(Oregon State University) Clinical trial data behind drug dose recommendations for elevated cholesterol and chronic obstructive pulmonary disease illustrate how larger doses may not be worth the extra costs for many types of patients.

(Virginia Institute of Marine Science) New study indicates the increase in rainfall forecast by global climate models is likely to hasten the release of carbon dioxide from tropical soils, further intensifying global warming by adding to human emissions of this greenhouse gas into Earth's atmosphere.

(University of Exeter) The public would comply with major changes to medical advice - but would then be less likely to follow other new guidelines in the future, research shows.

(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.

(Crime and Justice Research Alliance) A new study evaluated the effects of legalizing cannabis on police officers' law enforcement efforts in Washington. The study found that officers in that state, although not supportive of recriminalization, had a variety of concerns, from worries about the effect on youth to increases in impaired driving. The study can inform other states' efforts to address legalization.

(Penn State) A new process to harness multiple disease models for outbreak management has been developed by an international team of researchers. The team will immediately implement the process to help inform policy decisions for the COVID-19 outbreak.

Soren E. Skovlund
Jul 1, 2005; 18:136-142
Lifestyle and Behavior

A single tweet on the weekend about a possible collaboration between dancehall princess Shenseea and US rap sensation Nicki Minaj has left fans of the Romeich Entertainment singer bursting with excitement. Rumours of a pending project between...

Up-and-coming entertainer Shav-A says the COVID-19 pandemic made her reflect on her life. "I needed a reset. With all this downtime, I have realised that I needed to stop and rethink a lot of things that are going on in my life, and it also...

Dancehall artiste Stylysh is set to restart her Instagram (IG) show, which is centred around love, sex, and relationships. Last season's guests included the likes of Shauna Chin, Destiny Sparta, and Gaza Sheba, who spoke candidly of her sexual...

A man has been arrested in connection with the “vile and brutal” murders of 8-year-old Toya Brown and 15-year-old Nyron Taylor, who were shot and killed last evening, revealed Minister of National Security, Dr. Horace Chang. Chang says...

"It felt like prison." Those are the exact words of Jermaine who returned to the island yesterday after he was stranded on a cruise ship for 56 days in South Hampton, United Kingdom. "Bwoy we are out of prison ... it was rough mentally. They...

Data from March shows similarities in spending across various demographics.

Businesses will benefit from clear policy guidance from lawmakers

Retail giants like Yoox Net-a-Porter Group and Brooks Brothers quickly pivoted to offer life-saving services.

Research Event

Event participants

This event is now full and registration has closed.

Participants include

Zeinab Badawi, Presenter, BBC Global Questions and HardTalk
Lakhdar Brahimi, The Elders; Chair, Panel on United Nations Peace Operations (2000)
Alan Doss, President, Kofi Annan Foundation 
Raila Odinga, High Representative for Infrastructure Development, African Union; Prime Minister of Kenya (2008-13)
Patrick Gaspard, President, Open Society Foundations
Michèle Griffin, Senior Policy Advisor to the UN Secretary-General
Ian Martin, Special Representative of the UN Secretary-General in East Timor (1999), Nepal (2007-09) and Libya (2011-12)
Strive Masiyiwa, Chair of the Board, AGRA; CEO, Econet Wireless
Amina Mohammed, Deputy Secretary-General, United Nations
Kumi Naidoo, Secretary-General, Amnesty International
Danny Sriskandarajah, Chief Executive, Oxfam
Mark Suzman, Chief Strategy Officer and President of Global Policy and Advocacy, Bill & Melinda Gates Foundation

Invitation Only Research Event

Event participants

Chair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House

23 October 2019

The ‘Our Shared Humanity’ conference explored Kofi Annan’s legacy for the future of global governance in the run-up to the UN’s 75th anniversary. This paper summarizes key points raised during the conference, and presents the substantive recommendations that emerged from the discussion.

