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Ongoing Research

Shulamit Michaeli

Prof. Shulamit Michaeli

The Mina and Everard Goodman Faculty of Life Sciences

The Immune System Computes the State of the Body: Crowd Wisdom, Machine Learning, and Immune Cell Reference Repertoires Help Manage Inflammation

Nucleic Acids Research, 2019 1–15

doi: 10.1093/nar/gkz477

 

Pseudouridines on Trypanosoma brucei spliceosomal small nuclear RNAs and their implication for RNA and protein interactions

 

  1. Shanmugha Rajan1, Tirza Doniger 1, Smadar Cohen-Chalamish1, Dana Chen1,

Oz Semo1, Saurav Aryal1, Efrat Glick Saar2, Vaibhav Chikne1, Doron Gerber 1, Ron Unger1, Christian Tschudi3 and Shulamit Michaeli 1,*

 

1The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute,

Bar-Ilan University, Ramat-Gan 52900, Israel, 2Sheba Medical Center, Tel-HaShomer 5265601, Israel and

3Departmentof Epidemiology and Microbial Diseases, Yale School of Public Health, New Haven, CT 06536, USA

 

Received February 21, 2019; Revised May 11, 2019; Editorial Decision May 15, 2019

 

ABSTRACT

The parasite Trypanosoma brucei, the causative agent of sleeping sickness, cycles between an insect and a mammalian host. Here, we investigated the presence of pseudouridines (!s) on the spliceosomal small nuclear RNAs (snRNAs), which may enable growth at the very different temperatures characterizing the two hosts. To this end, we performed the first high-throughput mapping of spliceosomal snRNA !s by small RNA !-seq. The analysis revealed 42 !s on T. brucei snRNAs, which is the highest number reported so far. We show that a trypanosome protein analogous to human protein WDR79, is essential for guiding ! on snRNAs but not on rRNAs. snoRNA species implicated in snRNA pseudouridylation were identified by a genome-wide approach based on ligation of RNAs following in vivo UV cross-linking. snRNA !s are guided by single hairpin snoRNAs, also implicated in rRNA modification. Depletion of such guiding snoRNA by RNAi compromised the guided modification on snRNA and reduced parasite growth at elevated temperatures. We further demonstrate that ! strengthens U4/U6 RNA–RNA and U2B’/U2A’-U2 snRNA interaction at elevated temperatures. The existence of single hairpin RNAs that modify both the

spliceosome and ribosome RNAs is unique for these parasites, and maybe related to their ability to cycle between their two hosts that differ in temperature.

Shula Michaeli
Dr. Ayal Hendel

Dr. Ayal Hendel

The Mina and Everard Goodman Faculty of Life Sciences

Primary immunodeficiencies – from early diagnosis and gene discovery to personalized therapy

Biology and medicine are undergoing a tremendous revolution where the use of advanced technologies, sophisticated bioinformatics and big data, revealing immediate impact on translation to medicine including disease diagnosis, treatment and outcome. Thus the main objective of this proposal that combines clinical and scientific skills is to extend our knowledge on pathways controlling human immunity in early life, to increase the number of primary immunodeficiency diseases to be diagnosed early in life, understand new disease pathomechanisms and to develop a novel and personalized gene-based treatment.

From Bed to Bench to Bed

Prof. Raz Somech, Sheba Medical Center

Dr. Ayal Hendel, Bar Ilan University

Dr. Yu Nee Lee, Sheba Medical Center

Prof. Sol Efroni

Prof. Sol Efroni

The Mina and Everard Goodman Faculty of Life Sciences

The Immune System Computes the State of the Body: Crowd Wisdom, Machine Learning, and Immune Cell Reference Repertoires Help Manage Inflammation

Sol Efroni - Machine Learning

Nature communications

 

Abstract:

 

Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer

 

 

Network Representation of T-Cell Repertoire—A Novel Tool to Analyze Immune Response to Cancer Formation

Sol Efroni - Nature communications

Authors:

Avner Priel, Miri Gordin, Hagit Philip, Alona Zilberberg, and Sol Efroni

 

Frontiers in Immunology

 

Abstract:

 

