(Institute for Operations Research and the Management Sciences) New research to be published in the INFORMS journal Management Science has found popular rideshare platforms exhibit racial and other biases that penalize under-represented minorities and others seeking to use their services.

4 March 2020 , Volume 96, Number 2

7 May 2020 , Volume 96, Number 3

7 May 2020 , Volume 96, Number 3

SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.

In this EBM round-up, Carl Heneghan, Helen Macdonald and Duncan Jarvies are back to give you an update Dual vs single therapy for prevention of TIA or minor stroke - how does the advice that dual work better translate in the UK? Carl explains why Japan can teach us to get active and, how GPs can use that information to "drop a decade" in...

Around half of trials that supported new cancer drug approvals in Europe between 2014 and 2016 were judged to be at high risk of bias, in a new study. Huseyin Naci,assistant professor of health policy a the London School of Economics joins us to talk about why potential bias may mean potential exaggeration of treatment effects, and could be...

The Reds want to use Raisel Iglesias in the most intense moments, even if that means using someone else in the ninth.

Large outflows of educated young people escaping high levels of unemployment, in tandem with inflows of unauthorized migrants, pose a fresh set of challenges for Greek policymakers. This Transatlantic Council on Migration report examines Greek emigration, and its economic implications, before exploring policy directions to minimize the costs and maximize the benefits of this mobility.

The Armenian diaspora, which significantly exceeds the country's resident population, has played an instrumental role in Armenia's political and economic development since independence in 1991. Yet a picture emerges of divergent currents within the diaspora, often seen from above as a unified entity. Delve into differences in engagement among Armenia's "old" and "new" diasporas with this feature article.

Authoritarian states have long attempted to restrict citizens’ movement. But what happens when their reach extends beyond their borders? The October 2018 assassination of Saudi journalist Jamal Khashoggi brought into sharp relief the long arm of these regimes in reaching citizens abroad. This phenomenon, “transnational authoritarianism,” further shows that the relationship between migration and authoritarianism is becoming more complex.

From being a source of labor emigration to the Gulf region to a destination for refugees from Syria, sub-Saharan Africa, and elsewhere, Egypt has long experienced different forms of mobility. This article, which profiles the trends and policies that have shaped Egypt's migration history, focuses on its long-standing use of migration as a soft-power tool to achieve its foreign policy aims and as a safety valve for political discontent.

This report discusses Spain’s changing migration patterns in the wake of dramatic economic downturn, paying special attention to the effects of the emigration of young, native-born Spaniards. The report also focuses on policies geared toward engaging the increasing number of Spaniards abroad, finding that much of Spain's policy towards diasporas predates the 1980s.

Una llamada en español que analiza las dinámicas cambiantes y las cuestiones políticas relacionadas con la migración a través de México a los Estados Unidos.

Durante este seminario, ponentes presentaron hallazgos de un reciente informe que utiliza datos de agencias gubernamentales mexicanas, entrevistas con funcionarios clave y relatos de la sociedad civil para examinar el marco legal para la protección de menores no acompañados y su aplicación, al igual que las brechas entre este marco y su aplicación durante los procesos de detención, interrogación y alojamiento. El presidente de MPI, Andrew Selee, también expuso cómo el cambio en la dinámica política en Estados Unidos puede afectar las cuestiones migratorias con México, así como los efectos en la relación bilateral en medio de tensiones sobre el muro fronterizo, la renegociación del acuerdo del TLCAN y una cifra significativa de repatriaciones de migrantes mexicanos.

Samy Suissa
Jan 1, 2018; 41:6-10
Perspectives in Care

OBJECTIVE

To examine whether low baseline diastolic blood pressure (DBP) modifies the effects of intensive systolic blood pressure (SBP) lowering on cardiovascular outcomes in type 2 diabetes mellitus (T2DM).

Faced with high emigration rates and shrinking, aging populations, the Baltic states—Estonia, Latvia, and Lithuania—are exploring different ways to lure back nationals who have emigrated and establish or solidify ties with members of the diaspora. Of the three countries, Estonia is proving the most successful, while Latvia appears to be ignoring the looming demographic crisis and lacks an immigration plan.

You could be forgiven for thinking the television images in the experiment were from 2006. They were really from 1982: Israeli forces were clashing with Arab militants in Lebanon. The world was watching, charges were flying, and the air was thick with grievance, hurt and outrage.

Antiwar liberals last week got to savor the four most satisfying words in the English language: "I told you so."

Long before word recently broke that white referees in the National Basketball Association were calling fouls at a higher rate on black athletes than on white athletes, and long before studies found racial disparities in how black and white applicants get called for job interviews, researchers no...

On Oct. 10, 2002, Hillary Rodham Clinton stood in the Senate to explain why she was authorizing President Bush to use force against Iraq: "In balancing the risks of action versus inaction, I think New Yorkers who have gone through the fires of hell may be more attuned to the risk of not acting. I...

The local lady finger bananas are so sweet and moorish!

Responsables de políticos principales y partes interesadas de América Latina, así como representantes de instituciones internacionales claves, ofrecen sus puntos de vista sobre los desafíos futuros mientras gobiernos latinoamericanos buscan establecer las estrategias para responder a flujos migratorios forzados a gran escala, como los de Venezuela y Nicaragua.

Responsables de políticos principales y partes interesadas de América Latina, así como representantes de instituciones internacionales claves, ofrecen sus puntos de vista sobre los desafíos futuros mientras gobiernos latinoamericanos buscan establecer las estrategias para responder a flujos migratorios forzados a gran escala, como los de Venezuela y Nicaragua.