The promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation

Deciphering regulatory events that drive malignant transformation represents a major challenge for systems biology. Here we analyzed genome-wide transcription profiling of an in-vitro transformation process. We focused on a cluster of genes whose expression levels increased as a function of p53 and p16INK4A tumor suppressors inactivation. This cluster predominantly consists of cell cycle genes and constitutes a signature of a diversity of cancers. By linking expression profiles of the genes in the cluster with the dynamic behavior of p53 and p16INK4A, we identified a promoter architecture that integrates signals from the two tumor suppressive channels and that maps their activity onto distinct levels of expression of the cell cycle genes, which in turn, correspond to different cellular proliferation rates. Taking components of the mitotic spindle as an example, we experimentally verified our predictions that p53-mediated transcriptional repression of several of these novel targets is dependent on the activities of p21, NFY and E2F. Our study demonstrates how a well-controlled transformation process allows linking between gene expression, promoter architecture and activity of upstream signaling molecules.Comment: To appear in Molecular Systems Biolog

Efficient Multiparty Protocols via Log-Depth Threshold Formulae

We put forward a new approach for the design of efficient multiparty protocols: 1. Design a protocol for a small number of parties (say, 3 or 4) which achieves security against a single corrupted party. Such protocols are typically easy to construct as they may employ techniques that do not scale well with the number of corrupted parties. 2. Recursively compose with itself to obtain an efficient n-party protocol which achieves security against a constant fraction of corrupted parties. The second step of our approach combines the player emulation technique of Hirt and Maurer (J. Cryptology, 2000) with constructions of logarithmic-depth formulae which compute threshold functions using only constant fan-in threshold gates. Using this approach, we simplify and improve on previous results in cryptography and distributed computing. In particular: - We provide conceptually simple constructions of efficient protocols for Secure Multiparty Computation (MPC) in the presence of an honest majority, as well as broadcast protocols from point-to-point channels and a 2-cast primitive. - We obtain new results on MPC over blackbox groups and other algebraic structures. The above results rely on the following complexity-theoretic contributions, which may be of independent interest: - We show that for every integers j,k such that m = (k-1)/(j-1) is an integer, there is an explicit (poly(n)-time) construction of a logarithmic-depth formula which computes a good approximation of an (n/m)-out-of-n threshold function using only j-out-of-k threshold gates and no constants. - For the special case of n-bit majority from 3-bit majority gates, a non-explicit construction follows from the work of Valiant (J. Algorithms, 1984). For this special case, we provide an explicit construction with a better approximation than for the general threshold case, and also an exact explicit construction based on standard complexity-theoretic or cryptographic assumptions

Wide-Scale Analysis of Human Functional Transcription Factor Binding Reveals a Strong Bias towards the Transcription Start Site

We introduce a novel method to screen the promoters of a set of genes with shared biological function, against a precompiled library of motifs, and find those motifs which are statistically over-represented in the gene set. The gene sets were obtained from the functional Gene Ontology (GO) classification; for each set and motif we optimized the sequence similarity score threshold, independently for every location window (measured with respect to the TSS), taking into account the location dependent nucleotide heterogeneity along the promoters of the target genes. We performed a high throughput analysis, searching the promoters (from 200bp downstream to 1000bp upstream the TSS), of more than 8000 human and 23,000 mouse genes, for 134 functional Gene Ontology classes and for 412 known DNA motifs. When combined with binding site and location conservation between human and mouse, the method identifies with high probability functional binding sites that regulate groups of biologically related genes. We found many location-sensitive functional binding events and showed that they clustered close to the TSS. Our method and findings were put to several experimental tests. By allowing a "flexible" threshold and combining our functional class and location specific search method with conservation between human and mouse, we are able to identify reliably functional TF binding sites. This is an essential step towards constructing regulatory networks and elucidating the design principles that govern transcriptional regulation of expression. The promoter region proximal to the TSS appears to be of central importance for regulation of transcription in human and mouse, just as it is in bacteria and yeast.Comment: 31 pages, including Supplementary Information and figure

