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Huber T, Horioka-Duplix M, Chen YH, Saca VR, Ceraudo E, Chen Y, Sakmar TP
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The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte ... (opens in new window)

SCIENCE SIGNALING 2024 SEP 17; 17(854):? Article eadp3967
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In contrast with sun exposure-induced melanoma, rarer melanocytic tumors and neoplasms with low mutational burden present opportunities to study isolated signaling mechanisms. These include uveal melanoma and blue nevi, which are often driven by mutations within the G protein-coupled signaling cascade downstream of cysteinyl leukotriene receptor 2. Here, we review how the same mutations within this pathway drive the growth of melanocytes in one tissue but can inhibit the growth of those in another, exemplifying the role of the tissue environment in the delicate balance between uncontrolled cell growth and senescence.
Singh D, Soni N, Hutchings J, Echeverria I, Shaikh F, Duquette M, Suslov S, L...
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The molecular architecture of the nuclear basket (opens in new window)

CELL 2024 SEP 19; 187(19):?
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The nuclear pore complex (NPC) is the sole mediator of nucleocytoplasmic transport. Despite great advances in understanding its conserved core architecture, the peripheral regions can exhibit considerable variation within and between species. One such structure is the cage-like nuclear basket. Despite its crucial roles in mRNA surveillance and chromatin organization, an architectural understanding has remained elusive. Using in-cell cryo-electron tomography and subtomogram analysis, we explored the NPC's structural variations and the nuclear basket across fungi (yeast; S. cerevisiae), mammals (mouse; M. musculus), and protozoa (T. gondii). Using integrative structural modeling, we computed a model of the basket in yeast and mammals that revealed how a hub of nucleoporins (Nups) in the nuclear ring binds to basket-forming Mlp/Tpr proteins: the coiled-coil domains of Mlp/Tpr form the struts of the basket, while their unstructured termini constitute the basket distal densities, which potentially serve as a docking site for mRNA preprocessing before nucleocytoplasmic transport.
Friedman JM
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The discovery and development of GLP-1 based drugs that have revolutionized t... (opens in new window)

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2024 SEP 16; 121(39):? Article e2415550121
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The 2024 Lasker similar to DeBakey Clinical Medical Research Award has been given to Joel Habener and Svetlana Mojsov for their discovery of a new hormone GLP-1(7-37) and to Lotte Knudsen for her role in developing sustained acting versions of this hormone as a treatment for obesity. Each of the three had a distinct set of skills that made this advance possible; Habener is an endocrinologist and molecular biologist, Mojsov is a peptide chemist, and Knudsen is a pharmaceutical scientist. Their collective efforts have done what few thought possible-the development of highly effective medicines for reducing weight. Their research has also solved a mystery that began more than a century ago.
Ho CSE, Jutras-Dubé L, Zhao ML, Mönke G, Kiss IZ, François P, Aulehla A
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Nonreciprocal synchronization in embryonic oscillator ensembles (opens in new window)

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2024 SEP 3; 121(36):? Article e2401604121
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Synchronization of coupled oscillators is a universal phenomenon encountered across different scales and contexts, e.g., chemical wave patterns, superconductors, and the unison applause we witness in concert halls. The existence of common underlying coupling rules defines universality classes, revealing a fundamental sameness between seemingly distinct systems. Identifying rules of synchronization in any particular setting is hence of paramount relevance. Here, we address the coupling rules within an embryonic oscillator ensemble linked to vertebrate embryo body axis segmentation. In vertebrates, the periodic segmentation of the body axis involves synchronized signaling oscillations in cells within the presomitic mesoderm (PSM), from which somites, the prevertebrae, form. At the molecular level, it is known that intact Notch- signaling and cell-to-cell contact are required for synchronization between PSM cells. However, an understanding of the coupling rules is still lacking. To identify these, we develop an experimental assay that enables direct quantification of synchronization dynamics within mixtures of oscillating cell ensembles, for which the initial input frequency and phase distribution are known. Our results reveal a "winner-takes-it- all" synchronization outcome, i.e., the emerging collective rhythm matches one of the input rhythms. Using a combination of theory and experimental validation, we develop a coupling model, the "Rectified Kuramoto" (ReKu) model, characterized by a phase-dependent, nonreciprocal interaction in the coupling of oscillatory cells. Such nonreciprocal synchronization rules reveal fundamental similarities between embryonic oscillators and a class of collective behaviors seen in neurons and fireflies, where higher- level computations are performed and linked to nonreciprocal synchronization.
Ackermann-Gäumann R, Dentand A, Lienhard R, Saeed M, Speiser DE, MacDonald MR...
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A reporter virus particle seroneutralization assay for tick-borne encephaliti... (opens in new window)

JOURNAL OF MEDICAL VIROLOGY 2024 AUG; 96(8):? Article e29843
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Tick-borne encephalitis (TBE) virus is the most prevalent tick-transmitted orthoflavivirus in Europe. Due to the nonspecific nature of its symptoms, TBE is primarily diagnosed by ELISA-based detection of specific antibodies in the patient serum. However, cross-reactivity between orthoflaviviruses complicates the diagnosis. Specificity issues may be mitigated by serum neutralization assays (SNT), although the handling of clinically relevant orthoflaviviruses requires biosafety level (BSL) 3 conditions and they have highly divergent viral kinetics and cell tropisms. In the present study, we established a reporter virus particle (RVP)-based SNT in which the infectivity is measured by luminescence and that can be performed under BSL-2 conditions. The RVP-based SNT for TBEV exhibited a highly significant correlation with the traditional virus-based SNT (R-2 = 0.8637, p < 0.0001). The RVP-based assay demonstrated a sensitivity of 92.3% (95% CI: 79.7%-97.4%) and specificity of 100% (95% CI: 81.6%-100%). We also tested the cross-reactivity of serum samples in RVP-based assays against other orthoflaviviruses (yellow fever virus, dengue virus type 2, Zika virus, West Nile virus and Japanese encephalitis virus). Interestingly, all serum samples which had tested TBEV-positive by ELISA but negative by RVP-based SNT were reactive for antibodies against other orthoflaviviruses. Thus, the RVP-based seroneutralization assay provides an added value in clinical diagnostics as well as in epidemiological studies.
Karatayev O, Collier AD, Targoff SR, Leibowitz SF
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Neurological Disorders Induced by Drug Use: Effects of Adolescent and Embryon... (opens in new window)