The T cell repertoire potentially presents complexity compatible, or greater than, that of the human brain. T cell based immune response is involved with practically every part of human physiology, and high-throughput biology needed to follow the T-cell repertoire has made great leaps with the advent of massive parallel sequencing [1]. Nevertheless, tools to handle and observe the dynamics of this complexity have only recently started to emerge [e.g., 2, 3, 4] in parallel with sequencing technologies. Here, we present a network-based view of the dynamics of the T cell repertoire, during the course of mammary tumors development in a mouse model. The transition from the T cell receptor as a feature, to network-based clustering, followed by network-based temporal analyses, provides novel insights to the workings of the system and provides novel tools to observe cancer progression via the perspective of the immune system. The crux of the approach here is at the network-motivated clustering. The purpose of the clustering step is not merely data reduction and exposing structures, but rather to detect hubs, or attractors, within the T cell receptor repertoire that might shed light on the behavior of the immune system as a dynamic network. The Clone-Attractor is in fact an extension of the clone concept, i.e., instead of looking at particular clones we observe the extended clonal network by assigning clusters to graph nodes and edges to adjacent clusters (editing distance metric). Viewing the system as dynamical brings to the fore the notion of an attractors landscape, hence the possibility to chart this space and map the sample state at a given time to a vector in this large space. Based on this representation we applied two different methods to demonstrate its effectiveness in identifying changes in the repertoire that correlate with changes in the phenotype: (1) network analysis of the TCR repertoire in which two measures were calculated and demonstrated the ability to differentiate control from transgenic samples, and, (2) machine learning classifier capable of both stratifying control and trangenic samples, as well as to stratify pre-cancer and cancer samples.

Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types

Running title: A BCL2 T to C variant controls chemotherapy response

Sol Efroni - Resistance to paclitaxel

Rotem Ben-Hamo, Alona Zilberberg, Helit Cohen, Keren Bahar-Shany, Chaim Wachtel, Jacob Korach, Sarit Aviel-Ronen, Iris Barshack, Danny Barash, Keren Levanon, Sol Efroni

 

Nature Partner Journals Precision Oncology

 

ABSTRACT

Paclitaxel, the most commonly used form of chemotherapy, is utilized in curative protocols in different types of cancer. The response to treatment differs among patients. Biological interpretation of a mechanism to explain this personalized response is still unavailable. Since paclitaxel is known to target BCL2 and TUBB1, we used pan-cancer genomic data from hundreds of patients to show that a single nucleotide variant in the BCL2 sequence can predict a patient’s response to paclitaxel.

Here, we show a connection between this BCL2 genomic variant, its transcript structure, and protein abundance. We demonstrate these findings in silico, in vitro, in Formalin fixed paraffin embedded (FFPE) tissue and in patient lymphocytes. We show that tumors with the specific variant are more resistant to paclitaxel. We also show that tumor and normal cells with the variant express higher levels of BCL2 protein, a phenomenon that we validated in an independent cohort of patients. Our results indicate BCL2 sequence variations as determinants of chemotherapy resistance.

The knowledge of individual BCL2 genomic sequences prior to the choice of chemotherapy may improve patient survival. The current work also demonstrates the benefit of community-wide, integrative omics data sources combined with in-lab experimentation and validation sets.

tomerkalisky

Dr. Tomer Kalisky

The Alexander Kofkin Faculty of Engineering

Geometry of Gene Expression Space of Wilms’ Tumors

 

In this research we applied a new computational approach to high-throughput genomic datasets in order to understand how Wilms’ tumor - a type of kidney cancer occurring in young children – varies between different patients.

 

Wilms’ tumor is thought to arise from faulty development of the kidney at the embryonic stage. Although Wilms’ tumors are generally responsive to treatment and have a relatively good prognosis, there remains a need for measures to better classify them into subtypes and assess the progression of the tumor in each patient in order to design a more personalized treatment. To date, this is done by experienced pathologists that manually inspect tissue sections taken from a biopsy of the tumor. In our paper we looked for a more computational and quantitative way to do this.

 

To this end, we used a “data mining” approach. We analyzed genomic data from hundreds of Wilms’ tumors that were collected by the Children’s Oncology Group (COG) in a series of publications spanning a few years. We first tried to classify the tumors into sub-types according to the different genes that are turned “ON” and “OFF” in each tumor. However, we found that the tumors do not create distinct groups; rather, they create a continuous region in the mathematical “space” of gene expression.

