What the West owes Syrians

In What the West Owes Syrians, Diana Bashur explores another significant post-uprising reality, Syrian refugees and the costs involved in hosting them by Western countries. Here Bashur is seeking to draw our attention to an important, yet largely ignored, correlation between the profit incurred through arms sales by Western countries to countries that have provided support to the armed opposition and the costs involved in hosting Syrian refugees in the West. Bashur eloquently contrasts the extent to which the West was enthusiastic about the Arab Spring with the significant increase in arms sales to the region by EU and the US, 23% and 300% respectively. Bashur leaves us with the sobering probability that some European politicians “… may have opted for a tradeoff: making their taxpayers shoulder the short-term cost of hosting refugees in exchange for profits to the arms industry.”Publisher PD

The Day After: Post-Uprising Realities & Challenges

We are presently entering what might be termed the ‘Day After’ phase (or phases) of the Syrian Uprising; a period when the uprising and all the wars it unleashed gradually give way to the harsh realities of demarcation lines, the challenges of reconstruction, and the astronomical bill of the war effort. The fact that this phase involves a regime ‘victory’ that could not have been achieved without the overwhelming support of Russia and Iran, means that the regime is unable to enforce its own conditions and must constantly negotiate with the Russians, and at times the Iranians, regarding the optimal way to exercise its authority. The US military presence which, at least presently, appears to be long term, adds additional pressure on the regime and restricts its capacity to expand its territory. In this issue of Syria Studies, we are pleased to share three studies that shed light on some of these complex layers of post-uprising Syria

The master developmental regulator Jab1/Cops5/Csn5 is essential for proper bone growth and survival in mice

Jab1, also known as Csn5/Cops5, is a key subunit of the COP9 Signalosome, a highly conserved macromolecular complex. We previously reported that the conditional knockout of Jab1 in mouse limb buds and chondrocytes results in severely shortened limbs and neonatal lethal chondrodysplasia, respectively. In this study, we further investigated the specific role of Jab1 in osteoblast differentiation and postnatal bone growth by characterizing a novel mouse model, the Osx-cre; Jab1flox/flox conditional knockout (Jab1 cKO) mouse, in which Jab1 is deleted in osteoblast precursor cells. Jab1 cKO mutant mice appeared normal at birth, but developed progressive dwarfism. Inevitably, all mutant mice died prior to weaning age. The histological and micro-computed tomography analysis of mutant long bones revealed severely altered bone microarchitecture, with a significant reduction in trabecular thickness. Moreover, Jab1 cKO mouse tibiae had a drastic decrease in mineralization near the epiphyseal growth plates, and Jab1 cKO mice also developed spontaneous fractures near the tibiofibular junction. Additionally, our cell culture studies demonstrated that Jab1 deletion in osteoblast precursors led to decreased mineralization and a reduced response to TGFβ and BMP signaling. Moreover, an unbiased reporter screen also identified decreased TGFβ activity in Jab1-knockdown osteoblasts. Thus, Jab1 is necessary for proper osteoblast differentiation and postnatal bone growth, likely in part through its positive regulation of the TGFβ and BMP signaling pathways in osteoblast progenitor cells

The Crucial p53-Dependent Oncogenic Role of JAB1 in Osteosarcoma in vivo

Osteosarcoma (OS) is the most common primary bone cancer and ranks amongst the leading causes of cancer mortality in young adults. Jun activation domain binding protein 1 (JAB1) is overexpressed in many cancers and has recently emerged as a novel target for cancer treatment. However, the role of JAB1 in osteosarcoma was virtually unknown. In this study, we demonstrate that JAB1-knockdown in malignant osteosarcoma cell lines significantly reduced their oncogenic properties, including proliferation, colony formation, and motility. We also performed RNA-sequencing analysis in JAB1-knockdown OS cells and identified 4110 genes that are significantly differentially expressed. This demonstrated for the first time that JAB1 regulates a large and specific transcriptome in cancer. We also found that JAB1 is overexpressed in human OS and correlates with a poor prognosis. Moreover, we generated a novel mouse model that overexpresses Jab1 specifically in osteoblasts upon a TP53 heterozygous sensitizing background. Interestingly, by 13 months of age, a significant proportion of these mice spontaneously developed conventional OS. Finally, we demonstrate that a novel, highly specific small molecule inhibitor of JAB1, CSN5i-3, reduces osteosarcoma cell viability and has specific effects on the ubiquitin-proteasome system in OS. Thus, we show for the first time that the overexpression of JAB1 in vivo can result in accelerated spontaneous tumor formation in a p53-dependent manner. In summary, JAB1 might be a unique target for the treatment of osteosarcoma and other cancers

