Protection against Chlamydia Promoted by a Subunit Vaccine (CTH1) Compared with a Primary Intranasal Infection in a Mouse Genital Challenge Model

Background: The chlamydial proteins CT443 (OmcB) and CT521 (rl16) have previously been identified as human B and/or T cell targets during a chlamydial infection in humans. Here we compare the protective effector mechanism promoted by a fusion protein composed of CT521 and CT443 (CTH1) with a primary intranasal Chlamydia muridarum infection known to provide high levels of protection against a genital chlamydial challenge. Methodology/Principal Findings: The fusion protein CTH1, adjuvanted with a strong Th1 inducing cationic adjuvant (CAF01), significantly reduced the bacterial shedding compared to a control group in both a C. trachomatis Serovar D and C. muridarum challenge model. The CTH1/CAF01 vaccine was found to induce polyfunctional T cells consisting of TNFa/IL-2 and TNFa/IL-2/IFN-c positive cells and high titers of CTH1 specific IgG2a and IgG1. By depletion experiments the protection in the C. muridarum challenge model was demonstrated to be mediated solely by CD4 + T cells. In comparison, an intranasal infection with C. muridarum induced a T cell response that consisted predominantly of TNFa/IFN-c co-expressing effector CD4 + T cells and an antibody response consisting of C. muridarum specific IgG1, IgG2a but also IgA. This response was associated with a high level of protection against challenge—a protection that was only partially dependent on CD4 + T cells. Furthermore, whereas the antibody response induced by intranasal infection was strongly reactive against the native antigens displayed in the chlamydial elementary body, only low levels of antibodies against this preparation were foun

Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex

Peer reviewedPublisher PD

Multisite Phosphorylation of the Sum1 Transcriptional Repressor by S-Phase Kinases Controls Exit from Meiotic Prophase in Yeast.

Activation of the meiotic transcription factor Ndt80 is a key regulatory transition in the life cycle of Saccharomyces cerevisiae because it triggers exit from pachytene and entry into meiosis. The NDT80 promoter is held inactive by a complex containing the DNA-binding protein Sum1 and the histone deacetylase Hst1. Meiosis-specific phosphorylation of Sum1 by the protein kinases Cdk1, Ime2, and Cdc7 is required for NDT80 expression. Here, we show that the S-phase-promoting cyclin Clb5 activates Cdk1 to phosphorylate most, and perhaps all, of the 11 minimal cyclin-dependent kinase (CDK) phospho-consensus sites (S/T-P) in Sum1. Nine of these sites can individually promote modest levels of meiosis, yet these sites function in a quasiadditive manner to promote substantial levels of meiosis. Two Cdk1 sites and an Ime2 site individually promote high levels of meiosis, likely by preparing Sum1 for phosphorylation by Cdc7. Chromatin immunoprecipitation reveals that the phosphorylation sites are required for removal of Sum1 from the NDT80 promoter. We also find that Sum1, but not its partner protein Hst1, is required to repress NDT80 transcription. Thus, while the phosphorylation of Sum1 may lead to dissociation from DNA by influencing Hst1, it is the presence of Sum1 on DNA that determines whether NDT80 will be expressed

Rotational Atherectomy: A Contemporary Appraisal

Rotational atherectomy (RA) is an atheroablative technology that enables percutaneous coronary intervention for complex, calcified coronary lesions. RA works on the principle of ‘differential cutting’ and preferentially ablates hard, inelastic, calcified plaque. The objective of RA use has evolved from plaque debulking to plaque modification to enable balloon angioplasty and optimal stent expansion. The clinical experience over the past 30 years has informed the current best practices for RA with use of smaller burr sizes, short ablation runs a ‘pecking’ motion, and avoidance of sudden decelerations. This has led to significant improvements in procedural safety and a reduced rate of associated complications. This article reviews the principles, clinical indications, contemporary evidence, technical considerations and complications associated with the use of RA

Dbf4-dependent kinase (DDK)-mediated proteolysis of CENP-A prevents mislocalization of CENP-A in Saccharomyces cerevisiae

