Deicing of Sessile Droplets Using Surface Acoustic Waves.

Deicing has significant relevance in various applications such as transportation, energy production, and telecommunication. The use of surface acoustic waves (SAWs) is an attractive option for deicing as it offers several advantages such as localized heating, in situ control, low power, and system integration for highly efficient deicing. Here, we report an understanding of the dynamics of deicing of microlitre volume water droplets (1 to 30 µL) exposed to low power (0.3 W) SAW actuation using an interdigitated electrode on a piezoelectric (LiNbO3) substrate. We study the time variation of the volume of liquid water from the onset of SAW actuation to complete deicing, which takes 2.5 to 35 s depending on the droplet volume. The deicing phenomenon is attributed to acoustothermal heating which is found to be greatly influenced by the loss of ice adhesion with the substrate and the acoustic streaming within the liquid water. Acoustothermal heating inside the droplet is characterized by the temperature distribution inside the droplet using infrared thermography, and acoustic streaming is observed using dye-based optical microscopy. A rapid enhancement in deicing is observed upon the detachment of ice from the substrate and the onset of acoustic streaming, marked by a sudden increase in the liquid water volume, droplet temperature, and heat transfer coefficient. The deicing time is found to increase linearly with droplet volume as observed from experiments and further verified using a theoretical model. Our study provides an improved understanding of the recently introduced SAW-based deicing technique that may open up the avenue for a suitable alternative to standard deicing protocols.

Trapping of Aqueous Droplets under Surface Acoustic Wave-Driven Streaming in Oil-Filled Microwells.

Microwell arrays are ideal platforms for cell culturing, cell separation, and low-volume liquid handling. The ability to manipulate droplets in microwells could open up the opportunity for developing new biochemical assays. Here, we study the trapping of aqueous droplets in an oil-filled microwell driven by the application of nanometer amplitude vibrations called surface acoustic waves (SAW). We elucidate the dynamics of the droplet within the vortex toward the final trapping location and the physics of the trapping phenomenon using a theoretical model by considering the relevant forces. Our study revealed that the combined effect of acoustic radiation and hydrodynamic forces leads to droplet migration and trapping. We demarcate the trapping and nontrapping regimes in terms of the minimum critical input power required for the trapping of droplets of different sizes and densities. We find that the critical power varies as the square of the droplet size and is higher for a denser droplet. The effects of input power and droplet size on the trapping location and trapping time are also studied.

Coalescence of Droplets in a Microwell Driven by Surface Acoustic Waves.

Microwell arrays are amongst the most commonly used platforms for biochemical assays. However, the coalescence of droplets that constitute the dispersed phase of suspensions housed within microwells has not received much attention to date. Herein, we study the coalescence of droplets in a two-phase system in a microwell driven by surface acoustic waves (SAWs). The microwell structure, together with symmetric exposure to SAW irradiation, coupled from beneath the microwell via a piezoelectric substrate, gives rise to the formation of a pair of counter-rotating vortices that enable droplet transport, trapping, and coalescence. We elucidate the physics of the coalescence phenomenon using a scaling analysis of the relevant forces, namely, the acoustic streaming-induced drag force, the capillary and viscous forces associated with the drainage of the thin continuous phase film between the droplets and the van der Waals attraction force. We confirm that droplet-droplet interface contact is established through the formation of a liquid bridge, whose neck radius grows linearly in time in the preceding viscous regime and proportionally with the square root of time in the subsequent inertial regime. Further, we investigate the influence of the input SAW power and droplet size on the film drainage time and demarcate the coalescence and non-coalescence regimes to derive a criterion for the onset of coalescence. The distinct deformation patterns observed for a pair of contacting droplets in both the regimes are elucidated and the possibility for driving concurrent coalescence of multiple droplets is demonstrated. We expect the study will find relevance in the demulsification of immiscible phases and the mixing of samples/reagents within microwells for a variety of biochemical applications.

Dynamical motion of a pair of microparticles at the acoustic pressure nodal plane under the combined effect of axial primary radiation and interparticle forces.