 

We then looked at the shape of this continuum and found that it takes the form of a triangle, whose three vertices correspond to three “archetypes”. These archetypes represent abstract and idealized tumors with sharp and well-defined characteristics. In a sense, every tumor on the continuum is a mixture of cells from these three archetypical tumors. Moreover, we also found that tumors of higher stage tend to shift towards one of these archetypes. In this way, the location of each tumor in between the three archetypes can be used both for describing its cellular composition and for assessing disease progression.

 

Our method is more quantitative and less prone to human error, and can therefore be used to complement manual pathological inspection that is currently being done in order to classify Wilms’ tumors and assess them. In a sense, our method can be used as a “decision-support system” for the pathologist.

 In this work we were able to bridge multiple disciplines. We mined datasets from high throughput genomic technologies and used new computational tools from systems biology as well as clinical insight. Also participated in this research: Ariel Trink and Itamar Kanter from the Faculty of Engineering in Bar-Ilan, Dr. Achia Urbach from the Faculty of Life Sciences in Bar-Ilan, and Dr. Naomi Pode-Shakked and Prof. Benny Dekel from the Sheba Medical Center.

tomerkalisky 1
tomerkalisky2

REFERENCE:

 

Trink, A., Kanter, I., Pode-Shakked, N., Urbach, A., Dekel, B., & Kalisky, T. (2018). Geometry of Gene Expression Space of Wilms’ Tumors From Human Patients. Neoplasia, 20(8), 871–881. https://doi.org/10.1016/j.neo.2018.06.006

Prof. Arnon Blum

Azrieli Faculty of Medicine

QJM. 2018 May 16. doi: 10.1093/qjmed/hcy099. [Epub ahead of print]

Inhibition of Endothelial Progenitor Cells May Explain the High Cardiovascular Event Rate in Patients with Rheumatoid Arthritis.

Adawi M1,2, Pastuck N3, Saaida G2, Sirchan R1, Watad A, Blum A1,3,2.

Author information: Department of Medicine and the Rheumatology Unit, the Vascular Research Laboratory, Baruch Padeh Medical Center, Azrieli Faculty of Medicine Bar Ilan University, Galilee 15208 Israel

Abstract

Background:

Rheumatoid arthritis (RA) patients may suffer cardiovascular (CV) events much more than the general population, and CV disease is the leading cause of death in patients with RA. Our hypothesis was that impaired function of endothelial progenitor cells may contribute to endothelial dysfunction and the clinical CV events of patients with RA.

Methods:

27 RA patients (9 males and 18 females) with an active disease and 13 healthy subjects who served as the control group (9 males and 4 females) were enrolled to this prospective study. The ability to grow in culture colony-forming units of endothelial progenitor cells (CFU-EPCs) was measured, as well as their endothelial function using high-resolution ultrasonography of the brachial artery, and levels of C reactive protein (CRP) in the serum. For statistical analysis we used the students T-test test.

Results:

As a group, patients with RA were older (p < 0.0001), had severe endothelial dysfunction (<0.0001), with impaired ability to grow CFU-EPCs (<0.0001), and a higher inflammatory state (p = 0001). No difference was observed in BMI. All RA patients had an active disease (DAS28 3.9±0.9) for 9.2±6.5 years. The same differences were observed in both genders.

Conclusions:

Patients with RA had an impaired ability to grow endothelial progenitor cells and severe endothelial dysfunction. Inability to grow colonies of endothelial progenitor cells reflects the impaired regenerative capacity of patients with RA, and may explain the endothelial dysfunction and the high CV event rate among patients with RA.

 

Clin Exp Med. 2019 Jan 23. doi: 10.1007/s10238-019-00546-x. [Epub ahead of print]

Serum miR-122 levels correlate with diabetic retinopathy.

Pastukh N1, Meerson A2, Kalish D3, Jabaly H3, Blum A4.

