2023
Alessandro Bonadio, Wenig, Bernhard L, Hockla, Alexandra , Radisky, Evette S, ו Shifman, Julia M. 2023.
“Designed Loop Extension Followed By Combinatorial Screening Confers High Specificity To A Broad Matrix Metalloproteinaseinhibitor”. J. Mol. Biol., 435, Pp. 168095.
תקציר Matrix metalloproteinases (MMPs) are key drivers of various diseases, including cancer. Development of probes and drugs capable of selectively inhibiting the individual members of the large MMP family remains a persistent challenge. The inhibitory N-terminal domain of tissue inhibitor of metalloproteinases-2 (N-TIMP2), a natural broad MMP inhibitor, can provide a scaffold for protein engineering to create more selective MMP inhibitors. Here, we pursued a unique approach harnessing both computational design and combinatorial screening to confer high binding specificity toward a target MMP in preference to an anti-target MMP. We designed a loop extension of N-TIMP2 to allow new interactions with the non-conserved MMP surface and generated an efficient focused library for yeast surface display, which was then screened for high binding to the target MMP-14 and low binding to anti-target MMP-3. Deep sequencing analysis identified the most promising variants, which were expressed, purified, and tested for selectivity of inhibition. Our best N-TIMP2 variant exhibited 29 pM binding affinity to MMP-14 and 2.4 µM affinity to MMP-3, revealing 7500-fold greater specificity than WT N-TIMP2. High-confidence structural models were obtained by including NGS data in the AlphaFold multiple sequence alignment. The modeling together with experimental mutagenesis validated our design predictions, demonstrating that the loop extension packs tightly against non-conserved residues on MMP-14 and clashes with MMP-3. This study demonstrates how introduction of loop extensions in a manner guided by target protein conservation data and loop design can offer an attractive strategy to achieve specificity in design of protein ligands.
N. Shalom, Vaknin, Y. , Shaar, R. , Ben-Yosef, E. , Lipschits, O. , Shalev, Y. , Gadot, Y. , ו Boaretto, E.. 2023.
“Destruction By Fire: Reconstructing The Evidence Of The 586 Bce Babylonian Destruction In A Monumental Building In Jerusalem”. Journal Of Archaeological Science, 157, Pp. 105823. doi:https://doi.org/10.1016/j.jas.2023.105823.
Publisher's Version תקציר Evidence of fire is one of the most important features for identifying and characterizing destruction events. Analysis of microscopic remains of fire has developed exceedingly in recent years, enabling archaeologists to examine new questions relating to the intensity of destruction events and to the circumstances of the creation of destruction layers. One of the most crucial events in the history of the Southern Levant is the Babylonian destruction of Judah and its capital Jerusalem in 586 BCE, which shaped the biblical narrative and theology for generations to come. Building 100 was an extraordinarily large and rich elite building, thoroughly destroyed during the Babylonian campaign. This paper presents a study of the destruction layer excavated within the rooms of the building. FTIR spectrometry and archaeomagnetic analysis were combined in the micro-archaeological study of the remains in order to create a detailed reconstruction of the destruction event. This reconstruction sheds new light on how the Babylonian destruction was manifested in reality in the elite buildings of Jerusalem.
Dieses Buch analysiert das Verhältnis zwischen dem jemenitischen König Imam Yaḥyā Ḥamīd al-Dīn und den Juden:Jüdinnen Sanaas aus islamrechtlicher Perspektive. Es beleuchtet sowohl Imam Yahyas Dhimma-Politik als auch die Handlungsmacht von Juden:Jüdinnen als Dhimmis. Es kombiniert erstmals jüdische Erinnerungsliteratur und jemenitische Historiographie aus dem 20. Jhd. mit zum Teil bis heute grundlegenden Texten zaiditischen Rechts (fiqh) aus dem 14.-19. Jhd.
Substantial archaeological exposure of the ancient city of Yehud was achieved through as many as forty-four trial and salvage excavations conducted since 1993. The accumulated data has now reached a critical mass where a broad synthesis is made possible, concerning a site for which investigation has been slow due to the challenges of excavating within a densely populated and rapidly developing modern city. Excavations in the city, located in Israel’s central coastal plain, revealed a patchy history of human settlement, ranging in date between the Late Chalcolithic and Ottoman periods, with lengthy periods of sparse residential use, when the site was variably utilized for funerary, industrial, agricultural, or other types of yet unidentified activities. This comprehensive synthesis unravels the archaeology and history of this little-known site, located at the heart of a region that has undergone major social transformations and historical upheavals during the period in question. The information on Yehud is contextualized with up-to-date knowledge of the archaeology of the central coastal plain, especially concerning Yehud’s hinterland within the Ayalon valley.
Elisheva Rhodes-Mordov, Brandwine-Shemmer, Tal , Zaguri, Rachel , Gutorov, Rita , Peters, Maximilian , ו Minke, Baruch . 2023.