Sperm head shaping is a key event in spermiogenesis and is tightly controlled via the acrosome–manchette network. Linker of nucleoskeleton and cytoskeleton (LINC) complexes consist of Sad1 and UNC84 domain–containing (SUN) and Klarsicht/ANC-1/Syne-1 homology (KASH) domain proteins and form conserved nuclear envelope bridges implicated in transducing mechanical forces from the manchette to sculpt sperm nuclei into a hook-like shape. However, the role of LINC complexes in sperm head shaping is still poorly understood. Here we assessed the role of SUN3, a testis-specific LINC component harboring a conserved SUN domain, in spermiogenesis. We show that CRISPR/Cas9-generated Sun3 knockout male mice are infertile, displaying drastically reduced sperm counts and a globozoospermia-like phenotype, including a missing, mislocalized, or fragmented acrosome, as well as multiple defects in sperm flagella. Further examination revealed that the sperm head abnormalities are apparent at step 9 and that the sperm nuclei fail to elongate because of the absence of manchette microtubules and perinuclear rings. These observations indicate that Sun3 deletion likely impairs the ability of the LINC complex to transduce the cytoskeletal force to the nuclear envelope, required for sperm head elongation. We also found that SUN3 interacts with SUN4 in mouse testes and that the level of SUN4 proteins is drastically reduced in Sun3-null mice. Altogether, our results indicate that SUN3 is essential for sperm head shaping and male fertility, providing molecular clues regarding the underlying pathology of the globozoospermia-like phenotype.

Michael Plank
Apr 1, 2020; 19:655-671
Research

Nikita Prianichnikov
Mar 10, 2020; 0:TIR119.001720v1-mcp.TIR119.001720
Technological Innovation and Resources

Dorte B. Bekker-Jensen
Apr 1, 2020; 19:716-729
Technological Innovation and Resources

By William Yslas Vélez Professor Emeritus University of Arizona “When I go to a Mexican restaurant I would gladly pay the musicians to stop playing.” John (not his real name) did not like the noise level. This statement came up … Continue reading →

Guest blog by Professor Mohamed Omar It started as a dare between friends. Would you dare post a video of yourself doing math on YouTube, for the entire world to see? That was the seed of what has become a … Continue reading →

Guest blog by Stephen McKean On my first day of college, I showed up an hour early to my very first class. The class was Math 2210, multivariable calculus. For some reason, I thought this was the highest math class … Continue reading →

Student Authors: Mayleen Cortez, Brooke Keene-Gomez, Lucy Martinez, Amaury V. Miniño, Jenna Race, Kelemua Tesfaye, and Stephanie. Blog post compiled by Melissa Gutiérrez González, Pamela E. Harris, and Alicia Prieto Langarica. In this blog we center the voices of mathematics students as … Continue reading →

Invitation Only Research Event

4 March 2020 , Volume 96, Number 2

8 April 2020

7 May 2020 , Volume 96, Number 3

7 May 2020 , Volume 96, Number 3

The currently available therapeutic radiopharmaceutical for high-risk neuroblastoma, ¹³¹I-MIBG, is ineffective at targeting micrometastases due to the low linear energy transfer (LET) properties of high-energy beta particles. In contrast, Auger radiation has high-LET properties with nanometer ranges in tissue, efficiently causing DNA damage when emitted in close proximity to DNA. The aim of this study was to evaluate the cytotoxicity of targeted Auger therapy in pre-clinical models of high-risk neuroblastoma. Methods: Using a radiolabeled poly(ADP-ribose) polymerase (PARP) inhibitor, ¹²⁵I-KX1, we delivered an Auger emitter iodine-125 to PARP-1: a chromatin-binding enzyme overexpressed in neuroblastoma. In vitro cytotoxicity of ¹²⁵I-KX1 was assessed in nineteen neuroblastoma cell lines, followed by in-depth pharmacological analysis in a sensitive and resistant pair of cell lines. Immunofluorescence microscopy was used to characterize ¹²⁵I-KX1-induced DNA damage. Finally, in vitro/in vivo microdosimetry was modeled from experimentally derived pharmacological variables. Results: ¹²⁵I-KX1 was highly cytotoxic in vitro across a panel of neuroblastoma cell lines, directly causing double strand DNA breaks. Based on subcellular dosimetry, ¹²⁵I-KX1 was approximately twice as effective compared to ¹³¹I-KX1, whereas cytoplasmic ¹²⁵I-MIBG demonstrated low biological effectiveness. Despite the ability to deliver focused radiation dose to the cell nuclei, ¹²⁵I-KX1 remained less effective than its alpha-emitting analog ²¹¹At-MM4, and required significantly higher activity for equivalent in vivo efficacy based on tumor microdosimetry. Conclusion: Chromatin-targeted Auger therapy is lethal to high-risk neuroblastoma cells with potential use in micrometastatic disease. This study provides the first evidence for cellular lethality from a PARP-1 targeted Auger emitter, calling for further investigation into targeted Auger therapy.

