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De novo gene origination, where a previously nongenic genomic sequence becomes genic through evolution, is increasingly recognized as an important source of novelty. Many de novo genes have been proposed to be protein-coding, and a few have been experimentally shown to yield protein products. However, the systematic study of de novo proteins has been hampered by doubts regarding their translation without the experimental observation of protein products. Using a systematic, mass-spectrometry-first computational approach, we identify 993 unannotated open reading frames with evidence of translation (utORFs) in Drosophila melanogaster. To quantify the similarity of these utORFs across Drosophila and infer phylostratigraphic age, we develop a synteny-based protein similarity approach. Combining these results with reference datasets ontissue- and life stage-specific transcription and conservation, we identify different properties amongst these utORFs. Contrary to expectations, the fastest-evolving utORFs are not the youngest evolutionarily. We observed more utORFs in the brain than in the testis. Most of the identified utORFs may be of de novo origin, even accounting for the possibility of false-negative similarity detection. Finally, sequence divergence after an inferred de novo origin event remains substantial, suggesting that de novo proteins turn over frequently. Our results suggest that there is substantial unappreciated diversity in de novo protein evolution: many more may exist than previously appreciated; there may be divergent evolutionary trajectories, and they may be gained and lost frequently. All in all, there may not exist a single characteristic model of de novo protein evolution, but instead, there may be diverse evolutionary trajectories.
Omelchenko T
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Cellular protrusions in 3D: Orchestrating early mouse embryogenesis

SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY 2022 SEP; 129(?):63-74
Cellular protrusions generated by the actin cytoskeleton are central to the process of building the body of the embryo. Problems with cellular protrusions underlie human diseases and syndromes, including implantation defects and pregnancy loss, congenital birth defects, and cancer. Cells use protrusive activity together with actin -myosin contractility to create an ordered body shape of the embryo. Here, I review how actin-rich protrusions are used by two major morphological cell types, epithelial and mesenchymal cells, during collective cell migration to sculpt the mouse embryo body. Pre-gastrulation epithelial collective migration of the anterior visceral endoderm is essential for establishing the anterior-posterior body axis. Gastrulation mesenchymal collective migration of the mesoderm wings is crucial for body elongation, and somite and heart formation. Analysis of mouse mutants with disrupted cellular protrusions revealed the key role of protrusions in embryonic morphogenesis and embryo survival. Recent technical approaches have allowed examination of the mechanisms that control cell and tissue movements in vivo in the complex 3D microenvironment of living mouse embryos. Advancing our understanding of protrusion-driven morphogenesis should provide novel insights into human developmental disorders and cancer metastasis.
Erdos M, Boyarchuk O, Marodi L
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Case Report: Association between cyclic neutropenia and SRP54 deficiency

FRONTIERS IN IMMUNOLOGY 2022 SEP 8; 13(?):? Article 975017
Autosomal dominant mutations in the signal recognition particle (SRP) 54 gene were recently described in patients with severe congenital neutropenia (SCN). SRP54 deficiency cause a chronic and profound neutropenia with maturation arrest at the promyelocyte stage, occurring in the first months of life. Nearly all reported patients with SRP54 mutations had neutropenia without a cyclic pattern and showed a poor or no response to granulocyte colony-stimulating factor (G-CSF) therapy. We report here an 11-year-old female patient with cyclic neutropenia and recurrent heterozygous p.T117del (c.349_351del) in-frame deletion mutation in SRP54, who showed remarkable therapeutic response to G-CSF treatment. The diagnosis of cyclic pattern of neutropenia was established by acceptable standards. ELANE gene mutation was excluded by using various genetic approaches. The patient described here also had dolichocolon which has not been described before in association with SCN.
Plucinska K, Zaman S, Cohen P
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Fructose: Not sweet enough for brown fat?

