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Sensor technology has come a long way over the last 30 years, from the world’s first, bulky webcam at the University of Cambridge Computer Science Department to near ubiquitous networks of sleek sensors that can provide data at an unprecedented volume, velocity and quality. Today, sensors can even talk to each other to combine single points of data into useful insights about complex events. The new webcomic ‘Coffee Time’ by Dave Sheppard, part of the Digital Twin Journeys series, tells the story of this evolution and what it means for what we can learn about our built environment through smart sensors.

'Now We Know' tells the story of a fictional building manager, Hank, who isn't sure how a building digital twin can help him in his work when the existing building management system tells him what he thinks he needs to know.

There is debate as to whether the neurocognitive changes associated with HIV infection represent an acceleration of the typical aging process or more simply reflect a greater accentuated risk for age-related declines. We aimed to determine whether accelerated neurocognitive aging is observable in a sample of older HIV-infected individuals compared to age-matched seronegatives and older old (i.e., aged ≥65) seronegative adults. Participants in a cross-sectional design included 48 HIV-seronegative (O-) and 40 HIV-positive (O+) participants between the ages of 50-65 (mean ages=55 and 56, respectively) and 40 HIV-seronegative participants aged ≥65 (OO-; mean age=74) who were comparable for other demographics. All participants were administered a brief neurocognitive battery of attention, episodic memory, speeded executive functions, and confrontation naming (i.e., Boston Naming Test). The O+ group performed more poorly than the O- group (i.e., accentuated aging), but not differently from the OO- on digit span and initial recall of a supraspan word list, consistent with an accelerating aging profile. However, the O+ group's performance was comparable to the O- group on all other neurocognitive tests (ps>0.05). These data partially support a model of accelerated neurocognitive aging in HIV infection, which was observed in the domain of auditory verbal attention, but not in the areas of memory, language, or speeded executive functions. Future studies should examine whether HIV-infected adults over 65 evidence accelerated aging in downstream neurocognitive domains and subsequent everyday functioning outcomes.

A firm’s dependency on the information technology (IT) function is increasingly central to its ability to innovate. The IT function must balance this need for change with sustaining consistent, highly reliable operation of all existing services. A firm’s ability to rapidly change IT is impeded by its legacy portfolio of applications and infrastructure because changes need to be very carefully managed and understood in order to avoid unintended consequences leading to system failure and process breakdown. The change imperative for IT is urgent and often determines how IT is valued by the rest of the firm. Improving the IT function’s agility requires improvement in IT capabilities, which can be categorized into three broad classes: technology, process, and competency. This article identifies the critical success factors for creating sustainable change for each of these three capability classes. It draws on the practical experience of the authors and leverages appropriate standards that provide grounding for change within the IT function of the firm, along with the roles and tasks that will be involved in this change agency. The article is of primary benefit for IT executives seeking to sustain an ongoing, systematic transformation of the IT function to enable IT entrepreneurship and agility. Small opportunities are often the beginning of great enterprises. Demosthenes (384–322 BC) Statesman and orator

ObjectiveHIV is associated with frontostriatal dysregulation and executive dysfunction. This study evaluated whether HIV-infected individuals evidence deficits in random number generation (RNG), which is a strategic task requiring paced, rule-guided production of digits.MethodIn total, 74 HIV+ adults and 54 seronegative comparison participants completed a comprehensive research neuropsychological battery. Participants produced a random digit sequence by avoiding any order and using numbers 1 through 10 for 100 s at a pace of 1 digit/s. Outcomes included intrusions, repetitions, seriation (1-2-3-4), and cycling (median length of gaps between repeating digits).ResultsHIV disease was associated with higher levels of seriation and cycling (ps< .05) but not intrusions or repetitions (ps> .10). Among HIV+ individuals, higher seriation was associated with neuropsychological performance including poorer auditory attention, verbal learning, and delayed memory, whereas higher cycling scores were associated with poorer delayed memory and verbal fluency (ps< .05). Higher seriation also was independently associated with self-reported declines in activities of daily living (ADLs) in the HIV+ group.ConclusionsIndividuals living with HIV disease evidence moderate difficulties in inhibiting statistically unlikely non-random sequences, which showed medium associations with higher order verbal abilities and may contribute to greater declines in everyday functioning outcomes. Future studies might examine RNG's role in health behaviors such as medical decision-making or medication adherence.