The evolutionarily conserved centromeric histone H3 variant (Cse4 in budding yeast, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of CENP-A to non-centromeric chromatin contributes to chromosomal instability (CIN) in yeast, fly, and human cells and CENP-A is highly expressed and mislocalized in cancers. Defining mechanisms that prevent mislocalization of CENP-A is an area of active investigation. Ubiquitin-mediated proteolysis of overexpressed Cse4 (GALCSE4)byE3 ubiquitin ligases such as Psh1 prevents mislocalization of Cse4, and psh1D strains display synthetic dosage lethality (SDL) with GALCSE4. We previously performed a genome-wide screen and identified five alleles of CDC7 and DBF4 that encode the Dbf4-dependent kinase (DDK) complex, which regulates DNA replication initiation, among the top twelve hits that displayed SDL with GALCSE4. We determined that cdc7-7 strains exhibit defects in ubiquitin-mediated proteolysis of Cse4 and show mislocalization of Cse4. Mutation of MCM5 (mcm5-bob1) bypasses the requirement of Cdc7 for replication initiation and rescues replication defects in a cdc7-7 strain. We determined that mcm5-bob1 does not rescue the SDL and defects in proteolysis of GALCSE4 in a cdc7-7 strain, suggesting a DNA replication-independent role for Cdc7 in Cse4 proteolysis. The SDL phenotype, defects in ubiquitin-mediated proteolysis, and the mislocalization pattern of Cse4 in a cdc7-7 psh1D strain were similar to that of cdc7-7 and psh1D strains, suggesting that Cdc7 regulates Cse4 in a pathway that overlaps with Psh1. Our results define a DNA replication initiation-independent role of DDK as a regulator of Psh1-mediated proteolysis of Cse4 to prevent mislocalization of Cse4.Fil: Eisenstatt, Jessica R.. National Institutes of Health; Estados UnidosFil: Boeckmann, Lars. National Institutes of Health; Estados UnidosFil: Au, Wei Chun. National Institutes of Health; Estados UnidosFil: Garcia, Valerie. National Institutes of Health; Estados UnidosFil: Bursch, Levi. National Institutes of Health; Estados UnidosFil: Ocampo, Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. National Instituto of Child Health & Human Development; Estados UnidosFil: Costanzo, Michael. National Institutes of Health; Estados Unidos. University of Toronto; CanadáFil: Weinreich, Michael. Van Andel Research Institute; Estados UnidosFil: Sclafani, Robert A.. University of Colorado; Estados UnidosFil: Baryshnikova, Anastasia. University of Princeton; Estados UnidosFil: Myers, Chad L.. University of Minnesota; Estados UnidosFil: Boone, Charles. University of Toronto; Canadá. National Institutes of Health; Estados UnidosFil: Clark, David J.. National Institutes of Health; Estados UnidosFil: Baker, Richard. University of Massachusetts; Estados UnidosFil: Basrai, Munira A.. National Institutes of Health; Estados Unido

Atypical ST-Segment-Elevation Myocardial Infarction Presentation in Patients With COVID-19 at a High-Volume Center in New York City

Atypical presentations of ST-segment-elevation myocardial infarction (STEMI) have been reported in patients who have COVID-19. We have seen this occurrence in our center in Bronx, New York, where multitudes of patients sought treatment for the coronavirus. We studied the prevalence of atypical STEMI findings among patients with COVID-19 who presented during the first 2 months of the pandemic. Consistent with previous reports, 4 of our 10 patients with COVID-19 and STEMI had no identifiable culprit coronary lesion; rather, they often had diffuse ST-segment elevations on surface electrocardiograms along with higher levels of D-dimer and inflammatory markers. In contrast, 32 of 33 patients without COVID-19 (97%) had a culprit lesion. The patients with COVID-19 and a culprit lesion more often needed thrombectomy catheterization and administration of glycoprotein IIb/IIIa inhibitors. Our study confirms that patients with COVID-19 often have atypical STEMI presentations, including the frequent absence of a culprit coronary lesion. Our findings can help clinicians prepare for these atypical clinical presentations

Unveiling the oxidation behavior of liquid-phase exfoliated antimony nanosheets

Antimonene, a monolayer of β-antimony, is increasingly attracting considerable attention, more than that of other monoelemental two-dimensional materials, due to its intriguing physical and chemical properties. Under ambient conditions, antimonene exhibits a high thermodynamic stability and good structural integrity. Some theoretical calculations predicted that antimonene would have a high oxidation tendency. However, it remains poorly investigated from the experimental point of view. In this work, we study the oxidation behavior of antimonene nanosheets (ANS) prepared by ultrasonication-assisted liquid-phase exfoliation. Using a set of forefront analytical techniques, a clear effect of sonication time on the surface chemistry of prepared ANS is found. A dynamic oxidation behavior has been observed, which upon annealing at moderate temperature (210 °C) resulted in a semiconducting behavior with a bandgap of approximately 1 eV measured by ultraviolet photoelectron spectroscopy. This study yields valuable information for future applications of antimonene and paves the way towards novel modification approaches in order to tailor its properties and complement its limitations

HLA Associations and Risk of Posttransplant Lymphoproliferative Disorder in a Danish Population-Based Cohort

