John Hardy Research Articles

Employee Perception of Brand Value in the Jewelry Industry

This study aims to discuss more the brand value proposed by John Hardy and how John Hardy as jewelry retail can be seen from each of these brand values. The methodology used in this study is qualitative using interview or open questioner technique where the informants were all employees in John Hardy and focus on the sales department which is employees in all Bali Boutique that John Hardy has. Data collected will then be analyzed by reducing data, presenting data, and drawing conclusions. The validity of the data will be tested by triangulating the data so it is expected that the data presented is valid. As the result, community, artisanship, and sustainability which is pretty much linked to the brand and it can see it's linked together and implemented. John Hardy is required to know how to deliver the information correctly to the customer, mentioned the history of the company, the value, and also the DNA of the company.

Online platform allows credit for grant review

Publons, a website that lets peer reviewers claim credit for refereeing manuscripts, is expanding its remit to grant peer review. The new feature lets funders or individuals post on the site when a referee has completed a review for a funder, as long as both parties have agreed to it. To maintain confidentiality, the site records only the number of grant application reviews a person has done and for which funding agency. For journal peer review, Publons also allows researchers to post the content of their reports when journal policies allow it. John Hardy, a materials chemist at Lancaster University, is one of the academics to have logged his grant-reviewing activity on his Publons profile, noting that he has refereed grant proposals for the National Center of Science and Technology Evaluation (NCSTE) in Kazakhstan. Hardy tells C&EN that recording such activity online is useful when trying to convince senior colleagues

Perspective: Finding common ground

Two competing hypotheses about Parkinson's and Gaucher's diseases need to be knitted together, say Anthony H. Futerman and John Hardy.

John Hardy is the UK's first Breakthrough Prize laureate.

John Hardy, Professor of Neuroscience at University College London and Editorial Board member of The FEBS Journal, has been awarded The Breakthrough Prize in Life Sciences in recognition of his work identifying mutations that cause amyloid build-up in the brain--research that has transformed the study of Alzheimer's disease and other major neurodegenerative diseases.

Fast-forwarding treatment for neurodegenerative disorders

Fast-forwarding treatment for neurodegenerative disorders

John Hardy Price

After house jobs in Manchester Royal Infirmary John Hardy Price did national service in Jordan. On returning to the UK he went into general practice in Birmingham. He supported the...

Two Alzheimer's Immunotherapy Drugs Fail in Four Studies

Two Alzheimer's Immunotherapy Drugs Fail in Four Studies

Amyloid and tau in the brain in sporadic Alzheimer’s disease: defining the chicken and the egg

In the October 2013 issue of Acta Neuropathologica there were three very interesting articles on: Amyloid or tau: the chicken or the egg? In the first article, David Mann and John Hardy argued that the deposition of aggregated amyloid β (Aβ) protein in the brain is a primary driving force behind the pathogenesis of Alzheimer’s disease with tau pathology following as a consequential or at least a secondary event. In the communication that followed, Braak and Del Tredici presented the contrary argument with accumulation of tau protein as the primary event in sporadic Alzheimer’s disease. Attems and Jellinger questioned the concept of a chicken and egg and suggested that the majority of cases of age-associated dementia are not caused by one single primary pathological mechanism.

512: Evidence for participation of the acute phase reactive protein haptoglobin (Hp) in pathophysiologic events related to preterm birth (PTB)