“Diacylglycerol Activates The Light Sensitive Channel Trpl Expressed In Hek Cells”. Int J Mol Sci, 24, 7. doi:10.3390/ijms24076289.
תקציר Physiological activation by light of the TRP and TRP-like (TRPL) channels requires the activation of phospholipase Cβ (PLC). The hydrolysis of phosphatidylinositol 4,5, bisphosphate (PIP) by PLC is a crucial step in the still-unclear light activation, while the generation of Diacylglycerol (DAG) by PLC seems to be involved. In this study, we re-examined the ability of a DAG analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) to activate the TRPL channels expressed in HEK cells. Unlike previous studies, we added OAG into the cytosol via a patch-clamp pipette and observed robust activation of the expressed TRPL channels. However, TRPL channel activation was much slower than the physiologically activated TRPL by light. Therefore, we used a picosecond-fast optically activated DAG analogue, OptoDArG. Inactive OptoDArG was added into the intracellular solution with the patch-clamp pipette, and it slowly accumulated on the surface membrane of the recorded HEK cell in the dark. A fast application of intense UV light to the recorded cell resulted in a robust and relatively fast TRPL-dependent current that was greatly accelerated by the constitutively active TRPL pore-region mutation. However, this current of the mutant channel was still considerably slower than the native light-induced TRPL current, suggesting that DAG alone is not sufficient for TRPL channel activation under physiological conditions.
Since its publication and first performance, Edward Albee’s Who’s Afraid of Virginia Woolf? (1962) has often been interpreted with regard to the theme of truth and illusion. A less studied but nonetheless important aspect of the play concerns its relation to C. P. Snow’s concept of the “two cultures.” This article argues for the convergence of these two discussions, resulting in an epistemological understanding of Albee. The play not only rejects the mutual alienation of the “two cultures” but also constitutes a dramatic move toward a synthesizing “third culture.” Who’s Afraid of Virginia Woolf? is read as an epistemological drama of ideas.
September 2022: Andreas Tranvik is a PhD candidate in Comparative Literature at the Centre for Languages and Literature, Lund University. His research is primarily focused on literature as it relates to the history of knowledge. Currently, he is working on a research project about humour and knowledge in the works of the 18th century Danish-Norwegian writer Ludvig Holberg.
S Arjmand, Anania, MP , Biagioni, A , Ferrario, M , Galletti, M , Lollo, V , Pellegrini, D , Pompili, R , ו Zigler, A . 2023.
“Different Elements, Same Results: Time-Resolved Temperature Determination By Oxygen And Nitrogen Elements”. Journal Of Instrumentation, 18, Pp. P08003.
Arnon Haran, Bergel, Michael , Kleiman, Doron , Hefetz, Liron , Israeli, Hadar , Weksler-Zangen, Sarah , Agranovich, Bella , Abramovich, Ifat , Ben-Haroush Schyr, Rachel , Gottlieb, Eyal , ו Ben-Zvi, Danny . 2023.
“Differential Effects Of Bariatric Surgery And Caloric Restriction On Hepatic One-Carbon And Fatty Acid Metabolism”. Iscience, 26, 7, Pp. 107046. doi:10.1016/j.isci.2023.107046.
Weight loss interventions, including dietary changes, pharmacotherapy, or bariatric surgery, prevent many of the adverse consequences of obesity, and may also confer intervention-specific benefits beyond those seen with decreased weight alone. We compared the molecular effects of different interventions on liver metabolism to understand the mechanisms underlying these benefits. Male rats on a high-fat, high-sucrose diet underwent sleeve gastrectomy (SG) or intermittent fasting with caloric restriction (IF-CR), achieving equivalent weight loss. The interventions were compared to (AL)-fed controls. Analysis of liver and blood metabolome and transcriptome revealed distinct and sometimes contrasting metabolic effects between the two interventions. SG primarily influenced one-carbon metabolic pathways, whereas IF-CR increased lipogenesis and glycogen storage. These findings suggest that the unique metabolic pathways affected by SG and IF-CR contribute to their distinct clinical benefits, with bariatric surgery potentially influencing long-lasting changes through its effect on one-carbon metabolism.
Introduction: Both the calvarial and the cortical bones develop through intramembranous ossification, yet they have very different structures and functions. The calvaria enables the rapid while protected growth of the brain, whereas the cortical bone takes part in locomotion. Both types of bones undergo extensive modeling during embryonic and post-natal growth, while bone remodeling is the most dominant process in adults. Their shared formation mechanism and their highly distinct functions raise the fundamental question of how similar or diverse the molecular pathways that act in each bone type are. Methods: To answer this question, we aimed to compare the transcriptomes of calvaria and cortices from 21-day old mice by bulk RNA-Seq analysis. Results: The results revealed clear differences in expression levels of genes related to bone pathologies, craniosynostosis, mechanical loading and bone-relevant signaling pathways like WNT and IHH, emphasizing the functional differences between these bones. We further discussed the less expected candidate genes and gene sets in the context of bone. Finally, we compared differences between juvenile and mature bone, highlighting commonalities and dissimilarities of gene expression between calvaria and cortices during post-natal bone growth and adult bone remodeling. Discussion: Altogether, this study revealed significant differences between the transcriptome of calvaria and cortical bones in juvenile female mice, highlighting the most important pathway mediators for the development and function of two different bone types that originate both through intramembranous ossification.