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 2024 AUG; 25(15):? Article 8341
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Clinical studies demonstrate that the risk of developing neurological disorders is increased by overconsumption of the commonly used drugs, alcohol, nicotine and cannabis. These drug-induced neurological disorders, which include substance use disorder (SUD) and its co-occurring emotional conditions such as anxiety and depression, are observed not only in adults but also with drug use during adolescence and after prenatal exposure to these drugs, and they are accompanied by long-lasting disturbances in brain development. This report provides overviews of clinical and preclinical studies, which confirm these adverse effects in adolescents and the offspring prenatally exposed to the drugs and include a more in-depth description of specific neuronal systems, their neurocircuitry and molecular mechanisms, affected by drug exposure and of specific techniques used to determine if these effects in the brain are causally related to the behavioral disturbances. With analysis of further studies, this review then addresses four specific questions that are important for fully understanding the impact that drug use in young individuals can have on future pregnancies and their offspring. Evidence demonstrates that the adverse effects on their brain and behavior can occur: (1) at low doses with short periods of drug exposure during pregnancy; (2) after pre-conception drug use by both females and males; (3) in subsequent generations following the initial drug exposure; and (4) in a sex-dependent manner, with drug use producing a greater risk in females than males of developing SUDs with emotional conditions and female offspring after prenatal drug exposure responding more adversely than male offspring. With the recent rise in drug use by adolescents and pregnant women that has occurred in association with the legalization of cannabis and increased availability of vaping tools, these conclusions from the clinical and preclinical literature are particularly alarming and underscore the urgent need to educate young women and men about the possible harmful effects of early drug use and to seek novel therapeutic strategies that might help to limit drug use in young individuals.
Rottenstreich A
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Controversies and Clarifications Regarding the Role of Aspirin in Preeclampsi... (opens in new window)

JOURNAL OF CLINICAL MEDICINE 2024 AUG; 13(15):? Article 4427
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Preeclampsia is one of the leading causes of maternal and perinatal morbidity and mortality worldwide. In recent decades, many studies have evaluated different interventions in order to prevent the occurrence of preeclampsia. Among these, administration of low-dose aspirin from early pregnancy showed consistent evidence of its prophylactic role. In this article, we review the scientific literature on this topic, highlighting the rationale for aspirin use, who should be treated, the timing of initiation and cessation of therapy, the importance of proper dosing, and its role in the prevention of other adverse outcomes.
Yanai I, Bogler O, Carroll SB, Couch J, Dahlberg ML, Fuhrmann CN, Kaufman JC,...
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Teach creativity in science higher education (opens in new window)

SCIENCE 2024 AUG 23; 385(6711):?
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Kalbfleisch TS, McKay SD, Murdoch BM, Adelson DL, Almansa-Villa D, Becker G, ...
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The Ruminant Telomere-to-Telomere (RT2T) Consortium (opens in new window)

NATURE GENETICS 2024 AUG 5; ?(?):?
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Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock. Here we describe an open collaborative effort termed the 'Ruminant T2T Consortium'. It aims to generate complete diploid assemblies for many species of ruminants to examine chromosomal evolution in the context of natural selection and domestication.
Lacy KD, Hart T, Kronauer DJC
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Co-inheritance of recombined chromatids maintains heterozygosity in a parthen... (opens in new window)

NATURE ECOLOGY & EVOLUTION 2024 AUG; 8(8):?
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According to Mendel's second law, chromosomes segregate randomly in meiosis. Non-random segregation is primarily known for cases of selfish meiotic drive in females, in which particular alleles bias their own transmission into the oocyte. Here we report a rare example of unselfish meiotic drive for crossover inheritance in the clonal raider ant, Ooceraea biroi, in which both alleles are co-inherited at all loci across the entire genome. This species produces diploid offspring parthenogenetically via fusion of two haploid nuclei from the same meiosis. This process should cause rapid genotypic degeneration due to loss of heterozygosity, which results if crossover recombination is followed by random (Mendelian) segregation of chromosomes. However, by comparing whole genomes of mothers and daughters, we show that loss of heterozygosity is exceedingly rare, raising the possibility that crossovers are infrequent or absent in O. biroi meiosis. Using a combination of cytology and whole-genome sequencing, we show that crossover recombination is, in fact, common but that loss of heterozygosity is avoided because crossover products are faithfully co-inherited. This results from a programmed violation of Mendel's law of segregation, such that crossover products segregate together rather than randomly. This discovery highlights an extreme example of cellular 'memory' of crossovers, which could be a common yet cryptic feature of chromosomal segregation. This study reports non-random segregation of chromosomes during meiosis in the clonal raider ant, Ooceraea biroi, but no loss of heterozygosity because crossover products are faithfully co-inherited.