In Vitro Evaluation and Characterization of Newly Designed Alkylamidophospholipid Analogues as Anti-Human Immunodeficiency Virus Type 1 Agents

Our laboratories first reported two novel classes of complex synthetic lipids, including alkylamidophosphocholines (PC lipid; CP-51) and alkylamidophosphate ester-linked lipid-AZT conjugates (lipid-AZT conjugates; CP-92), with selective and potent activity against human immunodeficiency virus type 1 (HIV-1). To extend these observations, we synthesized additional PC lipids and lipid-AZT conjugates (INK and INK-AZT conjugate) to evaluate their structure-activity relationships by testing for selectivity against infectious wild-type (wt) and drug-resistant HIV-1 replication, virus fusogenic activity and toxicity for mouse bone marrow cells. PC lipid compounds with medium chain lengths at positions 1 and 2 gave an improved selective index (SI). INK-3, with 12 and 8 carbons and INK-15, with 10 and 12 carbons were among the most selective when evaluated in CEM-SS cells. INK-14, a lipid-AZT conjugate where AZT replaced the choline in PC lipid INK-3, gave the highest SI of > 1250 against both infectious wt HIV-1 replication in CEM-SS cells and a clinical isolate in peripheral blood leukocytes. Notably, the PC lipid compounds INK-3 and INK-15, but not the lipid-AZT conjugate INK-14, were potent inhibitors of matched pairs of AZT-sensitive and AZT-resistant HIV-1 clinical isolates. INK-3 also inhibited replication of HIV-2 and TIBO-resistant HIV-1, and inhibited HIV-1-mediated fusogenic activity by 78, 41 and 9% in a dose-dependent manner. The TC50 for mouse bone marrow cells was > 100 micrograms/ml for INK-3 compared to 9.15-14.17 micrograms/ml for CP-51 and 0.142-0.259 microgram/ml for AZT. These data suggest that optimum PC lipid compounds are significantly less toxic than AZT and have high potential as novel therapeutic agents for AIDS

Consumer bankruptcy: Decision, choice and access to credit afterwards

Data availability statement: The data that support the findings of this study are available from the UK's Office for National Statistics (ONS). Restrictions apply to the availability of these data, which were used under license for this study. Data are available from https://beta.ukdataservice.ac.uk/datacatalogue/series/series?id=2000056#!/access-data with the permission of ONS and UK Data Service.Copyright © 2023 The Authors. We examine the effects of the bankruptcy benefit and adverse events on the consumer bankruptcy decision. Employing zero-inflated ordered probit models and a unique longitudinal survey of approximately 66,000 individuals in Great Britain, we find that consumers are more likely to enter into bankruptcy proceedings when the bankruptcy benefit increases and when they become unemployed. We find that the effects of adverse events differ across bankruptcy types. Individuals who experience the onset of health problems are more likely to choose reorganization of debts (i.e., income gleaning), whereas individuals who get divorced or separated are more likely to prefer the discharge of debts (i.e., fresh start). We also examine access to credit after bankruptcy. We find that individuals are excluded from the credit markets post-bankruptcy and the impact differs across bankruptcy types. Credit exclusion for fresh starters is dramatic, swift but short-lived, while for income gleaners, it is gradual, slow but lasts longer

CMS search plans and sensitivity to new physics with dijets

CMS will use dijets to search for physics beyond the standard model during early LHC running. The inclusive jet cross section as a function of jet transverse momentum, with 10 inverse picobarns of integrated luminosity, is sensitive to contact interactions beyond the reach of the Tevatron. The dijet mass distribution will be used to search for dijet resonances coming from new particles, for example an excited quark. Additional sensitivity to the existence of contact interactions or dijet resonances can be obtained by comparing dijet rates in two distinct pseudorapidity regions.Comment: 10 pages, 4 figures, accepted for publication in J. Phys. G: Nucl. Part. Phy

A parametric integer programming algorithm for bilevel mixed integer programs

We consider discrete bilevel optimization problems where the follower solves an integer program with a fixed number of variables. Using recent results in parametric integer programming, we present polynomial time algorithms for pure and mixed integer bilevel problems. For the mixed integer case where the leader's variables are continuous, our algorithm also detects whether the infimum cost fails to be attained, a difficulty that has been identified but not directly addressed in the literature. In this case it yields a ``better than fully polynomial time'' approximation scheme with running time polynomial in the logarithm of the relative precision. For the pure integer case where the leader's variables are integer, and hence optimal solutions are guaranteed to exist, we present two algorithms which run in polynomial time when the total number of variables is fixed.Comment: 11 page