In the course of a seven-year-long project (2014–2021), all published architectural, archaeological, geographical, textual, and epigraphical data pertaining to early Christian churches (n=715) and monasteries (n=306) were collated in a comprehensive digital database. The objectives of the project and the structure of the database are described in detail, including an appendix outlining the templates of each section of the digital corpus (Appendix A). A designated section of the corpus is devoted to preconceived queries, which permit the generation of specific reports pertaining to geographical distribution, architectural components and members, index of terms mentioned in the inscriptions, and more. A Google search function covering the entire database is also available. At present, the database is undergoing the final stages of proofreading. When completed, it will be fully open to the public via the internet.
The digitization of Jerusalem Architectural Archives was a practical heritage documentation project establishing a platform for studying architecture and design in modern Jerusalem. The project ventured to locate, digitize, and catalog official and personal documents concerning the city’s modern development. The resulting database consists of elaborate Excel tablesincorporating seven archival and working collections produced under various regimes: Ottoman, British, and Israeli. Striving to divulge the material to as many readers as possible and facilitate multiple readings of the city’s history, we questioned the terms and categories traditionally used for tagging and cataloging documents in the historiography of Jerusalem. Technically, the main challenges we faced were inconsistent and incomplete cataloging of the original archives, obtaining document publishing rights, and creating a sustainable platform. More substantial challenges pertained to the cataloger’s interpretative role in objectively representing the information emerging from the various documents and the archive’s role as a mediator in research and practice.
Alon Gutfreund, Matsuki, Hisakazu , Plastovets, Vadim , Noah, Avia , Gorzawski, Laura , Fridman, Nofar , Yang, Guang , Buzdin, Alexander , Millo, Oded , Robinson, Jason WA, ו Anahory, Yonathan . 3/24/2023.
“Direct Observation Of A Superconducting Vortex Diode”. Nature Communications, 14, 1630. .
Publisher's Version Vivek Ambastha, Nevo, Yuval , Matityhu, Ifat , Honys, David , ו Leshem, Yehoram . 2023.
“Discovery Of Micrornas In Stigma Exudates Opens New Research Avenues In Horticulture”. Pnas Nexus, 2, 11, Pp. pgad332. doi:10.1093/pnasnexus/pgad332.
In many plant species, flower stigma secretions are important in early stages of sexual reproduction. Previous chemical analysis and proteomic characterization of these exudates provided insights into their biological function. Nevertheless, the presence of nucleic acids in the stigma exudates has not been previously reported. Here, we studied the stigma exudates of , , and and showed them to harbor extracellular RNAs of various sizes. RNA sequencing revealed, for the first time, the presence of known Rosaceae mature microRNAs (miRs), also abundant in the stigma source tissue. Predicted targets of the exudate miRs in the genome include genes involved in various biological processes. Several of these genes are pollen transcribed, suggesting possible involvement of exudate miRs in transcriptional regulation of the pollen. Moreover, extracellular miRs can potentially act across kingdoms and target genes of stigma interacting organisms/microorganisms, thus opening novel applicative avenues in Horticulture.
Can the extent of ethnic discrimination change quickly, and what circumstances and mechanisms make such changes possible? I address these questions by using scraped data to study the daily evolution of customer discrimination against Arab doctors in Israel from January 2020 to June 2021. Results show that: (1) the outbreak of the coronavirus crisis in March 2020 led to a dramatic decline in discrimination; (2) the eruption of a wave of ethnic riots in May 2021 had the opposite effect; (3) media coverage of the contribution of Arab doctors to the fight against the pandemic helped bring about the first change.
This article examines the importance of landholdings in explaining income inequality among family farms in four districts in Georgia following the land reform of the 1990s. Income inequality is decomposed by sources of income and by determinants of income. The results indicate that farm income is a disequalizing source of income among family farms in these districts. In addition, a uniform increase in landholding is expected to reduce income inequality. Combining the two results, we conclude that the impact of land reform on farm household income inequality depends on the resulting distribution of landholdings. It can reduce inequality if land is distributed relatively equally, but inequality can increase if the wealthier farmers are able to gain control of more (and perhaps better) land resources. A possible implication of this result is that for land reform to be equalizing, distributing land to smallholders should be accompanied by additional policies and regulations supporting small farmers, such as land titling and registration, support for cooperation, and access to credit and other market services.
