We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.

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.

Arrestin-1 is the arrestin family member responsible for inactivation of the G protein–coupled receptor rhodopsin in photoreceptors. Arrestin-1 is also well-known to interact with additional protein partners and to affect other signaling cascades beyond phototransduction. In this study, we investigated one of these alternative arrestin-1 binding partners, the glycolysis enzyme enolase-1, to map the molecular contact sites between these two proteins and investigate how the binding of arrestin-1 affects the catalytic activity of enolase-1. Using fluorescence quench protection of strategically placed fluorophores on the arrestin-1 surface, we observed that arrestin-1 primarily engages enolase-1 along a surface that is opposite of the side of arrestin-1 that binds photoactivated rhodopsin. Using this information, we developed a molecular model of the arrestin-1–enolase-1 complex, which was validated by targeted substitutions of charge-pair interactions. Finally, we identified the likely source of arrestin's modulation of enolase-1 catalysis, showing that selective substitution of two amino acids in arrestin-1 can completely remove its effect on enolase-1 activity while still remaining bound to enolase-1. These findings open up opportunities for examining the functional effects of arrestin-1 on enolase-1 activity in photoreceptors and their surrounding cells.

Type IV filaments (T4F), which are helical assemblies of type IV pilins, constitute a superfamily of filamentous nanomachines virtually ubiquitous in prokaryotes that mediate a wide variety of functions. The competence (Com) pilus is a widespread T4F, mediating DNA uptake (the first step in natural transformation) in bacteria with one membrane (monoderms), an important mechanism of horizontal gene transfer. Here, we report the results of genomic, phylogenetic, and structural analyses of ComGC, the major pilin subunit of Com pili. By performing a global comparative analysis, we show that Com pili genes are virtually ubiquitous in Bacilli, a major monoderm class of Firmicutes. This also revealed that ComGC displays extensive sequence conservation, defining a monophyletic group among type IV pilins. We further report ComGC solution structures from two naturally competent human pathogens, Streptococcus sanguinis (ComGCSS) and Streptococcus pneumoniae (ComGCSP), revealing that this pilin displays extensive structural conservation. Strikingly, ComGCSS and ComGCSP exhibit a novel type IV pilin fold that is purely helical. Results from homology modeling analyses suggest that the unusual structure of ComGC is compatible with helical filament assembly. Because ComGC displays such a widespread distribution, these results have implications for hundreds of monoderm species.

Arrestin-1 is the arrestin family member responsible for inactivation of the G protein–coupled receptor rhodopsin in photoreceptors. Arrestin-1 is also well-known to interact with additional protein partners and to affect other signaling cascades beyond phototransduction. In this study, we investigated one of these alternative arrestin-1 binding partners, the glycolysis enzyme enolase-1, to map the molecular contact sites between these two proteins and investigate how the binding of arrestin-1 affects the catalytic activity of enolase-1. Using fluorescence quench protection of strategically placed fluorophores on the arrestin-1 surface, we observed that arrestin-1 primarily engages enolase-1 along a surface that is opposite of the side of arrestin-1 that binds photoactivated rhodopsin. Using this information, we developed a molecular model of the arrestin-1–enolase-1 complex, which was validated by targeted substitutions of charge-pair interactions. Finally, we identified the likely source of arrestin's modulation of enolase-1 catalysis, showing that selective substitution of two amino acids in arrestin-1 can completely remove its effect on enolase-1 activity while still remaining bound to enolase-1. These findings open up opportunities for examining the functional effects of arrestin-1 on enolase-1 activity in photoreceptors and their surrounding cells.

Oct 1, 1992; 41:1368-1369
System[egrave] International (SI) Units Table

Errol B. Marliss
Feb 1, 2002; 51:S271-S283
Section 6: Pusatile and Phasic Insulin Release in Normal and Diabetic Men

Rhian M. Touyz
Jan 1, 2016; 65:19-21
Commentaries

16 March 2020

Research Event

Lord Mark Malloch-Brown, Chairman, SGO; Former Deputy Secretary-General and Chief of Staff, United Nations
Dr Elizabeth Cousens, President and CEO, United Nations Foundation
Ambassador Nicholas Burns, Roy and Barbara Goodman Family Professor of the Practice of Diplomacy and International Relations at the Harvard Kennedy School; US Under Secretary of State for Political Affairs, 2005 – 2008
Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House