A treatment applying a biomechanical device to the feet of patients with knee osteoarthritis results in reduced pain and improved function: a prospective controlled study

<p>Abstract</p> <p>Background</p> <p>This study examined the effect of treatment with a novel biomechanical device on the level of pain and function in patients with knee OA.</p> <p>Methods</p> <p>Patients with bilateral knee OA were enrolled to active and control groups. Patients were evaluated at baseline, at 4 weeks and at the 8-week endpoint. A novel biomechanical device was individually calibrated to patients from the active group. Patients from the control group received an identical foot-worn platform without the biomechanical elements. Primary outcomes were the WOMAC Index and ALF assessments.</p> <p>Results</p> <p>There were no baseline differences between the groups. At 8 weeks, the active group showed a mean improvement of 64.8% on the WOMAC pain scale, a mean improvement of 62.7% on the WOMAC function scale, and a mean improvement of 31.4% on the ALF scale. The control group demonstrated no improvement in the above parameters. Significant differences were found between the active and control groups in all the parameters of assessment.</p> <p>Conclusions</p> <p>The biomechanical device and treatment methodology is effective in significantly reducing pain and improving function in knee OA patients.</p> <p>The study is registered at clinicaltrials.gov, identifier NCT00457132, <url>http://www.clinicaltrials.gov/ct/show/NCT00457132?order=1</url></p

Dietary intake and stress fractures among elite male combat recruits

<p>Abstract</p> <p>Background</p> <p>Appropriate and sufficient dietary intake is one of the main requirements for maintaining fitness and health. Inadequate energy intake may have a negative impact on physical performance which may result in injuries among physically active populations. The purpose of this research was to evaluate a possible relationship between dietary intake and stress fracture occurrence among combat recruits during basic training (BT).</p> <p>Methods</p> <p>Data was collected from 74 combat recruits (18.2 ± 0.6 yrs) in the Israeli Defense Forces. Data analyses included changes in anthropometric measures, dietary intake, blood iron and calcium levels. Measurements were taken on entry to 4-month BT and at the end of BT. The occurrence of stress reaction injury was followed prospectively during the entire 6-month training period.</p> <p>Results</p> <p>Twelve recruits were diagnosed with stress fracture in the tibia or femur (SF group). Sixty two recruits completed BT without stress fractures (NSF). Calcium and vitamin D intakes reported on induction day were lower in the SF group compared to the NSF group-38.9% for calcium (589 ± 92 and 964 ± 373 mg·d^-1, respectively, <it>p </it>< 0.001), and-25.1% for vitamin D (117.9 ± 34.3 and 157.4 ± 93.3 IU·d^-1, respectively, <it>p </it>< 0.001). During BT calcium and vitamin D intake continued to be at the same low values for the SF group but decreased for the NSF group and no significant differences were found between these two groups.</p> <p>Conclusions</p> <p>The development of stress fractures in young recruits during combat BT was associated with dietary deficiency before induction and during BT of mainly vitamin D and calcium. For the purpose of intervention, the fact that the main deficiency is before induction will need special consideration.</p

UniMorph 4.0:Universal Morphology

The Universal Morphology (UniMorph) project is a collaborative effort providing broad-coverage instantiated normalized morphological inflection tables for hundreds of diverse world languages. The project comprises two major thrusts: a language-independent feature schema for rich morphological annotation and a type-level resource of annotated data in diverse languages realizing that schema. This paper presents the expansions and improvements made on several fronts over the last couple of years (since McCarthy et al. (2020)). Collaborative efforts by numerous linguists have added 67 new languages, including 30 endangered languages. We have implemented several improvements to the extraction pipeline to tackle some issues, e.g. missing gender and macron information. We have also amended the schema to use a hierarchical structure that is needed for morphological phenomena like multiple-argument agreement and case stacking, while adding some missing morphological features to make the schema more inclusive. In light of the last UniMorph release, we also augmented the database with morpheme segmentation for 16 languages. Lastly, this new release makes a push towards inclusion of derivational morphology in UniMorph by enriching the data and annotation schema with instances representing derivational processes from MorphyNet