Author information: Vascular Biology Research Laboratory, Baruch Padeh Medical Center and Azrieli Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel. MIGAL Galilee Research Institute and Tel Hai Academic College, Kiryat Shmona, Israel. Department of Ophthalmology, Baruch Padeh Medical Center, Azrieli Faculty of Medicine, Bar Ilan University, 15208, Ramat Gan, Israel. Department of Medicine, Baruch Padeh Medical Center, and Azrieli Faculty of Medicine, Bar Ilan University, 15208, Ramat Gan, Israel.

ABlum@poria.health.gov.il.

Abstract

Diabetic retinopathy is the most severe ocular complication of diabetes and may lead to visual disability and blindness. Proliferative diabetic retinopathy (PDR) is characterized by ischemia-induced neovascularization with associated complications. An association was established between the presence of PDR, cardiovascular disease, and mortality among patients with type 1 diabetes mellitus and type 2 diabetes mellitus in epidemiological studies. However, the mechanism underlying increased cardiovascular risk in patients with PDR is still unknown. In recent years, a group of miRNAs has been linked to the pathology of diabetes mellitus. Besides, miRNAs in biofluids such as serum have been suggested as potential minimally invasive biomarkers of diabetes and vascular complications. This was a prospective study that recruited 40 human subjects: 10 healthy subjects, 10 with diabetes but without retinopathy (NDR), 10 with diabetic non-proliferative retinopathy (NPDR), and 10 with proliferative diabetic retinopathy (PDR). To examine whether serum miRNAs show altered levels at different stages of diabetic retinopathy, seven specific miRNA candidates (miR-126-3p, miR-130a-3p, miR-21-1, let-7f-5p, miR-122, miR-30c and miR-451a) were measured by qRT-PCR in RNA isolated from sera of all subjects. miR-122 levels increased in parallel with retinopathy severity: from healthy controls to NDR and from NDR to NPDR. However, when the disease progressed to PDR a marked decrease in miR-122 level was noted. This decrease was significant both compared to NPDR samples (p = 0.016) and to all non-PDR samples (p = 0.0002). Additionally, a positive trend was observed comparing miR-122 levels and the number of endothelial progenitor cells in the sera of all subjects. A significant increase in miR-122 was found in patients with diabetic retinopathy that may be related to its role in preventing angiogenesis and proliferation. The dramatic decline in patients with PDR may represent an inhibition or exhaustion of the anti-angiogenic anti-proliferative defense system. Further studies are needed to understand whether miRNA-122 has a role in the pathogenesis of diabetic retinopathy.

KEYWORDS:

Diabetes mellitus; Diabetic reinopathy; miRNA 122

Serum miR-122 levels correlate with diabetic retinopathy

 Figures:

Figure 1

Figure 1: Relative MiRNA levels in different groups of T2DM patients designated by DR progress.

Bars: std err.

Figure 2

Figure 2: individual (A) and aggregate (B) associations between CFU-EPCs and serum miR-122 levels in all subjects. A, CFU numbers are displayed on a log scale; samples with 0 CFU were omitted from the plot. B, bars: std err

Prof. Dror Fixler

Prof. Dror Fixler

The Alexander Kofkin Faculty of Engineering

fixler1

OSA Continuum 2(1), 92-98 (2019).

Abstract: Near-infrared optical techniques permit tissue diagnosis by surface measurement. However, the geometrical shape of this interface profiles the intensity of the surface measurement, which is found to have an iso-pathlength (IPL) point allowing for absorption identification independent of tissue scattering. The IPL point was projected in Monte Carlo (MC) simulation, validated experimentally in cylindrical tissues, but remains underappreciated through analytical approaches. In this work, we present an analytical solution of an IPL point for steady-state diffusion based on the extrapolated zero-boundary condition. The same IPL points were found when comparing this solution to 3-D MC simulations for a tissue radius range of 5-8mm.

fixler2
fixler3

Abstract:

Atherosclerosis (AS), the leading cause of morbidity and mortality in cardiovascular disease, needs an early detection for treatment and prevention of fatal events. Here, for the first time, we applied gold nanorods (GNRs) assisted diffusion reflection (DR), a non invasive technique for in vivo detection of AS in a high-fat-diet induced c57bl mouse model, which resembles the manifestation of AS in humans. DR simply detects the change in light reflection profile of tissue due to the accumulation of GNRs in the AS plaques and enables clear detection of AS lesions in carotid and femoral arteries of these hyperlipidemic mice. After 24 hours post-GNRs injection DR showed the highest efficiency of AS detection. Moreover, the sensitivity of the DR method is much higher than computed tomography (CT) and is comparable to ex vivo high-resolution CT. Our results strongly suggest that the DR method can detect early atherosclerotic lesions in a sensitive and specific manner.