The dynamical motion of a pair of microparticles exposed to acoustic standing waves and located at the pressure nodal plane is studied using numerical simulations and experiments. The insight into their dynamical behavior along the pressure nodal plane due to the competition between the axial primary radiation and interparticle forces is elucidated. An expression for axial primary radiation force acting on a particle is derived, and the particle dynamics is simulated using fluid-structure interaction model based on the arbitrary Lagrangian-Eulerian method. Considering the total radiation force acting on a particle is the sum of the axial primary radiation force and the interparticle force, three distinct dynamical regimes are observed depending upon the relative magnitudes of the acoustic forces which in turn depend on the gradient of the acoustic energy density. Acceleration, deceleration, and constant velocity motion of the pair of approaching particles are observed, which are explained by the interplay of the acoustic and non-acoustic forces. The dynamical motion of the pair of particles predicted using the model is in very good agreement with the experimental observations.

Whole-body magnetic resonance angiography.

Vascular disease, whether it be atherosclerosis, inflammatory, or hereditary vasculitide, is a systemic disorder with disease in one territory predictive of disease in another. Despite this, current approaches focus on single-territory assessment ignoring the global burden of disease. Advances in MRI have enabled us to surmount previous limitations and expand our approach to such conditions with the ability to simultaneously assess the entirety of the arterial tree in a single examination, allowing a staging examination as it were, of the vascular health in its totality. This review will cover the acquisition technique, reporting, clinical utility, and current evidence base for such an approach.

A qualitative study of the acceptability of cognitive bias modification for paranoia (CBM-pa) in patients with psychosis.

BACKGROUND: Cognitive Bias Modification (CBM) has been used successfully as a computer-based intervention in disorders such as anxiety. However, CBM to modify interpretations of ambiguous information relevant to paranoia has not yet been tested. We conducted a qualitative investigation of a novel intervention called CBM for paranoia (CBM-pa) to examine its acceptability in patients with psychosis. METHODS: Eight participants with psychosis who completed CBM-pa were identified by purposive sampling and invited for a semi-structured interview to explore the facilitators and barriers to participation, optimum form of delivery, perceived usefulness of CBM-pa and their opinions on applying CBM-pa as a computerised intervention. The interviews were transcribed and analysed using thematic analysis by researchers working in collaboration with service users. RESULTS: Themes emerged relating to participants' perception about delivery, engagement, programme understanding, factors influencing experience, perceived impact and application of CBM-pa. CBM-pa was regarded as easy, straightforward and enjoyable. It was well-accepted among those we interviewed, who understood the procedure as a psychological intervention. Patients reported that it increased their capacity for adopting alternative interpretations of emotionally ambiguous scenarios. Although participants all agreed on the test-like nature of the current CBM-pa format, they considered that taking part in sessions had improved their overall wellbeing. Most of them valued the computer-based interface of CBM-pa but favoured the idea of combining CBM-pa with some form of human interaction. CONCLUSIONS: CBM-pa is an acceptable intervention that was well-received by our sample of patients with paranoia. The current findings reflect positively on the acceptability and experience of CBM-pa in the target population. Patient opinion supports further development and testing of CBM-pa as a possible adjunct treatment for paranoia. TRIAL REGISTRATION: Current Controlled Trials ISRCTN: 90749868 . Retrospectively registered on 12 May 2016.

Modelling lethality and teratogenicity of zebrafish (Danio rerio) due to ß-lactam antibiotics employing the QSTR approach.

Nowadays, ß-lactam antibiotics are one of the most consumed OTC (over-the-counter) medicines in the world. Its frequent use against several infectious diseases leads to the development of antibiotic resistance. Another unavoidable risk factor of ß-lactam antibiotics is environmental toxicity. Numerous terrestrial as well as aquatic species have suffered due to the excessive use of these pharmaceuticals. In this present study, we have performed a toxicity assessment employing a novel in silico technique like quantitative structure-toxicity relationships (QSTRs) to explore toxicity against zebrafish (Danio rerio). We have developed single as well as inter-endpoint QSTR models for the ß-lactam compounds to explore important structural attributes responsible for their toxicity, employing median lethal (LC50) and median teratogenic concentration (TC50) as the endpoints. We have shown how an inter-endpoint model can extrapolate unavailable endpoint values with the help of other available endpoint values. To verify the models' robustness, predictivity, and goodness-of-fit, several universally popular metrics for both internal and external validation were extensively employed in model validation (single endpoint models: r2 = 0.631 - 0.75, Q2F1 = 0.607 - 0.684; inter-endpoint models: r2 = 0.768 - 0.84, Q2F1 = 0.678 - 0.76). Again, these models were engaged in the prediction of these two responses for a true external set of ß-lactam molecules without response values to prove the reproducibility of these models.