CELL REPORTS MEDICINE 2022 SEP 20; 3(9):? Article 100747
In a randomized crossover study in humans, high fructose feeding reduced glucose uptake in brown fat without affecting the tissue's oxidative capacity. These effects were independent of alterations in the gut mi-crobiome.
Youssefian L, Saeidian AH, Tavasoli AR, Kalamati E, Naghipoor K, Hozhabrpour A, Mesdaghi M, Saffarian Z, Mahmoudi H, Nabavi M, Shokri S, Zeinali S, Beziat V, Casanova JL, Jouanguy E, Uitto J, Vahidnezhad H
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Recalcitrant Cutaneous Warts in a Family with Inherited ICOS Deficiency

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2022 SEP; 142(9):2435-2445
Recalcitrant warts, caused by human papillomaviruses (HPVs), can be a cutaneous manifestation of inborn error of immunity. This study investigated the clinical manifestations, immunodeficiency, single-gene susceptibility, and HPV repertoire in a consanguineous family with severe sinopulmonary infections and recalcitrant warts. Clinical and immunologic evaluations, including FACS and lymphocyte transformation test, provided evidence for immunodeficiency. Combined whole-exome sequencing and genome-wide homozygosity mapping were utilized to disclose candidate sequence variants. Whole-transcriptome sequencing was used to concomitantly investigate the HPV genotypes and the consequences of detected sequence variants in the host. The proband, a male aged 41 years, was found to be homozygous for the c.6delG, p.Lys2Asnfs*17 variant in ICOS, encoding the inducible T-cell costimulator. This variant was located inside the 5 megabase of runs of homozygosity on 2q33.2. RNA sequencing confirmed the deleteriousness of the ICOS variant in three skin biopsies revealing significant downregulation of ICOS and its ligand, ICOSLG. Reads unaligned to the human genome were applied to 926 different viruses, and alpha-HPV57, beta-HPV107, beta-HPV14, and beta-HPV17 were detected. Collectively, we describe a previously unrecognized inborn error of T-cell immunity to HPVs, indicating that autosomal recessive ICOS deficiency can underlie recalcitrant warts, emphasizing the immunologic underpinnings of recalcitrant warts at the nexus of human and viral genomic variation.
Haselwandtera CA, Guoc YR, Fuc Z, MacKinnon R
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Elastic properties and shape of the Piezo dome underlying its mechanosensory function

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2022 SEP 26; 119(40):? Article e2208034119
We show in the companion paper that the free membrane shape of lipid bilayer vesicles containing the mechanosensitive ion channel Piezo can be predicted, with no free parameters, from membrane elasticity theory together with measurements of the protein geometry and vesicle size [C. A. Haselwandter, Y. R. Guo, Z. Fu, R. MacKinnon, Proc. Natl. Acad. Sci. U.S.A., 10.1073/pnas.2208027119 (2022)]. Here we use these results to determine the force that the Piezo dome exerts on the free membrane and hence, that the free membrane exerts on the Piezo dome, for a range of vesicle sizes. From vesicle shape measurements alone, we thus obtain a force-distortion relationship for the Piezo dome, from which we deduce the Piezo dome's intrinsic radius of curvature, 42 +/- 12 nm, and bending stiffness, 18 +/- 2.1 k(B)T, in freestanding lipid bilayer membranes mimicking cell membranes. Applying these estimates to a spherical cap model of Piezo embedded in a lipid bilayer, we suggest that Piezo's intrinsic curvature, surrounding membrane footprint, small stiffness, and large area are the key properties of Piezo that give rise to low-threshold, high-sensitivity mechanical gating.
Cheng HY, Jarvis ED, Fedrigo O, Koepfli KP, Urban L, Gemmell NJ, Li H
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Haplotype-resolved assembly of diploid genomes without parental data

NATURE BIOTECHNOLOGY 2022 SEP; 40(9):1332-+
Routine haplotype-resolved genome assembly from single samples remains an unresolved problem. Here we describe an algorithm that combines PacBio HiFi reads and Hi-C chromatin interaction data to produce a haplotype-resolved assembly without the sequencing of parents. Applied to human and other vertebrate samples, our algorithm consistently outperforms existing single-sample assembly pipelines and generates assemblies of similar quality to the best pedigree-based assemblies.
Shebl B, Ng D, Lalazar G, Rosemore C, Finkelstein TM, Migler RD, Zheng GR, Zhang PY, Jiang CS, Qureshi A, Vaughan R, Yarchoan M, de Jong YP, Rice CM, Coffino P, Ortiz MV, Zhou DH, Simon SM
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Targeting BCL-XL in fibrolamellar hepatocellular carcinoma