Searching for Lee-Wick Gauge Bosons at the LHC

In an extension of the Standard Model(SM) based on the ideas of Lee and Wick, Grinstein, O'Connell and Wise have found an interesting way to remove the usual quadratically divergent contributions to the Higgs mass induced by radiative corrections. Phenomenologically, the model predicts the existence of Terascale, negative-norm copies of the usual SM fields with rather unique properties: ghost-like propagators and negative decay widths, but with otherwise SM-like couplings. The model is both unitary and causal on macroscopic scales. In this paper we examine whether or not such states with these unusual properties can be uniquely identified as such at the LHC. We find that in the extended strong and electroweak gauge boson sector of the model, which is the simplest one to analyze, such an identification can be rather difficult. Observation of heavy gluon-like resonances in the dijet channel offers the best hope for this identification.Comment: 17 pages, 4 figs; discussion adde

Functional brain activity constrained by structural connectivity reveals cohort-specific features for serum neurofilament light chain

Background: Neuro-axonal brain damage releases neurofilament light chain (NfL) proteins, which enter the blood. Serum NfL has recently emerged as a promising biomarker for grading axonal damage, monitoring treatment responses, and prognosis in neurological diseases. Importantly, serum NfL levels also increase with aging, and the interpretation of serum NfL levels in neurological diseases is incomplete due to lack of a reliable model for age-related variation in serum NfL levels in healthy subjects. Methods: Graph signal processing (GSP) provides analytical tools, such as graph Fourier transform (GFT), to produce measures from functional dynamics of brain activity constrained by white matter anatomy. Here, we leveraged a set of features using GFT that quantified the coupling between blood oxygen level dependent signals and structural connectome to investigate their associations with serum NfL levels collected from healthy subjects and former athletes with history of concussions. Results: Here we show that GSP feature from isthmus cingulate in the right hemisphere (r-iCg) is strongly linked with serum NfL in healthy controls. In contrast, GSP features from temporal lobe and lingual areas in the left hemisphere and posterior cingulate in the right hemisphere are the most associated with serum NfL in former athletes. Additional analysis reveals that the GSP feature from r-iCg is associated with behavioral and structural measures that predict aggressive behavior in healthy controls and former athletes. Conclusions: Our results suggest that GSP-derived brain features may be included in models of baseline variance when evaluating NfL as a biomarker of neurological diseases and studying their impact on personality traits

Recent evolution of an ice‐cored moraine at the Gentianes Pass, Valais Alps, Switzerland

International audienceLateral moraines located in permafrost environments often preserve large amounts of both glacier and periglacial ice. To understand how ice‐cored moraines located in high alpine environments evolve in a context of both glacier retreat and permafrost degradation, we performed 11 terrestrial laser‐scanning measurement campaigns between 2007 and 2014 on a highly anthropogenic overprinted moraine prone to instability. Resulting comparison of the subsequent 3D models allowed to qualitatively and quantitatively analyze the morphological evolution of the moraine. The comparisons indicate a very high geomorphic activity of the moraine including large areas affected by downslope movements of blocks and 10 landslides with a volume between 24 ± 1 and 1,138 ± 47 m3. Data also indicated a very strong ice melt with a loss of ice thickness locally reaching 17.7 m at the foot of the moraine. These results, compared with resistivity and thermal measurements of the ground, suggest the combined role of ice loss at the foot of the moraine and the permafrost activity/warming in triggering these processes

Temporal Orientation and its Relationships with Organizationally Valued Outcomes: Results from a 14 Country Investigation

In this investigation we were concerned with the cultural covariates of temporal orientation in 14 different national contexts. Data were collected from United States of America (US), Australia, Germany, Poland, Chile, Venezuela, Turkey, United Arab Emirates (UAE), India, Indonesia, Malaysia Japan, South Korea and China. Analyses show that collectivistic cultural orientation tends to be relatively important in the prediction of three facets of temporal orientation (i.e. emphasis on planning and scheduling; sense of time and attitude towards time)

Association of high risk human papillomavirus and breast cancer : a UK based study

Infection by human papillomaviruses (HPVs) has been implicated in the aetiology of a variety of cancers. Studies evaluating the presence of HPVs in breast cancer (BC) have generated considerable controversy. To date, most studies have focused on the presence of viral DNA in BC; however there are important gaps in evidencing the role of HPV persistence in the invasiveness of BC. While these studies have been conducted in several countries, none, on the presence and biological activity of high risk (HR) HPV in BC has been done in the UK. Hence, we aimed to investigate these gaps by screening a total of 110 fresh breast tissue specimens from UK patients for the presence of twelve HR-HPV types DNA using PCR and Sanger sequencing. Samples positive for HPV-DNA were screened for viral oncoprotein expression using western blot and dot blot. Data obtained showed the presence of HR-HPVs in 42% of breast tissues of which the viral activity was only confirmed in a number of invasive carcinomas (5/26). This finding, the first to report in the UK, suggests that the selective expression of viral oncoprotein in invasive cases may propose a role for HR-HPVs in the development of some types of BC