Development and In-Vitro Evaluation of Eugenol-Based Nanostructured Lipid Carriers for Effectual Topical Treatment Against C. albicans.

The main objective of the experiment is to develop and evaluate hydrogel-bearing nanostructured lipid carriers (NLCs) loaded with ketoconazole (KTZ) for the effective treatment of candidiasis. The eugenol was used as a liquid lipid (excipient) for the development of KTZ-loaded NLCs and was explored for anti-fungal effect. The production of NLCs involves high energy processes to generate spherical, uniform particles, having a higher percentage of entrapment efficiency (%EE) for KTZ with 89.83 ± 2.31 %. The data from differential scanning calorimeter (DSC), powder x-ray diffraction (PXRD), and attenuated total reflectance (ATR) demonstrated the KTZ dispersion in NLCs. The NLCs loaded hydrogel possessed optimum spreadability and exhibited shear thinning behavior, indicating the ease of application of the final formulation. The 6.41-fold higher transdermal flux (Jss) was governed for KTZ from KTZ-NLC than coarse-KTZ, which explains the usefulness of NLCs. The KTZ-NLCs exhibited significant 2.58 and 6.35-fold higher retention in the stratum corneum and viable epidermis of the skin. The cell cytotoxicity studies using human dermal fibroblast cell (HDFS) lines depicted the usefulness of NLCs in reducing cell toxicities for KTZ. The KTZ-NLCs were found to inhibit planktonic growth and hyphal transition and showed a larger zone of inhibition against C. albicans strains with a MIC-50 value of 0.39 µg/mL. The antibiofilm activity of KTZ-NLCs at lower concentrations, in contrast to plain KTZ, explained the interaction of developed NLCs with fungal membranes. The overall results depicted the effectiveness of the loading KTZ in the lipid matrix to achieve antifungal activity against C. albicans.

Recent Advances in the Use of Cubosomes as Drug Carriers with Special Emphasis on Topical Applications.

Topical drug delivery employing drug nanocarriers has shown prominent results in treating topical ailments, especially those confined to the skin and eyes. Conventional topical formulations persist with drug and disease-related challenges during treatment. Various nanotechnology-driven approaches have been adopted to mitigate the issues associated with conventional formulations. Among these, cubosomes have shown potential applications owing to their liquid crystalline structure, which aids in bioadhesion, retention, sustained release, and loading hydrophilic and hydrophobic moieties. The phase transition behavior of glyceryl monooleate, the concentration of stabilizers, and critical packing parameters are crucial parameters that affect the formation of cubosomes. Microfluidics-based approaches constitute a recent advance in technologies for generating stable cubosomes. This review covers the recent topical applications of cubosomes for treating skin (psoriasis, skin cancer, cutaneous candidiasis, acne, and alopecia) and eye (fungal keratitis, glaucoma, conjunctivitis, and uveitis) diseases. The article summarizes the manufacturing and biological challenges (skin and ocular barriers) that must be considered and encountered for successful clinical outcomes. The patented products are successful examples of technological advancements within cosmeceuticals that support various topical applications with cubosomes in the pharmaceutical field.

Detection of anti-tat antibodies in CSF of individuals with HIV-associated neurocognitive disorders.

