Trade-off between Responsiveness and Noise Suppression in Biomolecular System Responses to Environmental Cues

When living systems detect changes in their external environment their response must be measured to balance the need to react appropriately with the need to remain stable, ignoring insignificant signals. Because this is a fundamental challenge of all biological systems that execute programs in response to stimuli, we developed a generalized time-frequency analysis (TFA) framework to systematically explore the dynamical properties of biomolecular networks. Using TFA, we focused on two well-characterized yeast gene regulatory networks responsive to carbon-source shifts and a mammalian innate immune regulatory network responsive to lipopolysaccharides (LPS). The networks are comprised of two different basic architectures. Dual positive and negative feedback loops make up the yeast galactose network; whereas overlapping positive and negative feed-forward loops are common to the yeast fatty-acid response network and the LPS-induced network of macrophages. TFA revealed remarkably distinct network behaviors in terms of trade-offs in responsiveness and noise suppression that are appropriately tuned to each biological response. The wild type galactose network was found to be highly responsive while the oleate network has greater noise suppression ability. The LPS network appeared more balanced, exhibiting less bias toward noise suppression or responsiveness. Exploration of the network parameter space exposed dramatic differences in system behaviors for each network. These studies highlight fundamental structural and dynamical principles that underlie each network, reveal constrained parameters of positive and negative feedback and feed-forward strengths that tune the networks appropriately for their respective biological roles, and demonstrate the general utility of the TFA approach for systems and synthetic biology

СОВРЕМЕННЫЕ КРИТЕРИИ ОТБОРА ПАЦИЕНТОВ ДЛЯ РЕКОНСТРУКЦИИ ВИСЦЕРАЛЬНЫМИ АУТОТРАНСПЛАНТАТАМИ ВЕРХНИХ ОТДЕЛОВ АЭРОДИГЕСТИВНОГО ТРАКТА ПРИ ЛЕЧЕНИИ ЗЛОКАЧЕСТВЕННЫХ ОПУХОЛЕЙ ГОЛОВЫ И ШЕИ

Introduction. The high incidence of cancer of the upper aerodigestive tract, impairment of breathing, speech, and swallowing functions accompanied by prolonged and often persistent disability put the rehabilitation and the quality of life of patients among the most important social problems.Material and methods. We have gained experience in reconstructing the pharynx and esophagus with various fragments of the gastrointestinal tract in 121 cancer patients. Based on our own clinical experience, the most important criteria of selecting patients after laryngectomy for reconstruction of the upper aerodigestive tract with visceral flaps were identified. Visceral autografts formed from different parts of the patient’s gastrointestinal tract were full-layer fragments of the abdominal organs, which included the mucous membrane of the stomach, small intestine, or large intestine. In some patients, the choice of flap was limited by a large omentum.Results. In 9.9 % of cases, flap necrosis was observed. Oral nutrition was restored in 93.9 % of patients. In 90.5 % of cases, speech function was restored after the installation of avoice prosthesis. The method of autologous transplantation of the ileo-colonic flap made it possible not only to remove the organs affected by the tumor, but also to simultaneously restore the lost nutrition and vocal functions without resorting to artificial prostheses, but using only their own tissues. The 5-year survival rates were 36.4 % and 67.3 % in patients with simultaneous reconstruction and in patients with delayed reconstruction, respectively.Conclusion. The use of visceral flaps in the reconstruction of the upper aerodigestive tract allows patients to restore both the nutrition and voice functions after laryngectomy.Введение. Значительная распространенность опухолей верхних отделов аэродигестивного тракта, сложность и стойкость нарушения функций дыхания, речи, глотания, сопровождающиеся длительной и нередко стойкой утратой трудоспособности, ставят проблему реабилитации и качества жизни больных в ряд важнейших социальных задач.Материал и методы. нами накоплен опыт реконструкции глотки и пищевода различными фрагментами желудочно-кишечного тракта у 121 пациента со злокачественными опухолями. на основе собственного клинического опыта нами были сформированы основные критерии отбора пациентов после ларингэктомии для реконструкции верхних отделов аэродигестивного тракта висцеральными аутотрансплантатами. Это были полнослойные фрагменты органов брюшной полости, которые включали в себя слизистую оболочку желудка, тонкой или толстой кишки. У ряда больных выбор аутотрансплантата ограничивался большим сальником.Результаты. В 9,9 % наблюдений был отмечен некроз аутотрансплантата. Питание через рот было восстановлено у 93,9 % оперированных больных. В 90,5 % случаев после установки голосового протеза была восстановлена речевая функция. Способ аутотрансплантации подвздошно-толстокишечного лоскута позволил в один хирургический этап выполнить не только удаление пораженных опухолью органов, но и одномоментно восстановить утраченные пищепроводную и голосовую функции, не прибегая к помощи искусственных протезов, а используя только собственные ткани. Показатели 5-летней выживаемости в группе больных при одномоментной реконструкции составили 36,4 %, в группе с отсроченной реконструкцией – 67,3 %.Заключение. использование висцеральных аутотрансплантатов при реконструкции верхних отделов аэродигестивного тракта после ларингэктомии позволяет восстановить пациентам как пищепроводную, так и голосовую функции