reactive protein haptoglobin (Hp) in pathophysiologic events related to preterm birth (PTB) Megan McCarthy, John Hardy, Antonette Dulay, Christine Laky, Ramesha Papanna, Catalin Buhimschi, Irina Buhimschi Yale University, Ob/Gyn & Reprod. Sci., New Haven, CT OBJECTIVE: Hp plays key immunoregulatory roles. Its gene is polymorphic with evidence of functionally distinct phenotypes (Hp1-1, Hp2-1, Hp2-2). Fetal Hp is not expressed in utero unless an inflammatory response to infection is triggered. Given that in sepsis Hp has a vascular endothelial prostaglandin (PG) inhibitory effect, we hypothesized that when expressed, fetal Hp modulates placental biosynthesis of PG and matrix metalloproteinases (MMPs) and that this effect is phenotype dependent. STUDY DESIGN: Placentas from pregnancies complicated by PTB (n 11, GA: 26 3wks) were immunostained and scored for intensity of Hp expression. Histological chorioamnionitis (HCA) was present in 6 of 11 cases. Placental Hp gene expression was evaluated by RTPCR. Cord blood was obtained in all cases, and fetal Hp switch-on and phenotype status was determined by Western blotting. A villous trophoblast explant system (term elective CS, n 5) was used to investigate the effect of Hp phenotypes 1-1 and 2-2 on PGE2 and MMP9 biosynthesis in the presence and absence of LPS (50 ng/mL). Hp dose (10 ug/mL) mimicked fetal circulating level when exposed to infection. HEK-Blue LPS Detection Kit ruled-out LPS contamination of purified Hp. PGE2 and MMP9 were quantified by ELISA. RESULTS: There was positive Hp immunoreactivity within the vascular fetal spaces of all cases with HCA (n 6). There was no significant difference in the Hp gene expression level between placentas with and without HCA. In vitro, in the absence of LPS, Hp1-1 did not alter the release of PGE2 or MMP9, while Hp 2-2 exhibited an inhibitory effect (P .05). In the presence of LPS both Hp phenotypes upregulated PGE2 release (2-fold over the LPS level, P .05), while MMP9 biosynthesis remained unaffected. CONCLUSION: We provide evidence that in the presence of endotoxin, Hp stimulates placental PGE2 biosynthesis in a phenotype-specific manner, implying that this protein could play a role in infectioninduced PTB.

Young‐onset parkinsonism due to homozygous duplication of α‐synuclein in a consanguineous family

With a growing list of monogenetic causes of Parkinson's disease (PD),1–3 prioritization of genetic testing is made on the presumed mode of inheritance. In patients with early-onset PD from consanguineous families, the most common mode of inheritance is autosomal recessive. Rarely, an individual may be homozygous for a mutation inherited in an autosomal dominant manner, complicating the diagnostic process. The proband is a 36-year-old female from a consanguineous Pakistani family (Fig. 1A). She presented with a 5-year history of left-sided stiffness, micrographia, festinant gait, tremor, and falls. Past medical history included postpartum psychosis and severe depression. There were no symptoms of autonomic dysfunction. Neurological examination at the age of 35 years revealed severe bilateral bradykinesia, rigidity, worse on the left, and mild bilateral upper limb rest tremor. Gait was shuffling, with freezing and complete loss of postural reflexes. Bilateral ankle clonus was noted. Initially, there was a poor response to dopamine agonists. She responded well to 100/25 mg co-careldopa 3 times per day, but developed wearing offs and peak-dose dyskinesias after 4 months of treatment. There was no family history of parkinsonism. The proband's mother's neurological examination at the age of 72 years was normal. The proband's father, who died at age 64 years from a stroke, had no symptoms or signs of parkinsonism as described by his family. Her siblings and children were asymptomatic, but were unavailable for examination. Figure 1 A: Pedigree and clinical information on the family. A half filled symbol represents the proband (arrow), who is the only individual affected by parkinsonism. Clinically unaffected but confirmed mutation carrier (the proband's mother) is represented by ... Investigations in the proband included routine blood work, copper studies, and white cell enzymes, and were all normal. Dopamine transporter scan (DAT-SCAN) showed bilateral reduction in tracer uptake in the striatum, more significant on the right. Formal neuropsychological examination revealed a mild degree of intellectual under-functioning from premorbid estimates, with anterior/subcortical dysfunction. Mutations in PARKIN, PINK1, and common LRRK2 mutations were excluded. Multiplex ligation-dependent probe amplification (MLPA) showed 4 copies of SNCA (Fig. 1B). Comparative genomic hybridization (Nimblegen 135 K array Roche-Niblegen) showed copy number gain of 0.928 Mb, containing 5 genes including SNCA (Fig. 1C). Single-nucleotide polymorphism (SNP) array showed this to be homozygous. Fluorescent in situ-hybridization demonstrated duplication of SNCA on both alleles (Supplemental Figure 1). The proband's mother's MLPA showed SNCA duplication. Considering the proband's homozygosity for SNCA duplication, her father is likely to have had an SNCA duplication. Less likely, de novo duplication (in addition to duplication inherited from mother) occurred in the proband. SNCA multiplication is a rare cause of autosomal dominant PD.4,5 SNCA triplications (4 copies of SNCA) are fully penetrant; with early-onset and rapidly progressive parkinsonism associated with dementia, autonomic dysfunction, and psychiatric features.4 With SNCA duplications (3 SNCA copies), the disease clinically resembles idiopathic PD5 and reduced penetrance is recognized.6 Our patient has 4 SNCA copies and her clinical phenotype closely matches that of patients with SNCA triplications4 and is in keeping with the single previously described case of SNCA double duplication.7 Homozygous SNCA duplications are a rare cause of young-onset parkinsonism and should be considered in the patients with a family history compatible with recessive inheritance. Early cognitive dysfunction and depression are consistently reported in patients with 4 SNCA copies and may be regarded as “red flags” for SNCA multiplications.