Despite major advances in the development of antiretroviral therapies, currently available treatments have no effect on the production of HIV-Tat protein once the proviral DNA is formed. Tat is a highly neurotoxic and neuroinflammatory protein, but its effects may be modulated by antibody responses against it. We developed an indirect enzyme-linked immunosorbent assay and measured anti-Tat antibody titers in CSF of a well characterized cohort of 52 HIV-infected and 13 control individuals. We successfully measured anti-Tat antibodies in CSF of HIV-infected individuals with excellent sensitivity and specificity, spanning a broad range of detection from 10,000 to over 100,000 relative light units. We analyzed them for relationship to cognitive function, CD4 cell counts, and HIV viral load. Anti-Tat antibody levels were higher in those without neurocognitive dysfunction than in those with HIV-associated neurocognitive dysfunction (HAND) and in individuals with lower CD4 cell counts and higher viral loads. We provide details of an assay which may have diagnostic, prognostic, or therapeutic implications for patients with HAND. Active viral replication may be needed to drive the immune response against Tat protein, but this robust immune response against the protein may be neuroprotective.

Molecular and cellular characterization of buffalo bone marrow-derived mesenchymal stem cells.

Immune privileged mesenchymal stem cells (MSCs) can differentiate into multiple cell types and possess great potential for human and veterinary regenerative therapies. This study was designed with an objective to isolate, expand and characterize buffalo bone marrow-derived MSCs (BM-MSCs) at molecular and cellular level. Buffalo BM-MSCs were isolated by Ficoll density gradient method and cultured in Dulbecco's modified Eagle's medium supplemented with fetal bovine serum (FBS). These cells were characterized through alkaline phosphatase (AP) staining, colony-forming unit (CFU) assay, mRNA expression analysis (CD 73, CD 90, CD 105, Oct4 and Nanog), immunolocalization along with flow cytometry (Stro 1, CD 73, CD 105, Oct4, Sox2 and Nanog) and in situ hybridization (Oct4 and Sox2). Multilineage differentiation (osteogenic, adipogenic and chondrogenic) was induced in vitro, which was further assessed by specific staining. Buffalo BM-MSCs have the capacity to form plastic adherent clusters of fibroblast-like cells and were successfully maintained up to 16(th) passage. These cells were AP positive, and further CFU assay confirmed their clonogenic property. RT-PCR analysis and protein localization study showed that buffalo BM-MSCs are positive for various cell surface markers and pluripotency markers. Cytoplasmic distribution of mRNA for pluripotency markers in buffalo BM-MSCs and multilineage differentiation were induced in vitro, which was further assessed by specific staining. To the best of our knowledge, this is the first report of buffalo BM-MSCs, which suggests that MSCs can be derived and expanded from buffalo bone marrow and can be used after characterization as a novel agent for regenerative therapy.

A full genome search in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

Effect of slice thickness and blanching time on different quality attributes of instant ginger candy.

Fresh ginger (Zingiber officinale Rosc.) suffers from weight loss, shrinkage, sprouting and rotting during storage after 3-4 weeks. This spoilage may be overcome by processing fresh produce to some value added products. An attempt was made to optimize the protocol for production of instant ginger candy. The experimental parameters considered were slice thickness (5.0-25.0 mm) and blanching duration (10-30 min) followed by dipping in 40°B and 75°B sugar solutions containing 2.0% citric acid respectively, for 1 and 2 h at 95 °C and dried at 60 °C for 1 h. RSM design was considered for this experiment and final products were evaluated for their textural properties, TSS, acidity, TSS: acid ratio, taste score and overall acceptability. The optimum product qualities in terms of hardness (2.08 kg), TSS (73.4%), acidity (1.31%), TSS: acid ratio (56.3), taste score (7.98) and overall acceptability (8.07) were obtained for slice thickness of 10.9 mm and blanching time of 24.9 min.

QSAR assessment of aquatic toxicity potential of diverse agrochemicals.