Granični poremećaj ličnosti je učestali psihički poremećaj koji se manifestira kroz simptome afektivne nestabilnosti, impulzivnog i nekontroliranog ponašanja, poremećaj identiteta, nestabilne interpersonalne odnose i moguće pogreške u testiranju realiteta uslijed kojih osoba može imati značajnih poteškoća u osobnom, roditeljskom, obiteljskom, socijalnom i radnom funkcioniranju. Svrha ovog istraživanja je dobiti uvid u iskustva rada stručnih djelatnika Odjela za zaštitu djece, obitelji i braka pri centru za socijalnu skrb, a ciljevi istraživanju su dobiti uvid u prepoznavanje simptoma graničnog poremećaja ličnosti , teškoće i potrebe stručnih djelatnika Odjela za zaštitu djece, obitelji i braka. Kvalitativno istraživanje provedeno je metodom polustrukturiranog intervjua s 12 stručnjaka zaposlenih na Odjelu za zaštitu djece, obitelji i braka pri centrima za socijalnu skrb na području grada Zagreba i Zagrebačke županije. U obradi podataka korištena je tematska analiza. Rezultati istraživanja pokazuju da stručnjaci prepoznaju različite simptome afektivne nestabilnost, impulzivnog i nekontroliranog ponašanja, smetnji identiteta, nestabilnih i intenzivnih interpersonalnih odnosa te teškoća testiranja realiteta. Simptomi graničnog poremećaja ličnosti roditelja najčešće dolaze do izražaja u situacijama prekida bračne ili izvanbračne zajednice koji često imaju obilježja visokonfliktnih razvoda, tijekom postupaka odlučivanja o roditeljskoj skrbi, obiteljskog i partnerskog nasilja te zlostavljanja i zanemarivanja djece zbog čega stručnjaci poduzimaju različite psihosocijalne intervencije i mjere obiteljsko pravne zaštite. Prema rezultatima istraživanja teškoće stručnjaka tijekom rada s roditeljima s dijagnozom i/ili simptomima graničnog poremećaja ličnosti proizlaze iz neposrednog rada s roditeljima, organizacije i uvjeta rada u centrima za socijalnu skrb te suradnje s drugim sustavima. Roditelji sa simptomima ovog poremećaja ličnosti prepoznati su kao nedobrovoljni korisnici skloni manipulaciji djetetom, drugim roditeljem, stručnjacima, policijom, pravosudnim, zdravstvenim i socijalnim sustavom. Rad stručnjaka otežavaju i dodatne teškoće kao što su preopterećenost količinom posla, nedovoljan broj stručnih djelatnika, neadekvatni prostorni uvjeti rada u centrima za socijalnu skrb i otežana suradanja s drugim sustavima. Nadalje, stručnjaci izvještavaju o izloženosti visokoj razini profesionalnog stresa i doživljenim simptomima sagorijevanja. U skladu s iskazanim teškoćama, stručnjaci ukazuju na nužnost unaprjeđenja suradnje s drugim sustavima, posebice s pravosudnim, zdravstvenim i obrazovnim sustavom, povećanja broja zaposlenih stručnih djelatnika, zapošljavanje psihijatra u centre za socijalnu skrb, uključenost u redovite edukacije i supervizije. Nadalje, stručnjaci iskazuju potrebu za dodatnim ovlastima kao što su mogućnost obveznog upućivanja korisnika na liječenje i konstatiranja nedostupnosti intervencijama socijalne službe.Borderline personality disorder is a frequent psychiatric disorder which manifests itself through several symptoms: affective instability, impulsive and disinhibited behaviour, disturbed sense of identity, unstable interpersonal relationships and possible stress-related reduction of contact with reality. The afflicted person may have significant difficulties in personal, parental, familial, social and work functioning. The purpose of this research was to gain insight into experiences of experts working in the Department for protection of children, family and marriage of the Social Welfare Centre. Qualitative research has been conducted using semi-structured interviews with 12 experts working in the Department for protection of children, family and marriage of Social Welfare Centres located in Zagreb and Zagreb County. Collected data was analysed using thematic analysis. Results have demonstrated that experts recognize various symptoms of affective instability, impulsive and disinhibited behaviour, identity disturbances, unstable and intense interpersonal relationships and reduction of contact with reality. Symptoms of parental borderline personality disorder most frequently appear after a divorce or separation which often have characteristics of high-conflict divorce, during procedures related to child custody, familial and domestic violence, as well as child abuse and neglect, forcing experts to do various psychosocial interventions and implement measures related to protection of the family. According to results of this research difficulties expressed by experts working eith parents with a diagnosis and/or symptoms of borderline personality disorder are the result of direct work with the parents, organisation and work conditions in Social Welfare Centres and cooperation with other systems. Symptomatic parents are recognized as involuntary clients prone to manipulation of children, other parent, experts, the police, the justice system, healthcare system and social system. There are additional difficulties for experts working with these parents, such as work overload, insufficient number of experts, inadequate working space in Social Welfare Centres and difficulties cooperating with other systems. Experts also report being exposed to high level of professional stress and experiencing symptoms of burn-out. Consistently with these difficulties, experts reported needing to improve cooperation with other systems, especially with the justice, healthcare and education systems, increase the number of hired experts, hire psychiatrists in Social Welfare Centres and taking part regularly in educations and supervisions. Experts also reported needing additional authorities, such as the possibility of mandatory reference to treatment of clients and the possibility of establishing the unavailability of social services interventions