Genome-Wide Analysis of Effectors of Peroxisome Biogenesis

Peroxisomes are intracellular organelles that house a number of diverse metabolic processes, notably those required for β-oxidation of fatty acids. Peroxisomes biogenesis can be induced by the presence of peroxisome proliferators, including fatty acids, which activate complex cellular programs that underlie the induction process. Here, we used multi-parameter quantitative phenotype analyses of an arrayed mutant collection of yeast cells induced to proliferate peroxisomes, to establish a comprehensive inventory of genes required for peroxisome induction and function. The assays employed include growth in the presence of fatty acids, and confocal imaging and flow cytometry through the induction process. In addition to the classical phenotypes associated with loss of peroxisomal functions, these studies identified 169 genes required for robust signaling, transcription, normal peroxisomal development and morphologies, and transmission of peroxisomes to daughter cells. These gene products are localized throughout the cell, and many have indirect connections to peroxisome function. By integration with extant data sets, we present a total of 211 genes linked to peroxisome biogenesis and highlight the complex networks through which information flows during peroxisome biogenesis and function

Реконструкция гортаноглотки с использованием аутологичных тканеинженерных эпителизированных лоскутов

After removal of metastatic malignant tumors of the hypopharynx and larynx, hypopharyngeal defects are formed. To restore the hypopharynx, a mucosa and a muscular component are needed.The objective of this study is to develop a hypopharyngeal reconstruction technique using prelaminated pectoralis major flap with mucosal epithelium analogue from autologous epithelial layers.Materials and methods. Nine patients underwent reconstruction of the hypopharynx using bioengineered prelaminated pectoralis major flaps. The mucosa was restored by tissue-engineered autologous epithelial cell layers that were obtained by culturing in vitro cells isolated from skin biopsies that were previously obtained from patients.Results. Oral nutrition was restored in all cases. Pharyngeal stenosis was detected in one (11%) patient. A stratified squamous epithelium on the pectoral fascia was revealed in 67% of cases at week 2 after prelamination, in 89% of cases at week 4 after reconstruction and in 100% of cases at month 3, 6, 12 and 24 after reconstruction.Conclusion. Reconstruction using prelaminated bioengineered flaps allows recreating the anatomical integrity and function of the hypopharynx.После удаления распространенных злокачественных опухолей гортаноглотки и гортани образуются дефекты верхних пищеварительных путей, для устранения которых необходимы слизистая оболочка и мышечный компонент.Целью данного исследования является разработка методики реконструкции гортаноглотки с использованием преламинированных пекторальных лоскутов с аналогом эпителия слизистой оболочки из аутологичных эпителиальных пластов.Материалы и методы. Девяти пациентам выполнена реконструкция гортаноглотки биоинженерными преламинированными пекторальными лоскутами с восстановлением слизистой оболочки тканеинженерными аутологичными эпителиальными клеточными пластами, которые были получены путем культивирования in vitro клеток, выделенных из предварительно полученных у пациентов биоптатов кожи.Результаты. Во всех случаях было восстановлено пероральное питание. У одного (11%) пациента был выявлен стеноз глотки. Многослойный плоский эпителий на фасции пекторального лоскута выявлен в 67% случаев через 2 недели после преламинации, в 89% случаев – через 4 недели после реконструкции и в 100% случаев – через 3, 6, 12, 24 месяца после реконструкции.Заключение. Реконструкция с использованием преламинированных биоинженерных лоскутов позволяет воссоздать анатомическую целостность и функцию гортаноглотки

