The lateralized effects of Parkinson's Disease on motor imagery: Evidence from mental chronometry.

Alterations to the content of action representations may contribute to the movement challenges that characterize Parkinson's Disease (PD). One way to investigate action representations is through motor imagery. As PD motor symptoms typically have a unilateral onset, disease-related deficits related to action representations may follow a similarly lateralized pattern. The present study examined if temporal accuracy of motor imagery in individuals with PD differed according to the side of the body involved in the task. Thirty-eight participants with PD completed a mental chronometry task using their more affected and less affected side. Participants had significantly shorter mental versus physical movement times for the more affected. Higher imagery vividness in the kinaesthetic domain predicted shorter mental versus physical movement times for the more affected side, as did lower imagery vividness in the visual domain and poorer cognitive function. These results indicate that people with PD imagine movements differently when the target actions their more affected versus less affected side. It is additionally possible that side-specific deficits in the accurate processing of kinaesthetic information lead to an increased reliance on visual processes and cognitive resources to successfully execute motor imagery involving the more affected side.

The frontoparietal multiple demand network interacts with the dual pathways in auditory working memory.

The frontoparietal multiple demand (MD) network has been proposed as a control network that regulates processing demands while enabling goal-directed actions. This study tested the MD network account in auditory working memory (AWM) and identified its functional role and relationship with the dual pathways model in AWM, where segregation of function was based on the sound domain. Forty-one healthy young adults performed an n-back task consisting of an orthogonal combination of the sound domain (spatial versus nonspatial) and cognitive operation (low load versus high load). Functional connectivity and correlation analyses were performed to assess the connectivity of the MD network and the dual pathways. Our results confirmed the contribution of the MD network to AWM and identified its interactions with the dual pathways in both sound domains and during high and low load levels. At high loads, the strength of connectivity with the MD network correlated with task accuracy, indicating the key role of the MD network in supporting successful performance as cognitive load increases. This study contributed to the auditory literature by showing that both the MD network and dual pathways collaborate with each other to support AWM, and neither of them alone is adequate to explain auditory cognition.

Exploring the Predictive Ability of the Motor-Free Visual Perception Test (MVPT) and Trail Making Test (TMT) for On-Road Driving Performance.

IMPORTANCE: Resuming driving after a change in functional ability is challenging for patients with a neurological condition. Although a combination of assessment tools has been suggested for use in driving evaluation, resources and availability of tools have been a problem. OBJECTIVE: To examine the predictive ability of two commonly used tools, the Motor-Free Visual Perception Test (MVPT) and the Trail Making Test, Parts A and B (TMTA and TMTB), on on-road driving performance. DESIGN: Retrospective chart review of 82 patient charts between 2015 and 2016. SETTING: Local rehabilitation hospital. PARTICIPANTS: Eighty-two patients with a primary neurological diagnosis (general neurological condition, n = 13; spinal cord injury, n = 11; stroke, n = 58). OUTCOMES AND MEASURES: MVPT, TMTA, and TMTB. RESULTS: Among the patients, 36 passed and 46 failed the on-road evaluation. The TMTA and TMTB scores were significantly different between those who passed or failed the on-road evaluation. Logistic regression analyses revealed that the TMTB completion time was the only significant predictor of on-road driving performance (for the all-patient model, 66% prediction accuracy, -2 log-likelihood [LL] = 93.47, exp ß = 0.98; for the stroke-only model, 76% prediction accuracy, -2LL = 59.61, exp ß = 0.97). CONCLUSIONS AND RELEVANCE: Our findings suggest that the TMTB is a better predictor of on-road driving performance for patients with a neurological condition than the MVPT. The findings shed light on the importance of selecting proper tools when assessing driving performance. Future prospective studies with a wider array of predictive variables are recommended to support the present findings. WHAT THIS ARTICLE ADDS: Occupational therapists should revisit the use of the MVPT in driving assessment and consider multiple assessment tools when evaluating and predicting driving performance.