fixler4
Prof. Ramit Mehr

Prof. Ramit Mehr

The Mina and Everard Goodman Faculty of Life Sciences

Depletion of B cells rejuvenates the peripheral B cell compartment but is insufficient to restore immune competence in aging

Irit Avivi1, Simona Zisman-Rozen2, Shulamit Naor2, Isabelle Dai2, David Benhamou2, Gitit Shahaf3, Hilla Tabibian-Keissar4, Noemie Rosenthal3, Aviya Rakovsky3, Ammuri Hanna2, Arik Shechter6, Eli Peled7, Noam Benyamini1, Ekaterina Dmitrukha5, Iris Barshack4, Ramit Mehr5, and Doron Melamed2

1Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Medical School, Tel-Aviv University, Tel Aviv, Israel.

2Technion-Israel Institute of Technology, Faculty of Medicine, Department of Immunology, Haifa, Israel.

3The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University Ramat-Gan, Israel.

4Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.

5 RAMBAM Medical Center, Department of Hematology, Haifa, Israel.

6Department of Family Medicine, Technion Faculty of Medicine, Clalit Health Services and Neuro-urology Unit, RAMBAM Medical Center, Haifa, Israel.

7Orthopedic division Rambam health care campus, Haifa, Israel.

Summary

Aging is associated with increasing prevalence and severity of infections caused by a decline in bone marrow (BM) lymphopoiesis and reduced B cell repertoire diversity. The current study proposes a strategy to enhance immune responsiveness in aged mice and humans, through rejuvenation of the B lineage upon B-cell depletion. We used hCD20Tg mice to deplete peripheral B cells in old and young mice, analyzing B cell subsets, repertoire and cellular functions in vitro, and immune responsiveness in vivo. Additionally, elderly patients, previously treated with rituximab healthy elderly and young individuals were vaccinated against Hepatitis B (HBV) after undergoing a detailed analysis for B cell compartments. B cell depletion in old mice resulted in rejuvenated B cell population that was derived from de-novo synthesis in the bone marrow. The rejuvenated B cells exhibited a "young"-like repertoire and cellular responsiveness to immune stimuli in vitro. Yet, mice treated with B cell depletion did not mount enhanced antibody responses to immunization in vivo, nor did they survive longer than control mice in "dirty" environment. Consistent with these results, peripheral B cells from elderly-depleted patients showed a "young"-like repertoire, population dynamics and cellular responsiveness to stimulus. Nevertheless, the response rate to HBV vaccination was similar between elderly depleted and non-depleted subjects, although antibody titers were higher in depleted patients. This study proposes a proof of principle to rejuvenate the peripheral B cell compartment in aging, through B cell depletion. Further studies are warranted in order to apply this approach for enhancing humoral immune responsiveness among the elderly population.

Prof. Erez Levanon

Prof. Erez Levanon

The Mina and Everard Goodman Faculty of Life Sciences

RNA editing of Filamin A pre‐mRNA regulates vascular contraction and diastolic blood pressure

IEpitranscriptomic events such as adenosine‐to‐inosine (A‐to‐I) RNA editing by ADAR can recode mRNAs to translate novel proteins. Editing of the mRNA that encodes actin crosslinking protein Filamin A (FLNA) mediates a Q‐to‐R transition in the interactive C‐terminal region. While FLNA editing is conserved among vertebrates, its physiological function remains unclear. Here, we show that cardiovascular tissues in humans and mice show massive editing and that FLNA RNA is the most prominent substrate. Patient‐derived RNA‐Seq data demonstrate a significant drop in FLNA editing associated with cardiovascular diseases. Using mice with only impaired FLNA editing, we observed increased vascular contraction and diastolic hypertension accompanied by increased myosin light chain phosphorylation, arterial remodeling, and left ventricular wall thickening, which eventually causes cardiac remodeling and reduced systolic output. These results demonstrate a causal relationship between RNA editing and the development of cardiovascular disease indicating that a single epitranscriptomic RNA modification can maintain cardiovascular health.