Identical twins with Leucine rich repeat kinase type 2 mutations discordant for Parkinson's disease

Analysis of concordancy rates in monozygotic and dizygotic twins with Parkinson's disease (PD) has been an important subject for research into the disorder1 and discordancy between twins has traditionally been interpreted as evidence against a genetic etiology of disease. Discordancy in late-onset diseases such as PD is complicated by the possibility that the disease onset may vary considerably between twins, and cases with up to 20 years of discordance have been reported.2 Leucine-rich repeat-kinase type 2 (LRRK2) mutations are the most common Mendelian cause of PD,3, 4 with the G2109S mutation occurring in 1% to 2% of idiopathic cases in the UK.5 Here we report the identification of a pair of identical twins with this mutation who are discordant by more than 10 years. The twins, of English descent, are 70+ years old and were self-reported as identical. The proband developed the first symptoms of PD at age 60 years, with unilateral bradykinesia, rigidity, and rest tremor that became bilateral. The initial good response to levodopa therapy was followed in 5 years by development of motor fluctuations with wearing off, on-off effects, and peak dose and diphasic dyskinesias. The family had autosomal dominant inheritance of PD with a parent and 2 second-degree relatives affected by the disorder. On exam, the twin had a normal smell test and no signs of neurodegenerative disorder. DNA from the proband was sequenced as part of the clinical workup and the heterozygous LRRK2 G2109S mutation was identified. DNA from the twin was sequenced and the mutation was confirmed in the sample. DNA from both twins was run on genomewide arrays (Illumina 660) to confirm that the twins were identical; this also revealed no major chromosomal abnormalities in either twin. These data show that considerable variance in the penetrance of the mutation can occur even in the context of genetic identity. This suggests that the effects of other genetic loci in modifying the age at onset of disease must be minimal and, therefore, that identifying such loci through linkage or association methods will be extremely challenging because the variability in onset age between LRRK2 mutation carriers6 must be largely nongenetic in etiology. Identifying environmental risk factors for disease is notoriously difficult and there is nothing in the personal or medical histories of these twins that provides obvious clues for the reasons behind the current discordance. Indeed, both twins have had similar life courses. The recent data implicating pathology spread in PD is consistent with the notion that the disease process can start at a single site.7 If this is the case, then a stochastic initiation of disease may underlie the discordance as it may for prion disease.8, 9 For reasons of confidentiality minimal clinical details are presented. For further information please contact A.J.L. The funding organizations had no part in the study design or the writing up of this work. Author Roles: GX carried out the laboratory work, AS helped with the interpretation of the array data, LSM interviewed the proband and reviewed the ethical compliance, HH and JH obtained funds for the work, JH drafted the manuscript which all authors reviewed. AJL identified the patient and initiated the study. Financial Disclosures: JH is on Scientific Advisory Boards for Eisai and Merck Serono. AL is on Advisory Boards for Novartis. Teva, Meda, Boehringer Ingelheim, GSK, lpsen, Lundbeck, Allergan. Orion, BIAL, Noscira and Roche. None of the other authors have consultancy or advisory roles. Author Roles: GX carried out the laboratory work, AS helped with the interpretation of the array data, LSM interviewed the proband and reviewed the ethical compliance, HH and JH obtained funds for the work, JH drafted the manuscript which all authors reviewed. AJL identified the patient and initiated the study. Financial Disclosures: JH is on Scientific Advisory Boards for Eisai and Merck Serono. AL is on Advisory Boards for Novartis. Teva, Meda, Boehringer Ingelheim, GSK, lpsen, Lundbeck, Allergan. Orion, BIAL, Noscira and Roche. None of the other authors have consultancy or advisory roles. Georgia Xiromerisiou MD, PhD*, Henry Houlden PhD, MRCP*, Anna Sailer MD*, Laura Silveira-Moriyama MD, PhD*, John Hardy PhD*, Andrew J. Lees MD, FRCP*, * Reta Lila Weston Institute of Neurological Studies and Research Laboratories, Departments of Molecular Neuroscience and of Clinical Neuroscience, University College London (UCL) Institute of Neurology, Queen Square, London, UK.