Recent Treatment Advances and the Role of Nanotechnology, Combination Products, and Immunotherapy in Changing the Therapeutic Landscape of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia that is becoming more prevalent particularly in the older (65 years of age or older) population. For decades, "7 + 3" remission induction therapy with cytarabine and an anthracycline, followed by consolidation therapy, has been the standard of care treatment for AML. This stagnancy in AML treatment has resulted in less than ideal treatment outcomes for AML patients, especially for elderly patients and those with unfavourable profiles. Over the past two years, six new therapeutic agents have received regulatory approval, suggesting that a number of obstacles to treating AML have been addressed and the treatment landscape for AML is finally changing. This review outlines the challenges and obstacles in treating AML and highlights the advances in AML treatment made in recent years, including Vyxeos®, midostaurin, gemtuzumab ozogamicin, and venetoclax, with particular emphasis on combination treatment strategies. We also discuss the potential utility of new combination products such as one that we call "EnFlaM", which comprises an encapsulated nanoformulation of flavopiridol and mitoxantrone. Finally, we provide a review on the immunotherapeutic landscape of AML, discussing yet another angle through which novel treatments can be designed to further improve treatment outcomes for AML patients.

Transition Metal Ions Promote the Bioavailability of Hydrophobic Therapeutics: Cu and Zn Interactions with RNA Polymerase†I Inhibitor CX5461.

Low aqueous solubility is a major barrier to the clinical application of otherwise promising drug candidates. We demonstrate that this issue can be resolved in medicinal molecules containing potential ligating groups, through the addition of labile transition-metal ions. Incubation of the chemotherapeutic CX5461 with Cu2+ or Zn2+ enables solubilization at neutral pH but does not affect intrinsic cytotoxicity. Spectroscopic and computational studies demonstrate that this arises from coordination to the pyrazine functionality of CX5461 and may involve bidentate coordination at physiological pH.

Liposomal Formulations to Modulate the Tumour Microenvironment and Antitumour Immune Response.

Tumours are complex systems of genetically diverse malignant cells that proliferate in the presence of a heterogeneous microenvironment consisting of host derived microvasculature, stromal, and immune cells. The components of the tumour microenvironment (TME) communicate with each other and with cancer cells, to regulate cellular processes that can inhibit, as well as enhance, tumour growth. Therapeutic strategies have been developed to modulate the TME and cancer-associated immune response. However, modulating compounds are often insoluble (aqueous solubility of less than 1 mg/mL) and have suboptimal pharmacokinetics that prevent therapeutically relevant drug concentrations from reaching the appropriate sites within the tumour. Nanomedicines and, in particular, liposomal formulations of relevant drug candidates, define clinically meaningful drug delivery systems that have the potential to ensure that the right drug candidate is delivered to the right area within tumours at the right time. Following encapsulation in liposomes, drug candidates often display extended plasma half-lives, higher plasma concentrations and may accumulate directly in the tumour tissue. Liposomes can normalise the tumour blood vessel structure and enhance the immunogenicity of tumour cell death; relatively unrecognised impacts associated with using liposomal formulations. This review describes liposomal formulations that affect components of the TME. A focus is placed on formulations which are approved for use in the clinic. The concept of tumour immunogenicity, and how liposomes may enhance radiation and chemotherapy-induced immunogenic cell death (ICD), is discussed. Liposomes are currently an indispensable tool in the treatment of cancer, and their contribution to cancer therapy may gain even further importance by incorporating modulators of the TME and the cancer-associated immune response.

Copper (II) complexes of bidentate ligands exhibit potent anti-cancer activity regardless of platinum sensitivity status.