Synopsis

graphic-1

RNA‐editing of Filamin A pre‐mRNA is decreased in human cardiac disease. A mouse model lacking this editing site shows altered smooth muscle contraction and diastolic blood pressure, illustrating that ADAR2‐dependent RNA editing plays a functional role outside the central nervous system.

  • The Filamin A (FLNA) pre‐mRNA is subject to RNA editing with the highest rates seen in the cardiovascular system.

  • FLNA editing rates are reduced in cardiovascular disease patients.

  • In mice, FLNA editing controls smooth muscle contraction of the dorsal aorta.

  • Mice deficient in FLNA editing show elevated diastolic blood pressure and cardiac remodeling.

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Prof. Gal Yadid

Prof. Gal Yadid

The Mina and Everard Goodman Faculty of Life Sciences

A DNA Methylation Signature of Addiction in T Cells and Its Reversal With DHEA Intervention Gal Yadid - Front. Mol. Neurosci., 10 September 2018

Previous studies in animal models of cocaine craving have delineated broad changes in DNA methylation profiles in the nucleus accumbens. A crucial factor for progress in behavioral and mental health epigenetics is the discovery of epigenetic markers in peripheral tissues. Several studies in primates and humans have associated differences in behavioral phenotypes with changes in DNA methylation in T cells and brain. Herein, we present data showing that the T cell DNA methylation profile differentiates persons with a substance use disorder from controls. Intervention with dehydroepiandrosterone (DHEA), previously shown to have a long-term therapeutic effect on human addicts herein resulted in reversal of DNA methylation changes in genes related to pathways associated with the addictive state. Such studies should further confirm association of DNA methylation in peripheral white blood cells, and facilitate delineation of sites that predict both drug craving and response to treatment.

FIGURE 1. DNA methylation differences associated with addiction. (A) Box plot of average methylation of sites that are differentially methylated between addicted and healthy controls. Bottom panel: the average methylation of genes that become less methylated (hypomethylation) and more methylated (hypermethylation) in addicts ∗∗∗p < 2.2E-16; Mann–Whitney test. (B) Heat map showing clustering by one minus Pearson correlations of healthy controls and addicts using the 5,532 differentially methylated genes (4,458 probes were hypomethylated and 1,074 hypermethylated in addicts).

Yadid
Dr. Dana Atzil-Slonim

Dr. Dana Atzil-Slonim

Department of Psychology

Atzil-Slonim, D., Bar-Kalifa, E., Fisher, H.,  Lazarus, G., Hasson-Ohayon, I., Lutz, W., Rubel, J., & Rafaeli, E. (2018). Therapists` empathic accuracy regarding the clients` emotions on clients` outcomes. Journal of Consulting and Clinical Psychology.

 

Therapists’ Empathic Accuracy toward their Clients’ Emotions

Abstract

Objective: Therapists’ empathic accuracy (EA) toward their clients’ fluctuating emotions is a crucial clinical skill that underlies many therapeutic interventions. In contrast to the subjective components of empathy, limited empirical work has addressed EA or its effect on the outcomes of psychotherapy. Here, we differentiate between the components of EA (tracking accuracy, directional discrepancy) as well as the valence of the target emotions (positive vs. negative). We also investigated the relative contribution of cognitive and emotional processes to therapists’ EA and examined the associations between EA and treatment outcomes. Method: the sample comprised 93 clients treated by 62 therapists in a university setting. Prior to each session, clients self-reported their symptoms. Following each session, clients rated their positive (PE) and negative (NE) emotions during the session and therapists rated their own emotions, as well as their assessment of their clients’ emotions. Results: Therapists accurately tracked their clients’ PE and NE and were more accurate for NE. Therapists tended to overestimate their clients’ NE and underestimate their clients’ PE. Therapists' emotions were associated with their clients' emotions (real similarity). Therapists' emotions were also associated with their assessments of their clients' emotions (assumed similarity). Therapists' own emotions partially mediated the association between clients' emotions and therapists' assessments. Therapists' inaccuracy in assessing their clients' PE was associated with higher reported symptoms in the next session. Conclusion: These findings help provide a better understanding of the specific characteristics associated with more EA and underscore the importance of EA in facilitating clients’ emotional well-being.