Warplands: Alkborough

The river Trent merges with the Ouse and enters the Humber at Trent Falls, on the border of North Lincolnshire and Yorkshire. The landscape here is isolated, flat and agricultural; the skies are large. On the west bank of the Trent, the land is man-made, created by warping: by letting the silt-laden river waters flood and settle. At Ousefleet is the so-called ‘emptiest place in Britain’: the only one kilometre grid-square on a 1:50,000 scale Ordnance Survey map that is completely white, lacking any symbols to denote features either natural or constructed. On the east bank at Alkborough Flats, the river has been let back in, to create extensive wetlands in the first major UK example of coastline realignment. Contrasting twin processes: 19th century ‘winning’ and 21st century ‘letting go’. Shifting priorities. A seeming placid place where new and profound attitudes to, and relationships with, landscape and environment are being enacted. In 2011 – and building upon their Carrlands project <www.carrlands.org.uk> – Mike Pearson and composer John Hardy were commissioned by the Arts and Humanities Research Council Landscape and Environment Programme Director's Impact Fellowship to create Warplands, a performance combining text, music and projection which was premiered at the Royal Geographical Society, London on 1 September. The work is in two movements: this article describes its composition and includes the full text to Alkborough. As it traces the convolutions of Julian's Bower, a turf maze overlooking the realignment, it invites the reader to walk and contemplate, at least in the imagination. The aim of Warplands is to illuminate the historically and culturally diverse ways in which a particular landscape has been made, used, reused and interpreted; to help make sense of the multiplicity of meanings that resonate from it; and to strengthen regard for places off the beaten track. Primarily on foot…

The amyloid cascade hypothesis has misled the pharmaceutical industry

The pharmaceutical industry has invested a great deal of time and finance in the development of therapeutics targeting amyloid generation, signalling and plaque stability. This has been based on the amyloid cascade hypothesis which states that abnormal amyloid precursor protein processing and the formation of amyloid plaques is the central process in the development of the symptoms of Alzheimer's disease. However, most clinical trials in this area have been disappointing; therefore the attendees of the Models of Dementia: the Good, the Bad and the Future meeting were given the opportunity to openly debate the proposal 'the amyloid cascade has misled the pharmaceutical industry', with the main contributions from Professor John Hardy and Professor John Mayer. The present article is a representation of the debate.

Obituary of John Hardy (1935-2011)

Obituary of John Hardy (1935-2011)

Read all about it: Why we have an appetite for gossip

Our disingenuity towards celebrity tittle-tattle is part of our evolutionary legacy, says John Hardy

The Chiasmic Embrace of the Natural World in Eudora Welty’s Delta Wedding

The Chiasmic Embrace of the Natural World in Eudora Welty’s Delta Wedding Kelly Sultzbach (bio) In southern literature, interactions with the land have often defined the people themselves. Although Eudora Welty’s Delta Wedding has been labeled as a southern pastoral, the natural world in the novel doesn’t operate solely on a symbolic level; the environment Welty creates is thoroughly palpable. The heaving shoulder blades of birds in song, skin wet with bayou water, the heartbeats of kittens, the sting of a bee—all are examples of how non-human forces interact with her characters to create a natural world that is tactile and animate. Furthermore, characters’ sensory contact with the natural world shapes the novel’s themes of finding community and coping with the pain and loss necessary for new growth, as well as destabilizing hierarchical relationships between different classes and races of people. Understanding how nature functions as a physical presence in the novel is critical to recognizing Welty’s critiques of the society living within it. In her autobiography, Welty explains, “[t]he outside world is a vital component of my inner life” (One 76). Similarly, her characters, particularly Laura and George, gain new insight into their relationships with other humans and the land through embodied encounters with the environment. The philosophy of ecophenomenology illuminates how Delta Wedding intertwines humans within [End Page 88] “the flesh of the world” (Merleau-Ponty Visible 144)—in this case, the daily symbiotic union of humans and the landscape of the Mississippi River Delta, portending the slow evolution of positive change created by sensory interaction and small variations in repeated cycles of life. Thus, an ecocritical approach to Delta Wedding troubles reductive readings that oversimplify how Welty characterizes the rural South and reveals the novel’s subtle disruption of social hierarchies. Recent critical analyses of Delta Wedding are recovering the text’s complexity, rescuing it from initial reviews that tended to depreciate the novel by reading it merely as an attempt to justify a southern lifestyle. Paul Binding notes that “despite the insistent loveliness of much of the writing about the pattern of life at Fairchilds—we read only superficially (as Diana Trilling must have done) if we are not aware of all the time pressures from without, and the disruptions from within, threatening, almost certainly eventually combining to destroy this seemingly impregnable, peaceful place” (127). More nuanced readings of the racial aspects of Delta Wedding are also gaining recognition: “Though many of her characters may view southern racial traditions uncritically, I believe that Welty herself did not” (Entzminger 65). Even those who still critique Welty’s treatment of race cite Toni Morrison’s claim that Welty was one of a small number of white women who were able to “write about black people in a way that few white men have ever been able to write . . . not patronizing, not romanticizing,” and acknowledge that “what she cared about most . . . was the deeper mystery of individuals” (Flower 332). Yet, what has not been recognized is the extent to which Welty’s prioritization of sensual experience within the natural world grounds most of her social critiques. Further, her embodied treatment of the environment not only uncovers the tensions and lurking violence inherent in “the southern problem” of racial inequity but also incorporates wider modernist concerns of challenging traditional systems of knowledge. Critical articles examining Welty’s treatment of nature in Delta Wedding often analyze it as pastoral literature (Hardy 77, Westling Sacred 65). Admittedly, there are some obvious tropes of the pastoral in the novel, ranging from literal references to formal devices, including Shellmound as a “fairy world” in the “season of changeless weather” (291), Dabney’s shepherdess crooks for the wedding, the privileged leisure of the Fairchild family masking the labor of the servants around them, and even Laura’s providing a movement of retreat to the green space of Shellmound and then an imminent return to her father in Jackson. Unlike earlier critics, John Hardy’s analysis of the pastoral in Delta Wedding acknowledges that [End Page 89] Welty demonstrates “that double attitude of the pastoral which William Empson has defined, as well as . . . a more practical sense for...

Bengt Winblad: coaching the team in Alzheimer's disease

Bengt Winblad: coaching the team in Alzheimer's disease

Antiamyloid Therapy: Is the Party Over?

Antiamyloid Therapy: Is the Party Over?

Interview

Alison M Goate is the Samuel & Mae S Ludwig Professor of Genetics in Psychiatry, Professor of Genetics and Professor of Neurology at Washington University School of Medicine in St Louis (MO, USA). Dr Goate studied for her undergraduate degree in biochemistry at the University of Bristol (UK) and received her graduate training at Oxford University (UK). She performed postdoctoral studies with Professor Theodore Puck, Professor Louis Lim and Dr John Hardy before receiving a Royal Society University Research Fellowship to support her independent research program at St Mary's Hospital Medical School in London. In 1991, Dr Goate and colleagues reported the first mutation linked to an inherited form of Alzheimer's disease, in the amyloid precursor protein (APP) gene on chromosome 21. The mutation was found to be linked to inherited cases of early-onset Alzheimer's disease. In 1992, Dr Goate moved to Washington University as an Associate Professor in Genetics and Psychiatry. Dr Goate and colleagues have since identified mutations in four other genes, including two that cause Alzheimer's disease and two that cause the related dementia frontotemporal dementia. In addition to her work on dementia, Dr Goate's laboratory also studies the genetics of alcohol and nicotine dependence. Dr Goate has received numerous awards including the Potamkin Award from the American Academy of Neurology, the Zenith Award from the Alzheimer's Association, the Senior Investigator Award from the Metropolitan Life Foundation, the St Louis Academy of Science Innovation Award and the Carl and Gerty Cori Faculty Achievement Award at Washington University. Dr Goate has been a member of many scientific Review Boards and currently serves on the Editorial Boards of several journals.

John Hardy: which disease will he solve next?

John Hardy: which disease will he solve next?