Insensitivity to platinum, either through inherent or acquired resistance, is a major clinical problem in the treatment of many solid tumors. Here, we explored the therapeutic potential of diethyldithiocarbamate (DDC), pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ), clioquinol (CQ) copper complexes in a panel of cancer cell lines that differ in their sensitivity to platins (cisplatin/carboplatin) using a high-content imaging system. Our data suggest that the copper complexes were effective against both platinum sensitive (IC50 ~ 1 µM platinum) and insensitive (IC50 > 5 µM platinum) cell lines. Furthermore, copper complexes of DDC, Pyr and 8-HQ had greater therapeutic activity compared to the copper-free ligands in all cell lines; whereas the copper-dependent activities of Plum and CQ were cell-line specific. Four of the copper complexes (Cu(DDC)2, Cu(Pyr)2, Cu(Plum)2 and Cu(8-HQ)2) showed IC50 values less than that of cisplatin in all tested cell lines. The complex copper DDC (Cu(DDC)2) was selected for in vivo evaluation due to its low nano-molar range activity in vitro and the availability of an injectable liposomal formulation. Liposomal (Cu(DDC)2) was tested in a fast-growing platinum-resistant A2780-CP ovarian xenograft model and was found to achieve a statistically significant reduction (50%; p < 0.05) in tumour size. This work supports the potential use of copper-based therapeutics to treat cancers that are insensitive to platinum drugs.

Synthetic lethality in lung cancer and translation to clinical therapies.

Lung cancer is a heterogeneous disease consisting of multiple histological subtypes each driven by unique genetic alterations. Despite the development of targeted therapies that inhibit the oncogenic mutations driving a subset of lung cancer cases, there is a paucity of effective treatments for the majority of lung cancer patients and new strategies are urgently needed. In recent years, the concept of synthetic lethality has been established as an effective approach for discovering novel cancer-specific targets as well as a method to improve the efficacy of existing drugs which provide partial but insufficient benefits for patients. In this review, we discuss the concept of synthetic lethality, the various types of synthetic lethal interactions in the context of oncology and the approaches used to identify these interactions, including recent advances that have transformed the ability to discover novel synthetic lethal combinations on a global scale. Lastly, we describe the specific synthetic lethal interactions identified in lung cancer to date and explore the pharmacological challenges and considerations in translating these discoveries to the clinic.

Induction of Cytotoxicity in Pyridine Analogues of the Anti-metastatic Ru(III) Complex NAMI-A by Ferrocene Functionalization.

A series of novel ferrocene (Fc) functionalized Ru(III) complexes was synthesized and characterized. These compounds are derivatives of the anti-metastatic Ru(III) complex imidazolium [trans-RuCl4(1H-imidazole) (DMSO-S)] (NAMI-A) and are derived from its pyridine analogue (NAMI-Pyr), with direct coupling of Fc to pyridine at the 4 or 3 positions, or at the 4 position via a two-carbon linker, which is either unsaturated (vinyl) or saturated (ethyl). Electron paramagnetic resonance (EPR) and UV-vis spectroscopic studies of the ligand exchange processes of the compounds in phosphate buffered saline (PBS) report similar solution behavior to NAMI-Pyr. However, the complex with Fc substitution at the 3 position of the coordinated pyridine shows greater solution stability, through resistance to the formation of oligomeric species. Further EPR studies of the complexes with human serum albumin (hsA) indicate that the Fc groups enhance noncoordinate interactions with the protein and help to inhibit the formation of protein-coordinated species, suggesting the potential for enhanced bioavailability. Cyclic voltammetry measurements demonstrate that the Fc groups modestly reduce the reduction potential of the Ru(III) center as compared to NAMI-Pyr, while the reduction potentials of the Fc moieties of the four compounds vary by 217 mV, with the longer linkers giving significantly lower values of E1/2. EPR spectra of the compounds with 2-carbon linkers show the formation of a high-spin Fe(III) species (S = 5/2) in PBS with a distinctive signal at g = 4.3, demonstrating oxidation of the Fe(II) ferrocene center and likely reflecting degradation products. Density functional theory calculations and paramagnetic (1)H NMR describe delocalization of spin density onto the ligands and indicate that the vinyl linker could be a potential pathway for electron transfer between the Ru and Fe centers. In the case of the ethyl linker, electron transfer is suggested to occur via an indirect mechanism enabled by the greater flexibility of the ligand. In vitro assays with the SW480 cell line reveal cytotoxicity induced by the ruthenium ferrocenylpyridine complexes that is at least an order of magnitude higher than the unfunctionalized complex, NAMI-Pyr. Furthermore, migration studies with LNCaP cells reveal that Fc functionalization does not reduce the ability of the compounds to inhibit cell motility. Overall, these studies demonstrate that NAMI-A-type compounds can be functionalized with redox-active ligands to produce both cytotoxic and anti-metastatic activity.