            Keywords: Empathic accuracy, empathy, emotions, process-outcome research, truth and bias model, polynomial regression with response surface analysis

Public health significance statement

The current findings highlight the importance of therapists’ empathic accuracy regarding their clients’ emotions. The findings advance the idea that both cognitive and emotional empathy contribute to therapists’ ability to correctly assess their clients’ emotions. The results point to the risk on the part of therapists to neglect clients’ positive emotions and stress the importance of attending to these emotions.

108.דנה אציל_תמונה

Figure 2. Polynomial Regression with Response Surface Analysis (PRRSA) models predicting clients’ next session symptoms by clients’ emotions and therapists’ assessments of their clients’ emotions.

Prof. Eitan Okun

Prof. Eitan Okun

The Mina and Everard Goodman Faculty of Life Sciences

Restoring microglial and astroglial homeostasis using DNA immunization in a Down Syndrome mouse model.

Illouz T, Madar R, Biragyn A, Okun E.

Abstract

Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation as early as the age of 40. In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aβ1-11 fragment, in ameliorating Aβ-related neuropathology and rescue of cognitive and behavioral abilities. Anti-Aβ1-11 vaccination induced antibody production and facilitated clearance of soluble oligomers and small extracellular inclusions of Aβ from the hippocampus and cortex of Ts65Dn mice. This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglial and astroglial cells. Vaccinated Ts65Dn mice performed better in spatial-learning tasks, exhibited reduced motor hyperactivity typical for this strain, and restored short-term memory abilities. Our findings support the hypothesis that DS individuals may benefit from active immunotherapy against Aβ from a young age by slowing the progression of dementia.

איתן אוקון_תמונה.103

Brain Behav Immun. 2019 Jan;75:163-180.

Dr. Milana Frenkel-Morgenstern

Dr. Milana Frenkel-Morgenstern

The Azrieli Faculty of Medicine

A Comprehensive Method Characterizing Fusion Proteins and Their Interactions in Tailored Therapy Approaches

Somnath Tagore1,3, Alessandro Gorohovski1, Lars Juhl Jensen2 and Milana Frenkel-Morgenstern1,*

1 The Azrieli Faculty of Medicine, Bar-Ilan University, 8 Henrietta Szold St, Safed 13195, ISRAEL

2 Cellular Network Biology Group, the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DENMARK

3 Present Address: Department of Systems Biology, Columbia University, New York, NY, 10032, USA.

*Corresponding Author E-mail: milana.morgenstern@biu.ac.il

Abstract

Tailored therapy aims to cure cancer patients in an effective and safe way, based on the complex interactions among patients' genomic features, disease pathology and drug metabolism. Thus, the constant increase in scientific literature drives the need for efficient methods of data mining to improve the extraction of useful information from texts based on the patients' genomic features. One of the important application of text mining to tailored therapy in cancer encompasses the use of mutations and cancer fusion genes as moieties changing the patient's cellular networks to develop cancer as well as affecting drug metabolism. Fusion proteins that deriving from the slippage of two parental genes, are produced in cancer by chromosomal aberrations and/or trans-splicing. Given that the two parental proteins for predicted fusions are known, we used our previously developed method for identifying protein–protein interactions (PPIs) associated with the fusion proteins. Here, we present a validation approach that receive a full patient's genomic information (DNAseq and RNAseq data), use all the identified fusions and mutations, predict their cellular networks alterations and validate by the online literature search. As a result, we used a set of 358 fusions and their corresponding PPIs as a training set for a Naïve Bayes classifier to identify predicted fusions that have reliable evidence in the literature and were confirmed experimentally. Next, for test group of 1817 fusions, we were able to find 2908 PPIs in total across 18 cancer types, from literature. Next, we combined all the results in a framework that receives a genomic data from 672 patients, incorporate the mutations and fusions in the combined cellular networks and identify unique drug targets in these networks. Thus, our method can be used for screening literature for identifying mentions of unique cases of fusions in tailored therapy approaches, such as predicting drug targets and networks hubs based on the verified PPIs of fusions in cancer patients.

 

Availability: http://protfus.md.biu.ac.il/

 

Revision in PloS Computational Biology