Prospective memory (PM) is associated with antiretroviral (ARV) adherence in HIV, but little is known about how pill burden and age might affect this association. One hundred seventeen older (≥50years) and 82 younger (

With the rising number of individuals in their 50s and 60s who are infected with HIV, concerns have emerged about possible increases in the rates of non-HIV-associated dementias. The current study examined the prevalence of mild cognitive impairment (MCI) in older HIV-infected adults, since MCI is an intermediate state between typical cognitive aging and dementia that emerges in this age range. Participants included 75 adults with HIV disease aged 50 years and older who were on combination antiretroviral therapy (cART) and had undetectable plasma viral loads and 80 demographically similar HIV-seronegative comparison subjects. Participants completed a research neuropsychological evaluation that was used to classify MCI according to the comprehensive diagnostic scheme described by Bondi et al. (J Alzheimers Dis 42:275-289, 2014). HIV-infected persons were over seven times more likely to have an MCI designation (16 %) than their seronegative counterparts (2.5 %). Within the HIV+ cohort, MCI had minimal overlap with diagnoses of asymptomatic neurocognitive impairment and was significantly associated with older age, lower Karnofsky Scale of Performance Scores, and mild difficulties performing instrumental activities of daily living (iADLs). HIV infection in older adults is associated with a notably elevated concurrent risk of MCI, which may increase the likelihood of developing non-HIV-associated dementias as this population ages further.

ObjectiveThis study aimed to determine the combined effects of age and HIV infection on the risk of incident neurocognitive disorders.MethodA total of 146 neurocognitively normal participants were enrolled at baseline into one of four groups based on age (≤ 40 years and ≥ 50 years) and HIV serostatus resulting in 24 younger HIV-, 27 younger HIV+, 39 older HIV-, and 56 older HIV+ individuals. All participants were administered a standardized clinical neuropsychological battery at baseline and 14.3 ± .2 months later.ResultsA logistic regression predicting incident neurocognitive disorders from HIV, age group, and their interaction was significant (χ(2)[4] = 13.56, p = .009), with a significant main effect of HIV serostatus (χ(2)[1] = 5.01, p = .025), but no main effect of age or age by HIV interaction (ps > .10). Specifically, 15.7% of the HIV+ individuals had an incident neurocognitive disorder as compared to 3.2% of the HIV- group (odds ratio = 4.8 [1.2, 32.6]). Among older HIV+ adults, lower baseline cognitive reserve, prospective memory, and verbal fluency each predicted incident neurocognitive disorders at follow-up.ConclusionsIndependent of age, HIV infection confers a nearly fivefold risk for developing a neurocognitive disorder over approximately one year. Individuals with lower cognitive reserve and mild weaknesses in higher-order neurocognitive functions may be targeted for closer clinical monitoring and preventative measures.

We show that every morphism from a degree 5 hypersurface in 4-dimensional projective space to a nonsingular degree 3 hypersurface in 4-dimensional projective space is necessarily constant. In the process, we also classify morphisms from the projective plane to nonsingular cubic threefolds given by degree 3 polynomials., Comment: 22 pages, second paper of thesis

