Loss of pRB and p107 disrupts cartilage development and promotes enchondroma formation

The pocket proteins pRB, p107 and p130 have established roles in regulating the cell cycle through the control of E2F activity. The pocket proteins regulate differentiation of a number of tissues in both cell cycle-dependent and -independent manners. Prior studies showed that mutation of p107 and p130 in the mouse leads to defects in cartilage development during endochondral ossification, the process by which long bones form. Despite evidence of a role for pRB in osteoblast differentiation, it is unknown whether it functions during cartilage development. Here, we show that mutation of Rb in the early mesenchyme of p107-mutant mice results in severe cartilage defects in the growth plates of long bones. This is attributable to inappropriate chondrocyte proliferation that persists after birth and leads to the formation of enchondromas in the growth plates as early as 8 weeks of age. Genetic crosses show that development of these tumorigenic lesions is E2f3 dependent. These results reveal an overlapping role for pRB and p107 in cartilage development, endochondral ossification and enchondroma formation that reflects their coordination of cell-cycle exit at appropriate developmental stages.Virginia and D.K. Ludwig Fund for Cancer Research (Fellowship)National Cancer Institute (U.S.) (Grant CA121921

E2f4 and E2f5 are essential for the development of the male reproductive system

The E2F transcription factors are primarily implicated in the regulation of entry and exit from the cell cycle. However, in vivo studies have established additional roles for E2Fs during organ development and homeostasis. With the goal of addressing the intestinal requirements of E2f4 and E2f5, we crossed mice carrying Vil-cre, E2f4 conditional and E2f5 germline alleles. E2f4 deletion had no detectable effect on intestinal development. However, E2f4f/f;E2f5+/−;Vil-cre males, but not E2f4f/f;Vil-cre littermates, were unexpectedly sterile. This defect was not due to defective spermatogenesis. Instead, the seminiferous tubules and rete testes showed significant dilation, and spermatozoa accumulated aberrantly in the rete testis and efferent ducts. Our data show that these problems result from defective efferent ducts, a tissue whose primary function is to concentrate sperm through fluid absorption. First, Vil-cre expression, and consequent E2F4 loss, was specific to the efferent ducts and not other reproductive tract tissues. Second, the E2f4f/f;E2f5+/−;Vil-cre efferent ducts had completely lost multiciliated cells and greatly reduced levels of critical absorptive cell proteins: aquaporin1, a water channel protein, and clusterin, an endocytic marker. Collectively, the observed testis phenotypes suggest a fluid flux defect. Remarkably, we observed rete testis dilation prior to the normal time of seminiferous fluid production, arguing that the efferent duct defects promote excessive secretory activity within the reproductive tract. Finally, we also detect key aspects of these testis defects in E2f5−/− mice. Thus, we conclude that E2f4 and E2f5 display overlapping roles in controlling the normal development of the male reproductive system.National Institutes of Health (U.S.) (Grant NIH-P01 CA42063

E2F4 cooperates with pRB in the development of extra-embryonic tissues

August 1, 2010The retinoblastoma gene, RB-1, was the first identified tumor suppressor. Rb[superscript −/−] mice die in mid-gestation with defects in proliferation, differentiation and apoptosis. The activating E2F transcription factors, E2F1–3, contribute to these embryonic defects, indicating that they are key downstream targets of the retinoblastoma protein, pRB. E2F4 is the major pRB-associated E2F in vivo, yet its role in Rb[superscript −/−] embryos is unknown. Here we establish that E2f4 deficiency reduced the lifespan of Rb[superscript −/−] embryos by exacerbating the Rb mutant placental defect. We further show that this reflects the accumulation of trophectoderm-like cells in both Rb and Rb;E2f4 mutant placentas. Thus, Rb and E2f4 play cooperative roles in placental development. We used a conditional mouse model to allow Rb[superscript −/−];E2f4[superscript −/−] embryos to develop in the presence of Rb wild-type placentas. Under these conditions, Rb[superscript −/−];E2f4[superscript −/−] mutants survived to birth. These Rb[superscript −/−];E2f4[superscript −/−] embryos exhibited all of the defects characteristic of the Rb and E2f4 single mutants and had no novel defects. Taken together, our data show that pRB and E2F4 cooperate in placental development, but play largely non-overlapping roles in the development of many embryonic tissues.David H. Koch Institute for Integrative Cancer Research at MIT. Pearl Staller Graduate Student FundNational Institutes of Health (U.S.) (Grant GM53204)National Institutes of Health (U.S.) (Grant CA121921

Спрощені режими оподаткування: ретроспектива та перспектива

Даніелян С. А. Спрощені режими оподаткування: ретроспектива та перспектива / С. А. Даніелян // Правове життя сучасної України : матеріали Міжнар. наук. конф. проф.-викл. та аспірант. складу (м. Одеса, 16-17 травня 2013 р.) / відп. за вип. В. М. Дрьомін ; НУ "ОЮА". Півд. регіон. центр НАПрН України. - Одеса : Фенікс, 2013. - Т. 2. - С. 167-168

Enteric Neurospheres Are Not Specific to Neural Crest Cultures: Implications for Neural Stem Cell Therapies

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited

Паравертебральная блокада при лечении пациентов с закрытой травмой груди

The study was conducted in the Thoracoabdominal Department of the N.V. Sklifosovsky Research Institute for Emergency Medicine to explore the role of paravertebral block in the treatment of blunt chest trauma. The study included 715 patients with isolated chest trauma hospitalized between January 1, 2020 and August 2021. 55 patients received analgesic therapy in the form of paravertebral block. The comparison group included 660 patients who did not undergo paravertebral block, in their case pain relief was provided by systemic administration of analgesics. The compared groups did not differ significantly in sex and age composition. There were also no differences in the frequency of chronic diseases and interpleural complications. There were no significant complications during the block. The comparison revealed a significant decrease in the incidence of pleurisy and a shorter length of stay in hospital. Paravertebral block is an effective and safe method of pain management for patients with blunt chest trauma. The use of this technique reduces the incidence of post-traumatic pleurisy and duration of hospitalization.Исследование проведено в торакоабдоминальном отделении НИИ СП им. Н.В. Склифосовского с целью изучения значения паравертебральной блокады. Было включено 715 пациентов с изолированной травмой груди, госпитализированных в экстренном порядке в период с 1 января 2020 по август 2021 года; 55 пациентов в ходе лечения получили обезболивающую терапию в виде паравертебральной блокады. В группу сравнения включили 660 пациентов, которым не выполняли проводниковую блокаду, обезболивание обеспечивали системным введением анальгетиков. Сравниваемые группы значимо не отличались по половому и возрастному составу. Отличий в частоте хронических заболеваний и интраплевральных осложнений также не было. Значимых осложнений при выполнении блокады не отмечалось. При сравнении выявлено достоверное уменьшение частоты плеврита и более короткое время нахождения в стационаре. Паравертебральная блокада является эффективным и безопасным методом обезболивания пациентов с закрытой травмой груди. Использование этой методики снижает частоту развития посттравматического плеврита и ускоряет выписку больных

Circuit dissection of the role of somatostatin in itch and pain

Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+ neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide