(Postponed) We will be holding Dentons' first Global Competition Summit on Friday 19 June at our London office. Please join us for a series of panel discussions, in which we will provide insights on key current themes and issues in competition law.

This paper presents an analysis of business development programs (BDPs) based on a theoretical framework aimed at understanding the mixed effect of business training on entrepreneurs.

AN3455 - 1000BASE-T Transmitter Distortion

BANGALORE, INDIA –  HARMAN (NYSE:HAR), the premier connected technologies company for automotive, consumer and enterprise markets, today announced the launch of limited edition JBL® Raaga Synchros S500AR headphones, autographed by academy award winner...

All over the world, people and societies are adjusting to social distancing and a long-term work-from-home environment. Students and teachers too are now adapting to virtual classes, quickly mastering and equipping themselves with all tools necessary to...

Kabellose Freiheit verspricht der brandneue JBL LIVE 300TWS! Der neue True Wireless-Kopfhörer sorgt für perfekte Verbindung, glänzt mit seinem stylischen Design und garantiert jederzeit entfesselten Sound ohne Einschränkung. Ausgestattet mit leistungsstarken Treibern liefert der Kopfhörer einen verstärkten Bass, der jede Playlist zum Beben bringt.

For over a century, International Women’s Day (IWD) has recognized the social, economic, cultural, political and professional achievements of women around the world. At HARMAN, we also have a long history of championing women, especially those pursuing...

Olivia Colman and Helen Mirren have teamed up with the creators of Wallace & Gromit in a film called Turtle Journey to raise awareness about climate change and ocean pollution

The Tully Monster is a famously odd 300-million-year-old fossil that looks like an alien, but a new analysis suggests it was a backboned animal like a hagfish or lamprey

A decade ago, Johan Rockström identified the limits to Earth's life support systems. From chemical pollution to climate change, we're veering into the danger zone - so why is he (cautiously) optimistic about the future?

Olivia Colman and Helen Mirren have teamed up with the creators of Wallace & Gromit in a film called Turtle Journey to raise awareness about climate change and ocean pollution

Shards of pottery probably used for transporting food suggest a mountain site in the Czech Republic may have been a nature retreat for Iron Age religious hermits

The chief executive of United Airlines sat down before a House panel on Tuesday to testify about the forced removal on April 9 of a passenger from a Chicago flight, an incident that drew international condemnation.

The Tully Monster is a famously odd 300-million-year-old fossil that looks like an alien, but a new analysis suggests it was a backboned animal like a hagfish or lamprey

The leading hypothesis for how the moon formed involves a collision between a Mars-sized object and Earth that would have boiled away elements like carbon, making its discovery on the moon a mystery

Title: Amitiza Treats Irritable Bowel With Constipation
Category: Health News
Created: 5/1/2008 2:00:00 AM
Last Editorial Review: 5/1/2008 12:00:00 AM

Title: White House to Challenge Ruling on Unlimited Access to 'Morning-After' Pill
Category: Health News
Created: 5/2/2013 10:35:00 AM
Last Editorial Review: 5/2/2013 12:00:00 AM

Title: Spanking May Be More Common Than Parents Admit
Category: Health News
Created: 4/29/2014 7:36:00 PM
Last Editorial Review: 4/30/2014 12:00:00 AM

Title: Many Ivy League Students Admit Using ADHD Drugs for Better Grades: Study
Category: Health News
Created: 5/2/2014 12:36:00 PM
Last Editorial Review: 5/2/2014 12:00:00 AM

Title: Nevada Bill Aims to Limit Insulin Costs
Category: Health News
Created: 5/2/2017 12:00:00 AM
Last Editorial Review: 5/2/2017 12:00:00 AM

Title: How Long Does a Mitral Valvuloplasty Last?
Category: Procedures and Tests
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/7/2020 12:00:00 AM

Title: Is Coronavirus Also Sexually Transmitted?
Category: Health News
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/8/2020 12:00:00 AM

The most recent meeting of the PMC Advisory Committee was held at the National Library of Medicine on June 15, 2009. The committee meets at least once a year and its members are appointed by the NIH Director from the biomedical information communities and the general public. Dr. Gary Ward, of the Department of Microbiology & Molecular Genetics at the University of Vermont, has been appointed to serve as Chair of the Committee through January 2011.

Four new members have been appointed to serve on the PMC National Advisory Committee: Mike Rossner of Rockefeller University Press, Jan Fassler of the University of Iowa, Ivy Anderson of the California Digital Library, and Delores Meglio from the Knovel Corporation. Each member will serve a 4-year term. The next meeting of the committee is scheduled for June 4, 2010. For more information on the committee, see PMC National Advisory Committee.

Four new members have been appointed to serve on the PMC National Advisory Committee: Philip Bourne, of the University of California, San Diego; Sophia Colamarino, an independent consultant in San Francisco; Paul Courant, of the University of Michigan; and Patricia Thibodeau, of Duke University. Each member will serve a 4-year term. The next meeting of the committee is scheduled for Friday, June 17, 2011. For more information on the committee, see PMC National Advisory Committee.

The PMC Advisory Committee will hold its annual meeting at the National Library of Medicine on Friday, June 17, 2011 from 9:30 am to 3 pm. Four new committee members will be joining the group, see New Members Appointed to PMC Advisory Committee. Presentations will include discussions relating to the NIH Public Access policy and a viewing of the PMC 10th Anniversary video. For more information, see PMC National Advisory Committee.

The following new members have been appointed to serve on the PMC National Advisory Committee: Martha Bedard, Dean of Libraries at the University of New Mexico; and Lorraine Haricombe, Dean of Libraries at the University of Kansas and a member of SPARC's board. The next meeting of the committee is scheduled for June 19, 2012. For more information, see PMC National Advisory Committee.

As of February 1, 2013, the following new members have been appointed to serve on the PMC National Advisory Committee: Ms. Sharon Terry of the Genetic Alliance; Dr. C. Victor Jongneel of the University of Illinois at Urbana-Champaign; Dr. Bevin Engelward of the Massachusetts Institute of Technology; Dr. Randall Morse of the Wadsworth Center; and Dr. Adelita Cantu of the University of Texas. For more information, see PMC National Advisory Committee.

This year's PMC Advisory Committee meeting will be held on Tuesday, June 10. The meeting will take place in the NLM Board room starting at 9:30 am. Stay tuned for further details.

Title: Many Car Crash Deaths Involve Alcohol Levels Below Legal Limit: Study
Category: Health News
Created: 3/16/2020 12:00:00 AM
Last Editorial Review: 3/17/2020 12:00:00 AM

Title: Is the 'Gratitude Movement' Overrated? Study Finds It Has Limits
Category: Health News
Created: 3/16/2020 12:00:00 AM
Last Editorial Review: 3/17/2020 12:00:00 AM

There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor–targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1–targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic "class" effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC₅₀ and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1–targeted combination therapy for Ewing sarcoma.

Dysregulation of DNA methylation is an established feature of breast cancers. DNA demethylating therapies like decitabine are proposed for the treatment of triple-negative breast cancers (TNBC) and indicators of response need to be identified. For this purpose, we characterized the effects of decitabine in a panel of 10 breast cancer cell lines and observed a range of sensitivity to decitabine that was not subtype specific. Knockdown of potential key effectors demonstrated the requirement of deoxycytidine kinase (DCK) for decitabine response in breast cancer cells. In treatment-naïve breast tumors, DCK was higher in TNBCs, and DCK levels were sustained or increased post chemotherapy treatment. This suggests that limited DCK levels will not be a barrier to response in patients with TNBC treated with decitabine as a second-line treatment or in a clinical trial. Methylome analysis revealed that genome-wide, region-specific, tumor suppressor gene–specific methylation, and decitabine-induced demethylation did not predict response to decitabine. Gene set enrichment analysis of transcriptome data demonstrated that decitabine induced genes within apoptosis, cell cycle, stress, and immune pathways. Induced genes included those characterized by the viral mimicry response; however, knockdown of key effectors of the pathway did not affect decitabine sensitivity suggesting that breast cancer growth suppression by decitabine is independent of viral mimicry. Finally, taxol-resistant breast cancer cells expressing high levels of multidrug resistance transporter ABCB1 remained sensitive to decitabine, suggesting that the drug could be used as second-line treatment for chemoresistant patients.

ABSTRACT

Each year, >180,000 infants become infected via mother-to-child transmission (MTCT) of HIV despite the availability of effective maternal antiretroviral treatments, underlining the need for a maternal HIV vaccine. We characterized 224 maternal HIV envelope (Env)-specific IgG monoclonal antibodies (MAbs) from seven nontransmitting and transmitting HIV-infected U.S. and Malawian mothers and examined their neutralization activities against nontransmitted autologous circulating viruses and infant-transmitted founder (infant-T/F) viruses. Only a small subset of maternal viruses, 3 of 72 (4%), were weakly neutralized by maternal linear V3 epitope-specific IgG MAbs, whereas 6 out of 6 (100%) infant-T/F viruses were neutralization resistant to these V3-specific IgG MAbs. We also show that maternal-plasma broadly neutralizing antibody (bNAb) responses targeting the V3 glycan supersite in a transmitting woman may have selected for an N332 V3 glycan neutralization-resistant infant-T/F virus. These data have important implications for bNAb-eliciting vaccines and passively administered bNAbs in the setting of MTCT.

IMPORTANCE Efforts to eliminate MTCT of HIV with antiretroviral therapy (ART) have met little success, with >180,000 infant infections each year worldwide. It is therefore likely that additional immunologic strategies that can synergize with ART will be required to eliminate MTCT of HIV. To this end, understanding the role of maternal HIV Env-specific IgG antibodies in the setting of MTCT is crucial. In this study, we found that maternal-plasma broadly neutralizing antibody (bNAb) responses can select for T/F viruses that initiate infection in infants. We propose that clinical trials testing the efficacy of single bNAb specificities should not include HIV-infected pregnant women, as a single bNAb might select for neutralization-resistant infant-T/F viruses.

ABSTRACT

Mitochondrial Ca²⁺ transport mediated by the uniporter complex (MCUC) plays a key role in the regulation of cell bioenergetics in both trypanosomes and mammals. Here we report that Trypanosoma brucei MCU (TbMCU) subunits interact with subunit c of the mitochondrial ATP synthase (ATPc), as determined by coimmunoprecipitation and split-ubiquitin membrane-based yeast two-hybrid (MYTH) assays. Mutagenesis analysis in combination with MYTH assays suggested that transmembrane helices (TMHs) are determinants of this specific interaction. In situ tagging, followed by immunoprecipitation and immunofluorescence microscopy, revealed that T. brucei ATPc (TbATPc) coimmunoprecipitates with TbMCUC subunits and colocalizes with them to the mitochondria. Blue native PAGE and immunodetection analyses indicated that the TbMCUC is present together with the ATP synthase in a large protein complex with a molecular weight of approximately 900 kDa. Ablation of the TbMCUC subunits by RNA interference (RNAi) significantly increased the AMP/ATP ratio, revealing the downregulation of ATP production in the cells. Interestingly, the direct physical MCU-ATPc interaction is conserved in Trypanosoma cruzi and human cells. Specific interaction between human MCU (HsMCU) and human ATPc (HsATPc) was confirmed in vitro by mutagenesis and MYTH assays and in vivo by coimmunoprecipitation. In summary, our study has identified that MCU complex physically interacts with mitochondrial ATP synthase, possibly forming an MCUC-ATP megacomplex that couples ADP and P_i transport with ATP synthesis, a process that is stimulated by Ca²⁺ in trypanosomes and human cells.

IMPORTANCE The mitochondrial calcium uniporter (MCU) is essential for the regulation of oxidative phosphorylation in mammalian cells, and we have shown that in Trypanosoma brucei, the etiologic agent of sleeping sickness, this channel is essential for its survival and infectivity. Here we reveal that that Trypanosoma brucei MCU subunits interact with subunit c of the mitochondrial ATP synthase (ATPc). Interestingly, the direct physical MCU-ATPc interaction is conserved in T. cruzi and human cells.

ABSTRACT

Microbial pathogens exploit host nutrients to proliferate and cause disease. Intracellular pathogens, particularly those exclusively living in the phagosome such as Histoplasma capsulatum, must adapt and acquire nutrients within the nutrient-limited phagosomal environment. In this study, we investigated which host nutrients could be utilized by Histoplasma as carbon sources to proliferate within macrophages. Histoplasma yeasts can grow on hexoses and amino acids but not fatty acids as the carbon source in vitro. Transcriptional analysis and metabolism profiling showed that Histoplasma yeasts downregulate glycolysis and fatty acid utilization but upregulate gluconeogenesis within macrophages. Depletion of glycolysis or fatty acid utilization pathways does not prevent Histoplasma growth within macrophages or impair virulence in vivo. However, loss of function in Pck1, the enzyme catalyzing the first committed step of gluconeogenesis, impairs Histoplasma growth within macrophages and severely attenuates virulence in vivo, indicating that Histoplasma yeasts rely on catabolism of gluconeogenic substrates (e.g., amino acids) to proliferate within macrophages.

IMPORTANCE Histoplasma is a primary human fungal pathogen that survives and proliferates within host immune cells, particularly within the macrophage phagosome compartment. The phagosome compartment is a nutrient-limited environment, requiring Histoplasma yeasts to be able to assimilate available carbon sources within the phagosome to meet their nutritional needs. In this study, we showed that Histoplasma yeasts do not utilize fatty acids or hexoses for growth within macrophages. Instead, Histoplasma yeasts consume gluconeogenic substrates to proliferate in macrophages. These findings reveal the phagosome composition from a nutrient standpoint and highlight essential metabolic pathways that are required for a phagosomal pathogen to proliferate in this intracellular environment.

Heterozygous germline mutations in mammalian target of rapamycin (MTOR) (OMIM 601231) are known to underlie Smith-Kingsmore syndrome (SKS; OMIM 616638), an infrequent entity with autosomal dominant inheritance, also known as macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (ORPHA 457485).¹ Among the clinical features of SKS, the most common features include intellectual disability, macrocephaly, epilepsy, and facial dysmorphism. The aim of this case is to raise awareness of a distinct phenotypical presentation of SKS manifesting with bilateral cataracts and no history of seizures.

The spirochete Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD). The spirochetes produce the CspZ protein that binds to a complement regulator, factor H (FH). Such binding downregulates activation of host complement to facilitate spirochete evasion of complement killing. However, vaccination with CspZ does not protect against LD infection. In this study, we demonstrated that immunization with CspZ-YA, a CspZ mutant protein with no FH-binding activity, protected mice from infection by several spirochete genotypes introduced via tick feeding. We found that the sera from CspZ-YA-vaccinated mice more efficiently eliminated spirochetes and blocked CspZ FH-binding activity than sera from CspZ-immunized mice. We also found that vaccination with CspZ, but not CspZ-YA, triggered the production of anti-FH antibodies, justifying CspZ-YA as an LD vaccine candidate. The mechanistic and efficacy information derived from this study provides insights into the development of a CspZ-based LD vaccine.

In mammalian cells, alphavirus replication complexes are anchored to the plasma membrane. This interaction with lipid bilayers is mediated through the viral methyl/guanylyltransferase nsP1 and reinforced by palmitoylation of cysteine residue(s) in the C-terminal region of this protein. Lipid content of membranes supporting nsP1 anchoring remains poorly studied. Here, we explore the membrane binding capacity of nsP1 with regard to cholesterol. Using the medically important chikungunya virus (CHIKV) as a model, we report that nsP1 cosegregates with cholesterol-rich detergent-resistant membrane microdomains (DRMs), also called lipid rafts. In search for the critical factor for cholesterol partitioning, we identify nsP1 palmitoylated cysteines as major players in this process. In cells infected with CHIKV or transfected with CHIKV trans-replicase plasmids, nsP1, together with the other nonstructural proteins, are detected in DRMs. While the functional importance of CHIKV nsP1 preference for cholesterol-rich membrane domains remains to be determined, we observed that U18666A- and imipramine-induced sequestration of cholesterol in late endosomes redirected nsP1 to these compartments and simultaneously dramatically decreased CHIKV genome replication. A parallel study of Sindbis virus (SINV) revealed that nsP1 from this divergent alphavirus displays a low affinity for cholesterol and only moderately segregates with DRMs. Behaviors of CHIKV and SINV with regard to cholesterol, therefore, match with the previously reported differences in the requirement for nsP1 palmitoylation, which is dispensable for SINV but strictly required for CHIKV replication. Altogether, this study highlights the functional importance of nsP1 segregation with DRMs and provides new insight into the functional role of nsP1 palmitoylated cysteines during alphavirus replication.

IMPORTANCE Functional alphavirus replication complexes are anchored to the host cell membranes through the interaction of nsP1 with the lipid bilayers. In this work, we investigate the importance of cholesterol for such an association. We show that nsP1 has affinity for cholesterol-rich membrane microdomains formed at the plasma membrane and identify conserved palmitoylated cysteine(s) in nsP1 as the key determinant for cholesterol affinity. We demonstrate that drug-induced cholesterol sequestration in late endosomes not only redirects nsP1 to this compartment but also dramatically decreases genome replication, suggesting the functional importance of nsP1 targeting to cholesterol-rich plasma membrane microdomains. Finally, we show evidence that nsP1 from chikungunya and Sindbis viruses displays different sensitivity to cholesterol sequestering agents that parallel with their difference in the requirement for nsP1 palmitoylation for replication. This research, therefore, gives new insight into the functional role of palmitoylated cysteines in nsP1 for the assembly of functional alphavirus replication complexes in their mammalian host.

The Bcl-2 (B cell lymphoma 2)-related protein Nr-13 plays a major role in the regulation of cell death in developing avian B cells. With over 65% sequence similarity to the chicken Nr-13, herpesvirus of turkeys (HVT) vNr-13, encoded by the HVT079 and HVT096 genes, is the first known alphaherpesvirus-encoded Bcl-2 homolog. HVT-infected cells were reported to be relatively more resistant to serum starvation, suggested that vNr-13 could be involved in protecting the cells. Here, we describe CRISPR/Cas9-based editing of exon 1 of the HVT079 and HVT096 genes from the HVT genome to generate the mutant HVT-vNr-13 to gain insights into its functional roles. Overall, wild-type HVT and HVT-vNr-13 showed similar growth kinetics; however, at early time points, HVT-vNr-13 showed 1.3- to 1.7-fold-lower growth of cell-associated virus and 3- to 6.2-fold-lower growth of cell-free virus. In transfected cells, HVT vNr-13 showed a mainly diffuse cytoplasmic distribution with faint nuclear staining. Further, vNr-13 localized to the mitochondria and endoplasmic reticulum (ER) and disrupted mitochondrial network morphology in the transfected cells. In the wild-type HVT-infected cells, vNr-13 expression appeared to be directly involved in the disruption of the mitochondrial network, as the mitochondrial network morphology was substantially restored in the HVT-vNr-13-infected cells. IncuCyte S3 real-time apoptosis monitoring demonstrated that vNr-13 is unequivocally involved in the apoptosis inhibition, and it is associated with an increase of PFU, especially under serum-free conditions in the later stages of the viral replication cycle. Furthermore, HVT blocks apoptosis in infected cells but activates apoptosis in noninfected bystander cells.

IMPORTANCE B cell lymphoma 2 (Bcl-2) family proteins play important roles in regulating apoptosis during homeostasis, tissue development, and infectious diseases. Several viruses encode homologs of cellular Bcl-2-proteins (vBcl-2) to inhibit apoptosis, which enable them to replicate and persist in the infected cells and to evade/modulate the immune response of the host. Herpesvirus of turkeys (HVT) is a nonpathogenic alphaherpesvirus of turkeys and chickens that is widely used as a live vaccine against Marek’s disease and as recombinant vaccine viral vectors for protecting against multiple avian diseases. Identical copies of the HVT genes HVT079 and HVT096 encode the Bcl-2 homolog vNr-13. While previous studies have identified the potential ability of vNr-13 in inhibiting apoptosis induced by serum deprivation, there have been no detailed investigations on the functions of vNr-13. Using CRISPR/Cas9-based ablation of the vNr-13 gene, we demonstrated the roles of HVT vNr-13 in early stages of the viral replication cycle, mitochondrial morphology disruption, and apoptosis inhibition in later stages of viral replication.

Viruses commonly antagonize innate immune pathways that are primarily driven by nuclear factor kappa B (NF-B), interferon regulatory factor (IRF), and the signal transducer and activator of transcription proteins (STAT) family of transcription factors. Such a strategy allows viruses to evade immune surveillance and maximize their replication. Using an unbiased transcriptome sequencing (RNA-seq)-based approach to measure gene expression induced by transfected viral genomic RNA (vgRNA) and reovirus infection, we discovered that mammalian reovirus inhibits host cell innate immune signaling. We found that, while vgRNA and reovirus infection both induce a similar IRF-dependent gene expression program, gene expression driven by the NF-B family of transcription factors is lower in infected cells. Potent agonists of NF-B such as tumor necrosis factor alpha (TNF-α) and vgRNA failed to induce NF-B-dependent gene expression in infected cells. We demonstrate that NF-B signaling is blocked due to loss of critical members of the inhibitor of kappa B kinase (IKK) complex, NF-B essential modifier (NEMO), and IKKβ. The loss of the IKK complex components prevents nuclear translocation and phosphorylation of NF-B, thereby preventing gene expression. Our study demonstrates that reovirus infection selectively blocks NF-B, likely to counteract its antiviral effects and promote efficient viral replication.

IMPORTANCE Host cells mount a response to curb virus replication in infected cells and prevent spread of virus to neighboring, as yet uninfected, cells. The NF-B family of proteins is important for the cell to mediate this response. In this study, we show that in cells infected with mammalian reovirus, NF-B is inactive. Further, we demonstrate that NF-B is rendered inactive because virus infection results in reduced levels of upstream intermediaries (called IKKs) that are needed for NF-B function. Based on previous evidence that active NF-B limits reovirus infection, we conclude that inactivating NF-B is a viral strategy to produce a cellular environment that is favorable for virus replication.

Members of the flavivirus genus share a high level of sequence similarity and often circulate in the same geographical regions. However, whether T cells induced by one viral species cross-react with other related flaviviruses has not been globally addressed. In this study, we tested pools of epitopes derived from dengue (DENV), Zika (ZIKV), Japanese encephalitis (JEV), West Nile (WNV), and yellow fever (YFV) viruses by intracellular cytokine staining (ICS) using peripheral blood mononuclear cells (PBMCs) of individuals naturally exposed to DENV or immunized with DENV (TV005) or YF17D vaccine. CD8 T cell responses recognized epitopes from multiple flaviviruses; however, the magnitude of cross-reactive responses was consistently severalfold lower than those to the autologous epitope pools and was associated with lower expression of activation markers such as CD40L, CD69, and CD137. Next, we characterized the antigen sensitivity of short-term T cell lines (TCL) representing 29 different individual epitope/donor combinations. TCL derived from DENV monovalent vaccinees induced CD8 and CD4 T cells that cross-reacted within the DENV serocomplex but were consistently associated with >100-fold-lower antigen sensitivity for most other flaviviruses, with no cross-recognition of YFV-derived peptides. CD8 and CD4 TCL from YF17D vaccinees were associated with very limited cross-reactivity with any other flaviviruses and in five out of eight cases >1,000-fold-lower antigen sensitivity. Overall, our data suggest limited cross-reactivity for both CD4 and CD8 T cell responses between flaviviruses and have implications for understanding immunity elicited by natural infection and strategies to develop live attenuated vaccines against flaviviral species.

IMPORTANCE The envelope (E) protein is the dominant target of neutralizing antibodies for dengue virus (DENV) and yellow fever virus (YFV). Accordingly, several DENV vaccine constructs use the E protein in a live attenuated vaccine format, utilizing a backbone derived from a heterologous flavivirus (such as YF) as a delivery vector. This backbone comprises the nonstructural (NS) and capsid (C) antigens, which are dominant targets of T cell responses. Here, we demonstrate that cross-reactivity at the level of T cell responses among different flaviviruses is very limited, despite high levels of sequence homology. Thus, the use of heterologous flavivirus species as a live attenuated vaccine vector is not likely to generate optimal T cell responses and might thus impair vaccine performance.

Although pain is a prevalent nonmotor symptom in Parkinson’s disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that...

Deregulation of mitochondrial dynamics leads to the accumulation of oxidative stress and unhealthy mitochondria; consequently, this accumulation contributes to premature aging and alterations in mitochondria linked to metabolic complications. We postulate that restrained mitochondrial ATP synthesis might alleviate age-associated disorders and extend healthspan in mammals. Herein, we prepared a previously...

Microtubule-associated serine/threonine kinase like (MASTL), also known as Greatwall (Gwl) kinase, has an important role in the regulation of mitosis. By inhibiting protein phosphatase 2A (PP2A), it plays a crucial role in activating one of the most important mitotic kinases, known as cyclin-dependent kinase 1 (CDK1). MASTL has been seen to be upregulated in various types of cancers and is also involved in tumor recurrence. It is activated by CDK1 through phosphorylations in the activation/T-loop, but the complete mechanism of its activation is still unclear. Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation. Our results suggest that AKT increases CDK1-mediated phosphorylation and hence the activity of MASTL, which, in turn, promotes mitotic progression through PP2A inhibition. We also show that the oncogenic potential of AKT is augmented by MASTL activation, since AKT-mediated proliferation in colorectal cell lines can be attenuated by inhibiting and/or silencing MASTL. In brief, we report that AKT plays an important role in the progression of mitosis in mammalian cells and that it does so through the phosphorylation and activation of MASTL.

Zhi-Jun Zhao, Davina Derous, Abby Gerrard, Jing Wen, Xue Liu, Song Tan, Catherine Hambly, and John R. Speakman

Lactating mice increase food intake 4- to 5-fold, reaching an asymptote in late lactation. A key question is whether this asymptote reflects a physiological constraint, or a maternal investment strategy (a ‘restraint’). We exposed lactating mice to periods of food restriction, hypothesizing that if the limit reflected restraint, they would compensate by breaching the asymptote when refeeding. In contrast, if it was a constraint, they would by definition be unable to increase their intake on refeeding days. Using isotope methods, we found that during food restriction, the females shut down milk production, impacting offspring growth. During refeeding, food intake and milk production rose again, but not significantly above unrestricted controls. These data provide strong evidence that asymptotic intake in lactation reflects a physiological/physical constraint, rather than restraint. Because hypothalamic neuropeptide Y (Npy) was upregulated under both states of restriction, this suggests the constraint is not imposed by limits in the capacity to upregulate hunger signalling (the saturated neural capacity hypothesis). Understanding the genetic basis of the constraint will be a key future goal and will provide us additional information on the nature of the constraining factors on reproductive output, and their potential links to life history strategies.

Yi Huang, Jazmin Osorio Mendoza, Catherine Hambly, Baoguo Li, Zengguang Jin, Li Li, Moshen Madizi, Sumei Hu, and John R. Speakman

The heat dissipation limit theory predicts lactating female mice consuming diets with lower specific dynamic action (SDA) should have enhanced lactation performance. Dietary fat has lower SDA than other macronutrients. Here we tested the effects of graded dietary fat levels on lactating Swiss mice. We fed females five diets varying in fat content from 8.3 to 66.6%. Offspring of mothers fed diets of 41.7% fat and above were heavier and fatter at weaning compared to those of 8.3% and 25% fat diets. Mice on dietary fat contents of 41.7% and above had greater metabolizable energy intake at peak lactation (8.3%: 229.4±39.6, 25%: 278.8±25.8, 41.7%: 359.6±51.5, 58.3%: 353.7±43.6, 66.6%: 346±44.7 kJ day^–1), lower daily energy expenditure (8.3%: 128.5±16, 25%: 131.6±8.4, 41.7%: 124.4±10.8, 58.3%: 115.1±10.5, 66.6%: 111.2±11.5 kJ day^–1) and thus delivered more milk energy to their offspring (8.3%: 100.8±27.3, 25%: 147.2±25.1, 41.7%: 225.1±49.6, 58.3%: 238.6±40.1, 66.6%: 234.8±41.1 kJ day^–1). Milk fat content (%) was unrelated to dietary fat content, indicating females on higher fat diets (> 41.7%) produced more rather than richer milk. Mothers consuming diets with 41.7% fat or above enhanced their lactation performance compared to those on 25% or less, probably by diverting dietary fat directly into the milk, thereby avoiding the costs of lipogenesis. At dietary fat contents above 41.7% they were either unable to transfer more dietary fat to the milk, or they chose not to do so, potentially because of a lack of benefit to the offspring that were increasingly fatter as maternal dietary fat increased.

Background

The inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression.

BACKGROUND:The threshold of the lower limit of the normal range of lung function has been suggested to be more accurate than the 0.7 fixed ratio (FEV1/FVC < 0.7) for a diagnosis of COPD. We aimed to explore the health status and risk factors of patients overdiagnosed with COPD when using the lower limit of the normal range as a diagnostic reference.METHODS:Subjects with COPD diagnosed by a pulmonologist according to guidelines of the Global Initiative for Chronic Obstructive Lung Disease were recruited from October 2016 to April 2018. Overdiagnosed COPD was defined as FEV1/FVC that meets the criterion of the 0.7 fixed ratio but not the the lower limit of the normal range criterion. Spirometry and questionnaires were performed by eligible subjects.RESULTS:Of the 513 subjects included in the final analysis, 20 (3.9%) were overdiagnosed when using the lower limit of the normal range as the diagnostic reference. The subjects who were overdiagnosed were older, weighed more, had better lung function, lower modified Medical British Research Council scores, and higher St. George's Respiratory Questionnaire and 36-item Short Form Survey scores than the subjects who were correctly diagnosed. Older age, heavier weight, exposure to cooking oil fumes, or a new-built or newly renovated home were associated with an increased risk of overdiagnosis of COPD (age adjusted odds ratio (OR) 1.17, 95% CI 1.09–1.26; weight adjusted OR 1.08, 95% CI 1.03–1.13; exposure to cooking oil fumes adjusted OR 3.00, 95% CI, 1.04–8.68; exposure to new-built or newly renovated home adjusted OR 10.88, 95% CI 1.46–80.87.CONCLUSIONS:The subjects with overdiagnosed COPD had a better health status and lung function than the subjects who were correctly diagnosed. Older age, heavier weight, and exposure to cooking oil fumes or a new-built or newly renovated home were factors associated with the overdiagnosis of COPD. These findings may help reduce overdiagnosis of COPD.