Art+Politics

For the exhibition Art + Politics, students worked closely with the holdings of Gettysburg College\u27s Special Collections and College Archives to curate an exhibition in Schmucker Art Gallery that engages with issues of public policy, activism, war, propaganda, and other critical socio-political themes. Each of the students worked diligently to contextualize the objects historically, politically, and art-historically. The art and artifacts presented in this exhibition reveal how various political events and social issues have been interpreted through various visual and printed materials, including posters, pins, illustrations, song sheets, as well as a Chinese shoe for bound feet. The students\u27 essays that follow demonstrate careful research and thoughtful reflection on the American Civil War, nineteenth-century politics, the First and Second World Wars, World\u27s Fairs, Dwight D. Eisenhower\u27s campaign, Vietnam-War era protests, and the Cultural Revolution in China. [excerpt]https://cupola.gettysburg.edu/artcatalogs/1009/thumbnail.jp

Characterization of MAS1-86 Activity in Malaria Parasites

In 2019, ~ 229 million malaria cases were reported globally, causing 409,000 deaths. Malaria is caused by the Plasmodium parasite with cyclical infection in human and Anopheles mosquito host. P. falciparum is the most common species, causing approximately 75% of malaria. Asexual, blood stage parasites cause malaria symptoms. The lifecycle begins with merozoites that invade red blood cells and they develop into rings, then trophozoite, and mature into schizonts. Artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated falciparum malaria. Resistance to all artemisinin (ART) is a widespread problem, which is conferred by point mutations in Kelch 13. The K13C580Y mutation is the most abundant in SE Asia. P. falciparum’s apicoplast, an essential organelle that generates fatty acids, heme, and isoprenoid precursors, is a promising drug target since humans lack this organelle. The apicoplast’s primary function in asexual life stages is to produce isoprenoid precursor isopentenyl phosphate (IPP) via the methylerythritol phosphate (MEP) pathway. IPP supplementation has been shown to chemically rescue MEP inhibited cultures. Delayed death phenotype is defined as growth of treated parasite is unaffected, but growth arrest is observed in the progeny. This is seen when apicoplast biosynthesis and apicoplast metabolic pathways are inhibited. The apicoplast-located PfClpC/P complex degrades proteins and has chymotrypsinlike proteolytic activity. PfClpC is a chaperone to the PfClpP protease. P. falciparum 26S proteasome is a cytoplasmic protease with β1, β2, and β5 subunits that have caspase-like, trypsin-like and chymotrypsin-like activity, respectively. WLL, a proteasome inhibitor, targets the β2 and β5 subunits. An analog of MAS1-86 effectively inhibited multi-drug resistant Staphylococcus aureus ClpX, a homolog of PfClpC, in multi-drug resistant S. aureus. Analogs of MAS1-86 were then tested against P. falciparum and MAS1-86 was identified as the most potent inhibitor. We show that MAS1-86 selected parasites display a 6 - 23-fold increase in resistance to MAS1-86. IPP failed to rescue MAS1-86 parasite inhibition nor did MAS1-86 inhibition display a delayed death phenotype, defined as a 10-fold reduction in IC50 values at 120 hours compared to72 hours. We conclude that MAS1-86 does not target the MEP pathway. MAS1-86 inhibition caused a delay in late trophozoite stages through schizont stages, with fewer nuclei observed in schizonts. This observation is of interest since aberrant scizont morphology with fewer nuclei has been reported in auto-inhibited ClpC P. falciparum. There was no shift in the K13 mutant dose response curves, thus K13 haplotype does not influence parasite susceptibility to MAS1-86. MAS1-86-resistant parasites did not show cross-resistance to proteasome β2 and β5 subunit inhibitor, WLL, which has the same chymotrypsin-like activity as ClpP.https://digitalcommons.unmc.edu/surp2021/1052/thumbnail.jp

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Sistem pengendalian intern terhadap penerimaan kas : studi kasus PT. Sari Husada Yogyakarta

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.</p