Involvement in surface antigen expression by a moonlighting FG-repeat nucleoporin in trypanosomes

Components of the nuclear periphery coordinate a multitude of activities, including macromolecular transport, cell-cycle progression, and chromatin organization. Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport, mRNA processing, and transcriptional regulation, and NPC components can define regions of high transcriptional activity in some organisms at the nuclear periphery and nucleoplasm. Lineage-specific features underpin several core nuclear functions and in trypanosomatids, which branched very early from other eukaryotes, unique protein components constitute the lamina, kinetochores, and parts of the NPCs. Here we describe a phenylalanine-glycine (FG)-repeat nucleoporin, TbNup53b, that has dual localizations within the nucleoplasm and NPC. In addition to association with nucleoporins, TbNup53b interacts with a known trans-splicing component, TSR1, and has a role in controlling expression of surface proteins including the nucleolar periphery-located, procyclin genes. Significantly, while several nucleoporins are implicated in intranuclear transcriptional regulation in metazoa, TbNup53b appears orthologous to components of the yeast/human Nup49/Nup58 complex, for which no transcriptional functions are known. These data suggest that FG-Nups are frequently co-opted to transcriptional functions during evolution and extend the presence of FG-repeat nucleoporin control of gene expression to trypanosomes, suggesting that this is a widespread and ancient eukaryotic feature, as well as underscoring once more flexibility within nucleoporin function

MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and it presents a therapeutic challenge in organ transplant recipient patients. Despite the need, there are only a few targeted drug treatment options. Recent studies have revealed a pivotal role played by microRNAs (miRNAs) in multiple cancers, but only a few studies tested their function in cSCC. Here, we analyzed differential expression of 88 cancer related miRNAs in 43 study participants with cSCC; 32 immunocompetent, 11 OTR patients, and 15 non-lesional skin samples by microarray analysis. Of the examined miRNAs, miR-135b was the most upregulated (13.3-fold, 21.5-fold; p=0.0001) in both patient groups. Similarly, the miR-135b expression was also upregulated in three cSCC cell lines when evaluated by quantitative real-time PCR. In functional studies, inhibition of miR-135b by specific anti-miR oligonucleotides resulted in upregulation of its target gene LZTS1 mRNA and protein levels and led to decreased cell motility and invasion of both primary and metastatic cSCC cell lines. In contrast, miR-135b overexpression by synthetic miR-135b mimic induced further down-regulation of LZTS1 mRNA in vitro and increased cancer cell motility and invasiveness. Immunohistochemical evaluation of 67 cSCC tumor tissues demonstrated that miR-135b expression inversely correlated with LZTS1 staining intensity and the tumor grade. These results indicate that miR-135b functions as an oncogene in cSCC and provide new understanding into its pathological role in cSCC progression and invasiveness

p53 and TAp63 promote keratinocyte proliferation and differentiation in breeding tubercles of the zebrafish

p63 is a multi-isoform member of the p53 family of transcription factors. There is compelling genetic evidence that ΔNp63 isoforms are needed for keratinocyte proliferation and stemness in the developing vertebrate epidermis. However, the role of TAp63 isoforms is not fully understood, and TAp63 knockout mice display normal epidermal development. Here, we show that zebrafish mutants specifically lacking TAp63 isoforms, or p53, display compromised development of breeding tubercles, epidermal appendages which according to our analyses display more advanced stratification and keratinization than regular epidermis, including continuous desquamation and renewal of superficial cells by derivatives of basal keratinocytes. Defects are further enhanced in TAp63/p53 double mutants, pointing to partially redundant roles of the two related factors. Molecular analyses, treatments with chemical inhibitors and epistasis studies further reveal the existence of a linear TAp63/p53->Notch->caspase 3 pathway required both for enhanced proliferation of keratinocytes at the base of the tubercles and their subsequent differentiation in upper layers. Together, these studies identify the zebrafish breeding tubercles as specific epidermal structures sharing crucial features with the cornified mammalian epidermis. In addition, they unravel essential roles of TAp63 and p53 to promote both keratinocyte proliferation and their terminal differentiation by promoting Notch signalling and caspase 3 activity, ensuring formation and proper homeostasis of this self-renewing stratified epithelium