It was hypothesized that the brain β-amyloid buildup curve plateaus at an early symptomatic Alzheimer's disease (AD) stage. Atrophy-related partial volume effects (PVEs) degrade signal in hot-spot imaging techniques, such as amyloid positron emission tomography (PET). This longitudinal analysis of amyloid-sensitive PET data investigated the shape of the β-amyloid curve in AD applying PVE correction (PVEC). We analyzed baseline and 2-year follow-up data of 216 symptomatic individuals on the AD continuum (positive amyloid status) enrolled in Alzheimer's Disease Neuroimaging Initiative (17 AD dementia, 199 mild cognitive impairment), including 18F-florbetapir PET, magnetic resonance imaging and mini mental state examination (MMSE) scores. For PVEC, the modified Müller-Gärtner method was performed. Compared to non-PVE-corrected data, PVE-corrected data yielded significantly higher regional and composite standardized uptake value ratio (SUVR) changes over time (P=0.0002 for composite SUVRs). Longitudinal SUVR changes in relation to MMSE decreases showed a significantly higher slope of the regression line in the PVE-corrected as compared to the non-PVE-corrected PET data (F=7.1, P=0.008). These PVEC results indicate that the β-amyloid buildup curve does not plateau at an early symptomatic disease stage. A further evaluation of the impact of PVEC on the in-vivo characterization of time-dependent AD pathology, including the reliable assessment and comparison of other amyloid tracers, is warranted.

The value of interim ¹⁸F-fluorodeoxyglucose positron emission tomography (iPET) guided treatment decisions in patients with diffuse large B-cell lymphoma (DLBCL) has been the subject of much debate. This investigation focuses on a comparison of the Deauville score and the deltaSUV_max (SUV_max) approach – two methods to assess early metabolic response to standard chemotherapy in DLBCL. Methods: Of 609 DLBCL patients participating in the Positron Emission Tomography-guided Therapy of Aggressive non-Hodgkin Lymphomas (PETAL) trial, iPET scans of 596 patients originally evaluated using the SUV_max method were available for post-hoc assessment of the Deauville score. A commonly used definition of an unfavorable iPET result according to the Deauville score is an uptake greater than that of the liver, whereas an unfavorable iPET scan with regard to the SUV_max approach is characterized as a relative reduction of the maximum standardized uptake value between baseline and iPET staging of less than or equal to 66%. We investigated the two methods’ correlation and concordance by Spearman’s rank correlation coefficient and the agreement in classification, respectively. We further used Kaplan-Meier curves and Cox regression to assess differences in survival between patient subgroups defined by the pre-specified cut-offs. Time-dependent receiver operating curve analysis provided information on the methods’ respective discrimination performance. Results: Deauville score and SUV_max approach differed in their iPET-based prognosis. The SUV_max approach outperformed the Deauville score in terms of discrimination performance – most likely due to a high number of false-positive decisions by the Deauville score. Cut-off-independent discrimination performance remained low for both methods, but cut-off-related analyses showed promising results. Both favored the SUV_max approach, e.g. for the segregation by iPET response, where the event-free survival hazard ratio was 3.14 (95% confidence interval (CI): 2.22 – 4.46) for SUV_max and 1.70 (95% CI: 1.29 – 2.24) for the Deauville score. Conclusion: When considering treatment intensification, the currently used Deauville score cut-off of an uptake above that of the liver seems to be inappropriate and associated with potential harm for DLBCL patients. The SUV_max criterion of a relative reduction of the maximum standardized uptake value of less than or equal to 66% should be considered as an alternative.