Attentional Capacity Limits Gap Detection during Concurrent Sound Segregation.

Detecting a brief silent interval (i.e., a gap) is more difficult when listeners perceive two concurrent sounds rather than one in a sound containing a mistuned harmonic in otherwise in-tune harmonics. This impairment in gap detection may reflect the interaction of low-level encoding or the division of attention between two sound objects, both of which could interfere with signal detection. To distinguish between these two alternatives, we compared ERPs during active and passive listening with complex harmonic tones that could include a gap, a mistuned harmonic, both features, or neither. During active listening, participants indicated whether they heard a gap irrespective of mistuning. During passive listening, participants watched a subtitled muted movie of their choice while the same sounds were presented. Gap detection was impaired when the complex sounds included a mistuned harmonic that popped out as a separate object. The ERP analysis revealed an early gap-related activity that was little affected by mistuning during the active or passive listening condition. However, during active listening, there was a marked decrease in the late positive wave that was thought to index attention and response-related processes. These results suggest that the limitation in detecting the gap is related to attentional processing, possibly divided attention induced by the concurrent sound objects, rather than deficits in preattentional sensory encoding.

Multidimensional digital biomarker phenotypes for mild cognitive impairment: considerations for early identification, diagnosis and monitoring.

Mild Cognitive Impairment (MCI) poses a challenge for a growing population worldwide. Early identification of risk for and diagnosis of MCI is critical to providing the right interventions at the right time. The paucity of reliable, valid, and scalable methods for predicting, diagnosing, and monitoring MCI with traditional biomarkers is noteworthy. Digital biomarkers hold new promise in understanding MCI. Identifying digital biomarkers specifically for MCI, however, is complex. The biomarker profile for MCI is expected to be multidimensional with multiple phenotypes based on different etiologies. Advanced methodological approaches, such as high-dimensional statistics and deep machine learning, will be needed to build these multidimensional digital biomarker profiles for MCI. Comparing patients to these MCI phenotypes in clinical practice can assist clinicians in better determining etiologies, some of which may be reversible, and developing more precise care plans. Key considerations in developing reliable multidimensional digital biomarker profiles specific to an MCI population are also explored.

Transcranial direct current stimulation over the right dorsolateral prefrontal cortex increases oxyhemoglobin concentration and cognitive performance dependent on cognitive load.

Transcranial direct current stimulation (tDCS) has been explored as a potential method for cognitive enhancement. tDCS may induce a cascade of neurophysiological changes including alterations in cerebral oxygenation. However, the effects of tDCS on the cognitive-cerebral oxygenation interaction remains unclear. Further, oxygenation variability across individuals remains minimally controlled for. The purpose of this sham-controlled study was to test the effects of anodal tDCS over the right dorsolateral prefrontal cortex (DLPFC) on the interaction between working memory and cerebral oxygenation while controlling for individual oxygenation variability. Thirty-three adults received resting-state functional near-infrared spectroscopy (fNIRS) recordings over bilateral prefrontal cortices. Following this, working memory was tested using a Toulouse n-back task concurrently paired with fNIRS, with measurements taken before and after 20 min of anodal or sham tDCS at 1.5 mA. With individual oxygenation controlled for, anodal tDCS was found to increase the oxyhemoglobin concentration over the right DLPFC during the 2-back (q = .015) and 3-back (q = .008) conditions. Additionally, anodal tDCS was found to improve accuracy during the 3-back task by 13.4 % (p = .028) and decrease latency by 250 ms (p = .013). The increase in oxyhemoglobin was strongly correlated with increases in accuracy (p = .041) and decreases in latency during the 3-back span (p = .017). Taken together, anodal tDCS over the right DLPFC was found to regionally increase oxyhemoglobin concentrations and improve working memory performance in higher cognitive load conditions.