JCI INSIGHT 2022 SEP 8; 7(17):? Article e161820
Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal liver cancer with no proven effective systemic therapy. Inhibition of the antiapoptotic protein BCL-XL was found to synergize with a variety of systemic therapies in vitro using cells dissociated from patient-derived xenografts (PDX) of FLC or cells dissociated directly from surgical patient resections. As BCL-XL is physiologically expressed in platelets, prior efforts to leverage this vulnerability in other cancers have been hampered by severe thrombocytopenia. To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xenografts derived from patients with FLC demonstrated remarkable synergy and at clinically achievable doses not associated with significant thrombocytopenia.
Kim M, Mikhaylov D, Rangel SM, Pavel AB, He H, Renert-Yuval Y, Del Duca E, Malik K, Huynh T, Ibler E, Sun M, Zhang N, Estrada Y, Krueger J, Paller AS, Guttman-Yassky E
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Transcriptomic Analysis of the Major Orphan Ichthyosis Subtypes Reveals Shared Immune and Barrier Signatures

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2022 SEP; 142(9):2363-+
Preliminary work suggested upregulation of inflammatory pathways in patients with common forms of ichthyosis. However, a comprehensive characterization of skin from various ichthyosis subtypes is unavailable, precluding the development of targeted treatments. Thus, we sought to characterize the immune and barrier profiles of common and subtype-specific skin transcriptomes in a large group of patients with ichthyosis. We performed a global RNA-sequencing analysis in 54 patients with ichthyosis (7 with Netherton syndrome, 13 with epidermolytic ichthyosis, 16 with lamellar ichthyosis, and 18 with congenital ichthyosiform erythroderma) and 40 healthy controls. Differentially expressed genes were defined on the basis of fold changes > 2 and false discovery rate < 0.05 criteria. We found robust and significant T helper (Th) 22/Th17 skewing in all subtypes (e.g., IL-17A/C/F, S100A7/8/9/12; P < 0.001) with modest changes in Th2 pathway, primarily in Netherton syndrome, and Th1 skewing in congenital ichthyosiform erythroderma. Across all subtypes (less evident in epidermolytic ichthyosis), lipid metabolism and barrier junction markers were downregulated (e.g., FA2H, CDH10/ 11/12/2; P < 0.05), whereas epidermal cornification and proliferation measures were upregulated (e.g., SPRR1A/ 1B/2C/2G, EREG; P < 0.05). Our findings suggest that the common ichthyosis variants share aberrations in Th17/ Th22 and barrier function, with minimal Th2 modulation. This may help to elucidate the pathogeneses of these subtypes and inform the development of subtype-specific treatments.
Koschitzky M, Navrazhina K, Garshick MS, Gonzalez J, Han JS, Garcet S, Krueger JG
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Ustekinumab reduces serum protein levels associated with cardiovascular risk in psoriasis vulgaris

EXPERIMENTAL DERMATOLOGY 2022 SEP; 31(9):1341-1351
Psoriasis increases the risk of cardiovascular disease (CVD). Biomarkers for cardiovascular (CV) risk stratification in psoriasis are lacking, and the effects of psoriasis biologics on CV risk reduction remain unclear. The goal of this study was to identify biomarkers of CV risk in psoriasis blood that are reduced by ustekinumab. We quantified 276 inflammatory and CV-related serum proteins with Olink's multiplex assay in 10 psoriasis patients (vs. 18 healthy controls) and after 12 weeks of ustekinumab treatment. For each protein down-regulated after treatment, the literature was reviewed for studies assessing the protein's association with CVD. Data were collected from each study to calculate CV risk thresholds for each protein, which were compared with protein levels in psoriasis patients before and after treatment. Our results showed that 43 out of 276 proteins were down-regulated after treatment, 25 of which were initially up-regulated at baseline (vs. controls, all p-values <= 0.1). 8 down-regulated proteins were initially elevated above thresholds associated with enhanced CV risk in the literature (myeloperoxidase, C-X-C motif chemokine 10, E-selectin, interleukin-6, cystatin B, von Willebrand factor, tumor necrosis factor receptor 1 and N-terminal prohormone brain natriuretic peptide). Treatment lowered these proteins to below their risk thresholds, except for IL-6, which was lowered but remained at its risk threshold despite successful psoriasis skin treatment. In summary, 12 weeks of ustekinumab treatment reduced serum proteins present at levels associated with CV risk in psoriasis patients. Further studies can evaluate these proteins as potential ustekinumab-modulated biomarkers of CV risk in psoriasis and the impact of ustekinumab on CV risk reduction.