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is essential to maintain fluid homeostasis in key organs. Functional impairment of CFTR due to mutations in the cftr gene leads to cystic fibrosis. Here, we show that the first nucleotide-binding domain (NBD1) of CFTR can spontaneously adopt an alternate conformation that departs from the canonical NBD fold previously observed. Crystallography reveals that this conformation involves a topological reorganization of NBD1. Single-molecule fluorescence resonance energy transfer microscopy shows that the equilibrium between the conformations is regulated by adenosine triphosphate binding. However, under destabilizing conditions, such as the disease-causing mutation F508del, this conformational flexibility enables unfolding of the beta-subdomain. Our data indicate that, in wild-type CFTR, this conformational transition of NBD1 regulates channel function, but, in the presence of the F508del mutation, it allows domain misfolding and subsequent protein degradation. Our work provides a framework to design conformation-specific therapeutics to prevent noxious transitions. Fonds Forton, Welbio [CR-2012S-04R]; Vaincre la Mucoviscidose, Mukoviszidose e.V; Association Luxembourgeoise de Lutte contre la Mucoviscidose; ABCF2; Chiesi FondationChiesi Pharmaceuticals Inc; Cystic Fibrosis Foundation; Italian Cystic Fibrosis Research Foundation; Fibrosis FoundationItalian Cystic Fibrosis Research Foundation; [BB/M012573/1]; CF Foundation Therapeutics; Instruct-ERIC, part of the European Strategy Forum on Research Infrastructures (ESFRI); Instruct-ULTRA 731005; FWO

One therapeutic strategy for cystic fibrosis (CF) seeks to restore anion transport to affected epithelia by targeting other apical membrane Cl(-) channels to bypass dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. The properties and regulation of the Ca(2+)-activated Cl(-) channel TMEM16A argue that long-acting small molecules which target directly TMEM16A are required to overcome CFTR loss. Through genetic studies of lung diseases, SLC26A9, a member of the solute carrier 26 family of anion transporters, has emerged as a promising target to bypass CFTR dysfunction. An alternative strategy to circumvent CFTR dysfunction is to deliver to CF epithelia artificial anion transporters that shuttle Cl(-) across the apical membrane. Recently, powerful, non-toxic, biologically-active artificial anion transporters have emerged.

The mutation F508del is the commonest cause of the genetic disease cystic fi brosis (CF). CF disrupts the function of many organs in the body, most notably the lungs, by perturbing salt and water transport across epithelial surfaces. F508del causes harm in two principal ways. First, the mutation prevents delivery of the cystic fi brosis transmembrane conductance regulator (CFTR) to its correct cellular location, the apical (lumen-facing) membrane of epithelial cells. Second, F508del perturbs the Cl- channel function of CFTR by disrupting channel gating. Here, we discuss the development of rational new therapies for CF that target F508del-CFTR. We highlight how structural studies provide new insight into the role of F508 in the regulation of channel gating by cycles of ATP binding and hydrolysis. We emphasize the use of high-throughput screening to identify lead compounds for therapy development. These compounds include CFTR correctors that restore the expression of F508del-CFTR at the apical membrane of epithelial cells and CFTR potentiators that rescue the F508del-CFTR gating defect. Initial results from clinical trials of CFTR correctors and potentiators augur well for the development of small molecule therapies that target the root cause of CF: mutations in CFTR. Refereed/Peer-reviewed

Tese de doutoramento em Bioquímica (Genética Molecular), apresentada à Universidade de Lisboa através da Faculdade de Ciências, 2008 Nível de preservação: critical, Criado em: 2008-08-06 16:29:56, Criado por: creator:DIGITOOL, Alterado em: 2009-08-11 16:19:55, Modificado por: super:ULB59 Made available in DSpace on 2010-07-27T08:59:21Z (GMT). No. of bitstreams: 2 16450_ASchmidt%20Tese%20Doutoramento.pdf: 9007027 bytes, checksum: bd15c3170bb75fb9324c025f3d194bd0 (MD5) 16450.xml: 5788 bytes, checksum: 81c26293adc7d5d2303b0326f4adbcec (MD5) Previous issue date: 2008 Fundação para a Ciência e Tecnologia (FCT), (bolsa SFRH/BD/19415/2004)