Invitation Only Research Event

Event participants

Oscar Jonsson, Director, Stockholm Free World Forum (Frivärld)
Mathieu Boulègue, Research Fellow, Russia and Eurasia Programme, Chatham House
Chair: ​Alice Billon-Galland, Research Associate, Europe Programme, Chatham House

Dead beetles die in their skins, and Seychellois, Mauritanians, Maurtians, Martians, Fighting with sun-tans all, and Bad lip jobs, In Nairobi, Silent giraffes grope for love, God, Tends to antelopes, The world ends In a traffic jam or, Dicks in space-suits building railways​ through the heart of a city. ♦Photo♦ Friends of Nairobi National Park -short evocative […]

The first Hall of Famer to join the Astros at Spring Training is Craig Biggio, who was in uniform for morning workouts on Tuesday and will remain with the team throughout the week.

The National Surveys of Sexual Attitudes and Lifestyles is a deep look into the sex lives of us brits - and has been running now for 30 years, giving us some longitudinal data about the way in which those sex lives have changed. The latest paper to be published, based on that data, looks at the frequency of sex - how often different groups are...

Margaret Heffernan has thought a lot about whistleblowing, and why companies don't respond well to it. She wrote the "Book Wilful Blindness: Why We Ignore the Obvious at our Peril". In this podcast she talks about how culture, and groupthink, leads to a culture where whistleblowers are ignored, and why the NHS needs to change the way it treats...

Days after The Gleaner reported a clarion call from Port Maria Mayor Richard Creary for the quarantine of St Mary communities owing to growing concerns about the spread of COVID-19 in the parish, the Government responded with the lockdown of three...

GEORGETOWN, Guyana, CMC – The Guyana government Friday confirmed that US$4.9 million had been deposited into the Natural Resources Fund as a result of the first royalty payment for the country’s crude oil. Finance Minister, Winston...

Studies on magnetic resonance neurography (MRN) in diabetic polyneuropathy (DPN) have found proximal sciatic nerve lesions. The aim of this study was to evaluate the functional relevance of sciatic nerve lesions in DPN, with the expectation of correlations with the impairment of large-fiber function. Sixty-one patients with type 2 diabetes (48 with and 13 without DPN) and 12 control subjects were enrolled and underwent MRN, quantitative sensory testing, and electrophysiological examinations. There were differences in mechanical detection (Aβ fibers) and mechanical pain (A fibers) but not in thermal pain and thermal detection clusters (C fibers) among the groups. Lesion load correlated with lower Aα-, Aβ-, and A-fiber but not with C-fiber function in all participants. Patients with lower function showed a higher load of nerve lesions than patients with elevated function or no measurable deficit despite apparent DPN. Longer diabetes duration was associated with higher lesion load in patients with DPN, suggesting that nerve lesions in DPN may accumulate over time and become clinically relevant once a critical amount of nerve fascicles is affected. Moreover, MRN is an objective method for determining lower function mainly in medium and large fibers in DPN.

Diabetic retinopathy (DR) is a widespread vision-threatening disease, and neuroretinal abnormality should be considered as an important problem. Brain-derived neurotrophic factor (BDNF) has recently been considered as a possible treatment to prevent DR-induced neuroretinal damage, but how BDNF is upregulated in DR remains unclear. We found an increase in hydrogen peroxide (H₂O₂) in the vitreous of patients with DR. We confirmed that human retinal endothelial cells secreted H₂O₂ by high glucose, and H₂O₂ reduced cell viability of MIO-M1, Müller glia cell line, PC12D, and the neuronal cell line and lowered BDNF expression in MIO-M1, whereas BDNF administration recovered PC12D cell viability. Streptozocin-induced diabetic rats showed reduced BDNF, which is mainly expressed in the Müller glia cell. Oral intake of eicosapentaenoic acid ethyl ester (EPA-E) ameliorated BDNF reduction and oscillatory potentials (OPs) in electroretinography (ERG) in DR. Mass spectrometry revealed an increase in several EPA metabolites in the eyes of EPA-E–fed rats. In particular, an EPA metabolite, 18-hydroxyeicosapentaenoic acid (18-HEPE), induced BDNF upregulation in Müller glia cells and recovery of OPs in ERG. Our results indicated diabetes-induced oxidative stress attenuates neuroretinal function, but oral EPA-E intake prevents retinal neurodegeneration via BDNF in Müller glia cells by increasing 18-HEPE in the early stages of DR.