Polymer fiber-based models of connective tissue repair and healing

National Institutes of Health (R01-AR055280, Presidential Early Career Award for Scientists and Engineers, HHL)), the DoD CDMRP award (W81XWH-15-1-0685, HHL&WNL), and the Columbia University Center for Technology, Innovation and Communicty Engagement (CTICE Fellowship, NML)

Unusual congenital polydactyly in mini-pigs from the breeding group of the Institute of Cytology and Genetics (Novosibirsk, Russia)

The article describes a new phenomenon in the breeding group of mini-pigs at the Institute of Cytology and Genetics (ICG, Novosibirsk): polydactyly (extra digits), which is unusual because the additional digits are situated at the lateral surface of legs or at the lateral and medial ones. This anomaly was first found here in 2017 in adult animals intended for culling due to incorrect positioning of the legs caused by flexor tendon laxity and resulting in weight-bearing on the palmar surface of the proximal phalanges (“bear’s paw”). Therefore, the polydactyly of mini-pigs has a pronounced negative selection effect. A visual survey of the livestock was conducted, and a description of the detected anomaly was compiled. The polydactyly in mini-pigs is a stand-alone trait and is not part of any syndromes. Individuals with polydactyly may have extra digits either on pectoral or on pectoral and pelvic limbs. On thoracic limbs, there may be either one lateral digit or a lateral digit and a medially located rudimentary hooflet. On pelvic limbs, only lateral extra digits can occur. Anatomical and morphological analyses showed that the lateral extra digit is an anatomically complete (“mature”) structure, whereas the medial rudimentary digit consists of only a hooflet without other structures characteristic of normal digits. Cytological examination revealed no specific karyotypic features, except for Robertsonian translocation Rb 16;17 previously reported for the mini-pigs of the same livestock. Cytological findings indicated that the polydactyly and Robertsonian translocation are not linked genetically. Genealogical analysis and results of crosses are consistent with a working hypothesis of recessive inheritance of the trait. Overall, the study shows that this type of polydactyly is anatomically and morphologically unique and not typical of Sus scrofa. In this species, only polydactyly types with medial accessory toes have been described and are usually inherited as a dominant trait with incomplete penetrance. In our case, the results of test crosses indicate recessive inheritance of the trait with varying expression and incomplete penetrance, because of which poorly expressed phenotypes are not visually detectable

Immunocompetent 3D Model of Human Upper Airway for Disease Modeling and In Vitro Drug Evaluation

The development of more complex in vitro models for the assessment of novel drugs and chemicals is needed because of the limited biological relevance of animal models to humans as well as ethical considerations. Although some human-cell-based assays exist, they are usually 2D, consist of single cell type, and have limited cellular and functional representation of the native tissue. In this study, we have used biomimetic porous electrospun scaffolds to develop an immunocompetent 3D model of the human respiratory tract comprised of three key cell types present in upper airway epithelium. The three cell types, namely, epithelial cells (providing a physical barrier), fibroblasts (extracellular matrix production), and dendritic cells (immune sensing), were initially grown on individual scaffolds and then assembled into the 3D multicell tissue model. The epithelial layer was cultured at the air–liquid interface for up to four weeks, leading to formation of a functional barrier as evidenced by an increase in transepithelial electrical resistance (TEER) and tight junction formation. The response of epithelial cells to allergen exposure was monitored by quantifying changes in TEER readings and by assessment of cellular tight junctions using immunostaining. It was found that epithelial cells cocultured with fibroblasts formed a functional epithelial barrier at a quicker rate than single cultures of epithelial cells and that the recovery from allergen exposure was also more rapid. Also, our data show that dendritic cells within this model remain viable and responsive to external stimulation as evidenced by their migration within the 3D construct in response to allergen challenge. This model provides an easy to assemble and physiologically relevant 3D model of human airway epithelium that can be used for studies aiming at better understanding lung biology, the cross-talk between immune cells, and airborne allergens and pathogens as well as drug delivery