Profiling the Research Activities of Canadian Occupational Therapy and Occupational Science Faculty Members.

Background. There is a lack of knowledge on the scope and nature of the research by faculty members in occupational science (OS) and/or occupational therapy (OT) programs in Canada. Purpose. To describe the research activities of faculty members in these programs and directions. Method. A cross-sectional survey was distributed to 173 faculty members across all 14 Canadian OT that addressed: 1) research topics and methods, 2) populations, and 3) funding. Findings. Based on respondents (N = 121), research is focused on a range of topics and populations with most conducting qualitative research. Many conduct research examining the effectiveness of interventions, with few respondents focused on OS research. Federal and provincial grants agencies were the largest source of funding. Implications. Research topics studied were not always proportional to practice although emerging areas were being investigated that can expand the evidence base and scope of practice. Despite limited occupation-specific funding options, respondents were accessing funding from varied sources. Collaborations among faculty members, clinicians, and individuals with lived experience can create priorities for future OS and/or OT research in Canada.

Optimizing Lipid Nanoparticles for Delivery in Primates.

Lipid nanoparticles (LNPs) are clinically proven to successfully deliver both small interfering RNA (siRNA) therapeutics and larger mRNA payloads for prophylactic vaccine applications. Non-human primates (NHPs) are generally considered to be the most predictive of human responses. However, for ethical and economic reasons, LNP compositions have historically been optimized in rodents. It has been difficult to translate LNP potency data from rodents to NHPs for intravenously (IV) administered products in particular. This presents a major challenge for preclinical drug development. An attempt to investigate LNP parameters, which have historically been optimized in rodents, is carried out, and seemingly innocuous changes are found to result in large potency differences between species. For example, the ideal particle size for NHPs (50-60 nm) is found to be smaller than for rodents (70-80 nm). Surface chemistry requirements are also different, with almost double the amount of poly(ethylene glycol) (PEG)-conjugated lipid needed for maximal potency in NHPs. By optimizing these two parameters, approximately eight-fold increase in protein expression from intravenously administered messenger RNA (mRNA)-LNP in NHP is gained. The optimized formulations are well tolerated when administered repeatedly with no loss of potency. This advancement enables the design of optimal LNP products for clinical development.

Functional Brain Regions Linked to Tinnitus Pathology and Compensation During Task Performance: A Systematic Review.

OBJECTIVE: To systematically search the literature and organize relevant advancements in the connection between tinnitus and the activity of different functional brain regions using functional magnetic resonance imaging (fMRI). DATA SOURCES: MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO), Web of Science, ProQuest Dissertations & Theses Global, Cochrane Database of Systematic Reviews, and PROSPERO from inception to April 2022. REVIEW METHODS: Studies with adult human subjects who suffer from tinnitus and underwent fMRI to relate specific regions of interest to tinnitus pathology or compensation were included. In addition, fMRI had to be performed with a paradigm of stimuli that would stimulate auditory brain activity. Exclusion criteria included non-English studies, animal studies, and studies that utilized a resting state magnetic resonance imaging or other imaging modalities. RESULTS: The auditory cortex may work to dampen the effects of central gain. Results from different studies show variable changes in the Heschl's gyrus (HG), with some showing increased activity and others showing inhibition and volume loss. After controlling for hyperacusis and other confounders, tinnitus does not seem to influence the inferior colliculus (IC) activation. However, there is decreased connectivity between the auditory cortex and IC. The cochlear nucleus (CN) generally shows increased activation in tinnitus patients. fMRI evidence indicates significant inhibition of thalamic gating. Activating the thalamus may be of important therapeutic potential. CONCLUSION: Patients with tinnitus have significantly altered neuronal firing patterns, especially within the auditory network, when compared to individuals without tinnitus. Tinnitus and hyperacusis commonly coexist, making differentiation of the effects of these 2 phenomena frequently difficult.

Unsaturated, Trialkyl Ionizable Lipids are Versatile Lipid-Nanoparticle Components for Therapeutic and Vaccine Applications.