The fast-increasing number of commercially produced chemicals challenges the experimental ecotoxicity assessment methods, which are costly, time-consuming, and dependent on the sacrifice of animals. In this regard, Quantitative Structure-Property/Activity Relationships (QSPR/QSAR) have led the way in developing ecotoxicity assessment models. In this study, QSAR models have been developed using the pEC50 values of 82 diverse agrochemicals or agro-molecules against a planktonic crustacean Daphnia magna with easily interpretable 2D descriptors. Moreover, a link among octanol-water partition coefficient (KOW), bio-concentration factor (BCF), and critical body residue (CBR) has been addressed, and their imputation for the prediction of the toxicity endpoint (EC50) has been done with an objective of the advanced exploration of several ecotoxicological parameters for toxic chemicals. The developed partial least squares (PLS) models were validated rigorously and proved to be robust, sound, and immensely well-predictive. The final Daphnia toxicity model derived from experimental derived properties along with computed descriptors emerged better in statistical quality and predictivity than those obtained solely from computed descriptors. Additionally, the pEC50 and other important properties (log KOW, log BCF, and log CBR) for a set of external agro-molecules, not employed in model development, were predicted to show the predictive ability of the models.

In-vivo lymphoscintigraphy of sinonasal tumors identifies retropharyngeal node and level I as predominant sentinel nodes.

OBJECTIVE: To evaluate by in- vivo lymphoscintigraphy and SPECT-CT imaging, the lymphatic drainage patterns of para-nasal sinus(PNS) tumors. To confirm or refute the belief of the retropharyngeal lymph node (RPLN) being the significant draining lymph node for such tumors. METHODS: Prospective cohort study conducted on previously untreated PNS tumors with no clinico-radiological evidence of lymph node metastasis. Lymphoscintigraphy undertaken by nasal endoscopic assisted peritumoral injection of 99mTc Sulfur colloid. Injections were classified as anterior or posterior as per a vertical line along the maxillary sinus ostium. RESULTS: 17 patients were included. Lymphoscintigraphy successfully identified 17 sentinel nodes in 15 patients and was unsuccessful (lymphoscintigraphy failure) in 2 patients. Predominant sites of sentinel lymphatic drainage were noted to be the RPLN (n = 8; 47%), and Level I (n = 7; 42%). Occasional drainage was identified at the peri-parotid node(n = 1) and at Level II (n = 1). Contralateral drainage was noted in 2 patients (level I-1 and RPLN-1). Anterior injections drained predominantly to Level I (6/8) and RPLN (2/8), while posterior injections drained predominantly to the RPLN ( 6/7). The relative risk of RPLN being identified as the sentinel node was significantly higher for posteriorly placed injections than for anteriorly placed injections (RR- 3.43; 95% CI-1.0-11.8, p = 0.05). CONCLUSION: The RPLN is noted as a frequent draining node for sino-nasal tumours and merits routine attention in all sino-nasal tumors. The radio-colloid SPECT-CT technique described here offers an excellent in-vivo technique to further explore and validate the lymphatic drainage pathways of these tumours.

Expression and characterization of constitutive heat shock protein 70.1 (HSPA-1A) gene in in vitro produced and in vivo-derived buffalo (Bubalus bubalis) embryos.

Cells are blessed with a group of stress protector molecules known as heat shock proteins (HSPs), amongst them HSP70, encoded by HSPA-1A gene, is most abundant and highly conserved protein. Variety of stresses hampers the developmental competence of embryos under in vivo and in vitro conditions. Present work was designed to study the quantitative expression of HSPA-1A mRNA in immature oocytes (IMO), matured oocytes (MO), in vitro produced (IVP) and in vivo-derived (IVD) buffalo embryos to assess the level of stress to which embryos are exposed under in vivo and in vitro culture conditions. Further, HSPA-1A gene sequence was analysed to determine its homology with other mammalian sequences. The mRNA expression analysis was carried out on 72 oocytes (40 IMO; 32 MO), 76 IVP and 55 IVD buffalo embryos. Expression of HSPA-1A was found in oocytes and throughout the developmental stages of embryos examined irrespective of the embryo source; however, higher (p < 0.05) expression was observed in 8-16 cell, morula and blastocyst stages of IVP embryos as compared to IVD embryos. Phylogenetic analysis of bubaline HSPA-1A revealed that it shares 91-98% identity with other mammalian sequences. It can be concluded that higher level of HSPA-1A mRNA in IVP embryos in comparison with in vivo-derived embryos is an indicator of cellular stress in IVP system. This study suggests need for further optimization of in vitro culture system in which HSPA-1A gene could be used as a stress biomarker during pre-implantation development.

Optimization of HTST process parameters for production of ready-to-eat potato-soy snack.

