and chromosome topology during X-reactivation, observe A/B-like compartments on the inactive X that guide TAD formation independently of transcription during X-reactivation.

Electromechanical characterization during atrial fibrillation (AF) remains a significant gap in the understanding of AF-related atrial myopathy. Here, the authors use non-invasive atrial electromechanical assessment during AF to identify early remodeling changes associated with underlying myopathy, which in the clinic decrease the probability of acute and mid-term successful rhythm control.

Solá, Mereu and colleagues describe a chronic inflammatory state in the aging mouse skin that is characterized by IL-17 production by dermal lymphoid cells and demonstrate the potential of inhibition of IL-17 signaling in protection against skin aging.

The immunobiology regulating the contribution of monocytes to severe COVID-19 immunopathology are not fully understood. Here the authors show that SARS-CoV-2 S1 and NP proteins differentially promote NLRP3/NLRC4 inflammasome activity, differentiation, and T cell-priming function of monocytes.

Tonic antigen receptor signaling contributes to the homeostasis of naive lymphocytes. Alarcón and colleagues show that resting lymphocytes transmit tonic antigen receptor signals through the GTPase TC21 to trigger the PI(3)K pathway.

Gawrzak et al. show that MSK1 regulates bone metastatic dormancy of ER⁺ breast cancer. MSK1 affects histone modifications at luminal transcription factor promoters to prevent cell differentiation and bone homing.

We identify that the larval zebrafish unpaired pre-anal fin fold is derived from the lateral plate mesoderm, can be readily duplicated, and thus may represent a developmental intermediate between median and paired fins.

An autism-associated mutation in Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and altered social behavioural responses in mice, and treatment with an inhibitor of MAP kinase-interacting kinases rescues these phenotypes.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Mitochondrial complex I deficiency is frequent in congenital, neurologic and cardiovascular disease. Here the authors demonstrate that Complex I stimulates the turnover of a mitochondrial calcium channel, which becomes stabilized during Complex I deficiency, preserving energetic homeostasis.

Autophagosomes are specialized vesicles that target and deliver cargo to the lytic vacuole. Here the authors show that plasma-membrane derived lipid phosphatidylinositol-4-phosphate supports the assembly and expansion of autophagosomes in Arabidopsis

The gut microbiome can change with age and influence aging-related diseases systemically, including in the brain. The authors show that rejuvenation of the gut microbiome by fecal microbiota transplantation from young mice reverses aging-induced deficits in the hippocampal immune system, metabolome and transcriptome, and rescues selective cognitive deficits.

A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent risk loci. Comparisons with other psychiatric disorders and candidate gene analyses provide new insights into major depressive disorder.

Tian et al. report that the chromatin-related factor Whsc1 regulates the exit from pluripotency and germ layer specification of mouse embryonic stem cells by binding to enhancers of mesendodermal regulators.

Identifying actionable components in castration–resistant prostate cancer (CRPC) is critical for the development of effective treatments. Here, the authors show that the inhibition of the redox-protective protein TRX1 decreases the growth of CRPC cells through the regulation of ROS levels, p53 and androgen receptor expression.

Degradation of the recalcitrant polysaccharide fucoidan, produced by marine brown algae, is carried out by some bacteria through unclear mechanisms. Here, the authors provide insights into fucoidan processing mechanisms by studying two alga-associated bacterial strains, using microscopy, multi-omic, biochemical and structural techniques.