4 December 2019

This discussion on the 1986 Immigration Reform and Control Act (IRCA) showcases MPI Fellow Charles Kamasaki's book, Immigration Reform: The Corpse That Will Not Die. Kamasaki is joined by other veterans of the IRCA debate for a conversation on the lessons, the intended and unintended consequences, and how the law’s legacy has shaped contemporary politics on immigration.

Although long one of the world's top migrant destinations, only in the recent past has Germany come to acknowledge and adjust to its role as a country of immigration. Its welcoming approach—a relatively new development—has been put to the test amid massive humanitarian inflows beginning in 2015. This country profile examines Germany's history on immigration and highlights current and emerging debates.

One of the most rapidly aging societies in the world, Japan is looking to immigration to address increased labor shortages—albeit slowly and largely without public debate. This country profile offers a brief overview of Japan’s migration history and examines the current immigration system, in particular policies and programs to bring in foreign workers, particularly on a temporary basis.

OBJECTIVE

Diabetes is a rapidly growing health problem in low- and middle-income countries (LMICs), but empirical data on its prevalence and relationship to socioeconomic status are scarce. We estimated diabetes prevalence and the subset with undiagnosed diabetes in 29 LMICs and evaluated the relationship of education, household wealth, and BMI with diabetes risk.

Though it has achieved success in some areas, the Trump administration’s many efforts to stiffen immigration enforcement in the U.S. interior and at the Southwest border are being consistently stymied by court injunctions, existing laws and settlements, state and local resistance, congressional pushback, and migration pressures that are beyond the government’s ability to swiftly address, as this article explores.

With a backlog of more than 1 million removal cases, the U.S. immigration court system is in crisis. Pressure from external forces, internal challenges, and lagging resources for the courts at a time of massive increases in spending on immigration enforcement have contributed to the backlog. This article explores how the system got to the breaking point, and what opportunities for reform exist.

Hannele Yki-Järvinen
Dec 1, 2014; 37:3235-3243
Emerging Technologies and Therapeutics

Muh Geot Wong
May 1, 2016; 39:694-700
Cardiovascular Disease and Diabetes

Matthew C. Riddle
Oct 1, 2014; 37:2755-2762
Emerging Technologies and Therapeutics

A panel of 11 judges ruled that Israeli Prime Minister Benjamin Netanyahu can form a government after reaching a deal with rival Benny Gantz.

At least two people died and more than a dozen were hurt Friday when a moderate earthquake struck in Iran's northern city of Damavand, near Tehran.

Apr 1, 1994; 17:360-361
Syst[egrave]me International (SI) Units

Nov 1, 1995; 18:1524-1525
Syst[egrave]me International (SI) Units

Aug 1, 1995; 18:1223-1224
Syst[egrave]me International (SI) Units

Even as refugee admissions have dropped sharply during the Trump administration, some countries and religions have been significantly more affected than others, as this commentary explores. In fiscal year 2019, 79 percent of refugees were Christian and 16 percent Muslim—as compared to 44 percent Christian and 46 percent Muslim in fiscal year 2016, which was the last full year of the Obama administration.

Greater compliance with dietary guidelines may reduce the chance of untreated caries in adults, according to a study published in the February issue of The Journal of the American Dental Association.

The Commission on Dental Accreditation announced April 3 that it will reschedule all postponed and remaining site visits this year, including regular/reaccreditation and special focused site visits, to 2021 in response to the COVID-19 pandemic.

As Congress works on the next coronavirus-related relief package, the ADA and 37 other health care organizations are asking lawmakers to support nonprofit groups in those efforts.

OBJECTIVE

We examined detailed renal and cardiovascular (CV) outcomes after gastric bypass (GBP) surgery in people with obesity and type 2 diabetes mellitus (T2DM), across several renal function categories, in a nationwide cohort study.

OBJECTIVE

To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes.

While migration once was a lower-priority topic for African governments, the last decade has seen a deepening in governance. Policymakers have integrated migration into their national development strategies and mainstreamed it across policy domains such as health and education. The actions are promising on paper, yet questions remain about the extent to which they will translate to more effective migration management.

This provocative discussion showcases Charles Kamasaki's book, Immigration Reform: The Corpse That Will Not Die, and explores the lessons that can be learned from the Immigration Reform and Control Act of 1986, its intended and unintended consequences, and how the law’s legacy has shaped contemporary politics surrounding immigration.

Poland announced a delay of its Sunday presidential election, Europe's first planned vote during the coronavirus pandemic.

Queen guitarist Brian May is recovering after tearing his gluteus maximus during a moment of "over-enthusiastic" gardening.