Ready-to-eat (RTE) potato-soy snacks were developed using high temperature short time (HTST) air puffing process and the process was found to be very useful for production of highly porous and light texture snack. The process parameters considered viz. puffing temperature (185-255 °C) and puffing time (20-60 s) with constant initial moisture content of 36.74% and air velocity of 3.99 m.s(-1) for potato-soy blend with varying soy flour content from 5% to 25% were investigated using response surface methodology following central composite rotatable design (CCRD). The optimum product in terms of minimum moisture content (11.03% db), maximum expansion ratio (3.71), minimum hardness (2,749.4 g), minimum ascorbic acid loss (9.24% db) and maximum overall acceptability (7.35) were obtained with 10.0% soy flour blend in potato flour at the process conditions of puffing temperature (231.0 °C) and puffing time (25.0 s).

Extension of shelf life of pear fruits using different packaging materials.

An experiment was conducted on pear fruit (cv. 'Lagoon') to extend the shelf life by using different packaging materials. Fruits were packed in low density polyethylene (LDPE, 0.025 mm), polypropylene (PP, 0.025 mm), linear low density polyethylene (LLDPE, 0.0125 mm) and high density polyethylene (HDPE, 0.025 mm) with or without perforation and stored at ambient condition (25 ± 2 °C and 65.0 ± 5% RH). Periodical observations were recorded on CO2 & O2 concentration (%), physiological loss in weight (PLW, %), decay loss (%), firmness (kgf), colour value (colour difference and colour index), total soluble solid (TSS, °Brix), acidity (mg of malic acid/g), and ascorbic acid loss (%) at 3 days interval. Reduced rate of PLW and decay losses was recorded in pear fruits packed in PP non-perforated (8.04%) and PP perforated (12.5%), respectively as compared to other treatments. The maximum firmness (5.18 kgf) and minimum ascorbic acid loss (49.97%) were also recorded in PP non-perforated up to 12 and 15 days of storage, respectively. It could be inferred that the, PP non-perforated (0.025 mm) was the most suitable packaging materials for extending the shelf life of pear fruits up to 15 days at ambient condition.

Acoustic particle trapping driven by axial primary radiation force in shaped traps.

We study particle trapping driven by the axial primary radiation force (A-PRF) in shaped traps exposed to standing bulk acoustic waves (S-BAW) using numerical simulations and experiments. The utilization of the stronger A-PRF as the main retention force is a consequence of standing-wave formation along the flow direction, instead of the orthogonal direction as in the case of traditionally used lateral-PRF S-BAW trapping setups. The study of particle dynamics reveals that the competition between A-PRF and viscous drag force governs particle trajectory. The ratio of the acoustic energy to the viscous work (ß) provides a general criterion for particle trapping at a distinctive off-node site that is spatially controllable. Particles get trapped for ß≥ß_{cr} at some distance away from the nodal plane and the distance varies as ß^{-c} (c=0.6-1.0). The use of A-PRF as the retention force could potentially allow traditional S-BAW trapping systems to envisage high-throughput advancements surpassing the current standards in cell-handling unit operations.

Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands.

Neurological disorders develop in most people infected with human immunodeficiency virus type 1 (HIV-1). However, the underlying mechanisms remain largely unknown. Here we report that binding of HIV-1 transactivator (Tat) protein to low-density lipoprotein receptor-related protein (LRP) promoted efficient uptake of Tat into neurons. LRP-mediated uptake of Tat was followed by translocation to the neuronal nucleus. Furthermore, the binding of Tat to LRP resulted in substantial inhibition of neuronal binding, uptake and degradation of physiological ligands for LRP, including alpha2-macroglobulin, apolipoprotein E4, amyloid precursor protein and amyloid beta-protein. In a model of macaques infected with a chimeric strain of simian-human immunodeficiency virus, increased staining of amyloid precursor protein was associated with Tat expression in the brains of simian-human immunodeficiency virus-infected macaques with encephalitis. These results indicate that HIV-1 Tat may mediate HIV-1-induced neuropathology through a pathway involving disruption of the metabolic balance of LRP ligands and direct activation of neuronal genes.