31 October 2019

Trade between Central and Eastern Europe and sub-Saharan Africa has increased significantly in the last decade and a half. There is a strong case to be made for greater economic re-engagement, especially in terms of investment, that has the potential to support inclusive growth in both regions.

Research Event

Event participants

HE Nabil Ben Khedher, Ambassador of Tunisia to the United Kingdom
Professor Naohiro Kitano, Visiting Fellow, Japan International Cooperation Agency Research Institute (JICA-RI); Professor, Waseda University
Taku Miyazaki, Deputy Director General, Japan External Trade Organisation (JETRO) London
Serge Mouangue, Founder and Art Director, WAfrica
Norio Suzuki, Senior Strategist, BBOXX
HE Professor Mohammed Gana Yisa, Ambassador of the Federal Republic of Nigeria to Japan; Chairman, African Diplomatic Corps in Tokyo (ADC) TICAD Committee

Chairs:
Dr Champa Patel, Director, Asia-Pacific Programme, Chatham House
Dr Alex Vines OBE, Managing Director, Ethics, Risk & Resilience; Director, Africa Programme

7 May 2020

State-of-the-art proteomics-grade mass spectrometers can measure peptide precursors and their fragments with ppm mass accuracy at sequencing speeds of tens of peptides per second with attomolar sensitivity. Here we describe a compact and robust quadrupole-orbitrap mass spectrometer equipped with a front-end High Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) Interface. The performance of the Orbitrap Exploris 480 mass spectrometer is evaluated in data-dependent acquisition (DDA) and data-independent acquisition (DIA) modes in combination with FAIMS. We demonstrate that different compensation voltages (CVs) for FAIMS are optimal for DDA and DIA, respectively. Combining DIA with FAIMS using single CVs, the instrument surpasses 2500 peptides identified per minute. This enables quantification of >5000 proteins with short online LC gradients delivered by the Evosep One LC system allowing acquisition of 60 samples per day. The raw sensitivity of the instrument is evaluated by analyzing 5 ng of a HeLa digest from which >1000 proteins were reproducibly identified with 5 min LC gradients using DIA-FAIMS. To demonstrate the versatility of the instrument, we recorded an organ-wide map of proteome expression across 12 rat tissues quantified by tandem mass tags and label-free quantification using DIA with FAIMS to a depth of >10,000 proteins.

Protein phosphorylation cascades play a central role in the regulation of cell growth and protein kinases PKA, Sch9 and Ypk1 take center stage in regulating this process in S. cerevisiae. To understand how these kinases co-ordinately regulate cellular functions we compared the phospho-proteome of exponentially growing cells without and with acute chemical inhibition of PKA, Sch9 and Ypk1. Sites hypo-phosphorylated upon PKA and Sch9 inhibition were preferentially located in RRxS/T-motifs suggesting that many are directly phosphorylated by these enzymes. Interestingly, when inhibiting Ypk1 we not only detected several hypo-phosphorylated sites in the previously reported RxRxxS/T-, but also in an RRxS/T-motif. Validation experiments revealed that neutral trehalase Nth1, a known PKA target, is additionally phosphorylated and activated downstream of Ypk1. Signaling through Ypk1 is therefore more closely related to PKA- and Sch9-signaling than previously appreciated and may perform functions previously only attributed to the latter kinases.

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.

Marriage vows are one thing, but the public service Code of Conduct, that's serious.