КРУПНОПЛОДНОСТЬ МИНИ-СВИНЕЙ ИЦиГ СО РАН: ПОТЕНЦИАЛ НЕРЕАЛИЗУЕМЫХ ВОЗМОЖНОСТЕЙ

This publication presents the results of the analysis of the dynamics of changes in the largefruited indicators of the breeding group of minipigs of the ICG SB RAS. The analysis showed that the four large-copious indicators are divided into two pairs. The first pair is made up of sample values of the characteristic: average and maximum. These indicators are characterized by stability throughout the studied period. The second pair includes the sample minimum values and standard deviations of the trait. These two indicators are dynamic: the sample minimum values are characterized by a decrease, and the sample standard deviations are characterized by a uniform increase, described by linear regression equations. It is shown that the dynamic characteristics are related to each other. It is determined that in this complex, the leader is the minimum value, and the follower is the standard deviation. This is explained by the fact that an increase in the standard deviation is associated with a decrease in the minimum value and the stability of the maximum in the studied period of time. The result of this process is the growth of the genetic potential in the breeding group, which is responsible for the high weight of the newborn individual. However, due to the small size of sows in comparison with commercial breeds (60-70 kg), this potential cannot be realized. Nevertheless, its redundancy ensures the stabilization of the maximum and average values of the trait - the mass of a newborn individual in minipigs of the ICG SB RAS. A possible way to increase the realization of the potential of large-copious breeding group is to reduce the multiple fertility of sows, which is quite solvable, but hardly advisable. Thus there is natural selection directed against individuals with a low birth weight in the herd. Natural and artificial selection for live weight of piglets at birth of 700 g or more, both help to stabilize the average value of the trait at the level optimal for the broodstock.Настоящая публикация представляет результаты анализа динамик изменения показателей крупноплодности селекционной группы мини-свиней ИЦиГ СО РАН. Анализ показал, что четыре показателя крупноплодности делятся на две пары. Первую пару составляют выборочные значения признака: среднее и максимальное. Для этих показателей характерна стабильность на протяжении изучаемого периода. Во вторую пару вошли выборочные минимальные значения и стандартные отклонения признака. Эти два показателя являются динамическими: для выборочных минимальных значений характерно снижение, а для выборочных стандартных отклонений равномерное повышение, описываемое уравнениями линейной регрессии. Показано, что динамические характеристики связаны друг с другом. Определено, что в данном комплексе ведущим является минимальное значение, а ведомым – стандартное отклонение. Объясняется это тем, что увеличение стандартного отклонения сопряжено с уменьшением минимального значения и стабильностью максимального в изучаемый промежуток времени. Результатом этого процесса является рост в селекционной группе генетического потенциала, отвечающего за высокую массу новорожденной особи. Однако из-за малых по сравнению с коммерческими породами размеров свиноматок (60–70 кг) этот потенциал не может быть реализован. Тем не менее его избыточность обеспечивает стабилизацию максимального и среднего значения признака – массы новорождённой особи у мини-свиней ИЦиГ СО РАН. Возможный путь повышения реализации потенциала крупноплодности селекционной группы – это снижение многоплодия свиноматок, что вполне решаемо, но вряд ли целесообразно. Таким образом, в стаде присутствует естественный отбор, направленный против особей с малой массой при рождении, который в совокупности с искусственным отбором на живую массу поросят при рождении 700 г и более способствует стабилизации среднего значения признака на оптимальном для маточного поголовья уровне

Directed cell migration in multi-cue environments

Cell migration plays a critical role in development, angiogenesis, immune response, wound healing and cancer metastasis. During these processes, cells are often directed to migrate towards targets by sensing aligned fibers or gradients in concentration, mechanical properties or electric field. Often times, cells must integrate migrational information from several of these different cues. While the cell migration behavior, signal transduction and cytoskeleton dynamics elicited by individual directional cues has been largely determined, responses to multiple directional cues are much less understood. However, initial work has pointed to several interesting behaviors in multi-cue environments, including competition and cooperation between cues to determine the migrational responses of cells. Much of the work on multi-cue sensing has been driven by the recent development of approaches to systematically and simultaneously control directional cues in vitro coupled with analysis and modeling that quantitatively describe those responses. In this review we present an overview of multi-cue directed migration with an emphasis on how cues compete or cooperate. We outline how multi-cue responses such as cue dominance might change depending on other environmental inputs. Finally, the challenges associated with the design of the environments to control multiple cues and the analysis and modeling of cell migration in multi-cue environments as well as some interesting biological questions associated with migration in complex environments are discussed. Understanding multi-cue migrational responses is critical to the mechanistic description of physiology and pathology, but also to the design of engineered tissues, where cell migration must be orchestrated to form specific tissue structures