Lipid nanoparticles (LNPs) have proven a successful platform for the delivery of nucleic acid (NA)-based therapeutics and vaccines, with the ionizable lipid component playing a key role in modulating potency and tolerability. Here, a library of 16 novel ionizable lipids is screened hypothesizing that short, branched trialkyl hydrophobic domains can improve LNP fusogenicity or endosomal escape, and potency. LNPs formulated with the top-performing trialkyl lipid (Lipid 10) encapsulating transthyretin siRNA elicit significantly greater gene silencing and are better tolerated than those with the benchmark Onpattro lipid DLin-MC3-DMA. Lipid 10 also demonstrates superior liver delivery of mRNA when compared to other literature ionizable lipids, is well tolerated, and successfully repeat-doses in nonhuman primates. In a prime-boost hemagglutinin rodent vaccine model, intramuscular administration of Lipid-10 LNP elicits comparable or better antibody titers to the SM-102 and ALC-0315 lipid compositions used in the U.S. Food and Drug Administration approved mRNA COVID vaccines. These data suggest that Lipid 10 is a particularly versatile ionizable lipid, well-suited for both systemic therapeutic and intramuscular vaccine applications and able to successfully deliver diverse NA payloads.

Contributions of conserved residues at the gating interface of glycine receptors.

Glycine receptors (GlyRs) are chloride channels that mediate fast inhibitory neurotransmission and are members of the pentameric ligand-gated ion channel (pLGIC) family. The interface between the ligand binding domain and the transmembrane domain of pLGICs has been proposed to be crucial for channel gating and is lined by a number of charged and aromatic side chains that are highly conserved among different pLGICs. However, little is known about specific interactions between these residues that are likely to be important for gating in α1 GlyRs. Here we use the introduction of cysteine pairs and the in vivo nonsense suppression method to incorporate unnatural amino acids to probe the electrostatic and hydrophobic contributions of five highly conserved side chains near the interface, Glu-53, Phe-145, Asp-148, Phe-187, and Arg-218. Our results suggest a salt bridge between Asp-148 in loop 7 and Arg-218 in the pre-M1 domain that is crucial for channel gating. We further propose that Phe-145 and Phe-187 play important roles in stabilizing this interaction by providing a hydrophobic environment. In contrast to the equivalent residues in loop 2 of other pLGICs, the negative charge at Glu-53 α1 GlyRs is not crucial for normal channel function. These findings help decipher the GlyR gating pathway and show that distinct residue interaction patterns exist in different pLGICs. Furthermore, a salt bridge between Asp-148 and Arg-218 would provide a possible mechanistic explanation for the pathophysiologically relevant hyperekplexia, or startle disease, mutant Arg-218 → Gln.

tDCS over the left prefrontal Cortex improves mental flexibility and inhibition in geriatric inpatients with symptoms of depression or anxiety: A pilot randomized controlled trial.

Background: Patients with depression and/or anxiety are commonly seen in inpatient geriatric settings. Both disorders are associated with an increased risk of cognitive impairments, notably in executive functioning. Transcranial direct current stimulation (tDCS), a type of non-invasive brain stimulation, involves the administration of a low-dose electrical current to induce neuromodulation, which ultimately may act on downstream cognitive processing. Objective: The purpose of this study was to determine the effects of tDCS on executive functioning in geriatric inpatients with symptoms of depression and/or anxiety. Design: Pilot Randomized Controlled Trial. Setting: Specialized geriatric wards in a tertiary rehabilitation hospital. Methods: Thirty older-aged adults were recruited, of which twenty completed ten-to-fifteen sessions of 1.5 mA anodal or sham tDCS over the left dorsolateral prefrontal cortex. Cognitive assessments were administered at baseline and following the tDCS protocol; analyses examined the effects of tDCS on cognitive performance between groups (anodal or sham tDCS). Results: tDCS was found to increase inhibitory processing and cognitive flexibility in the anodal tDCS group, with significant changes on the Stroop test and Trail Making Test-Part B. No significant changes were observed on measures of attention or working memory. Discussion: These results provide preliminary evidence that tDCS-induced neuromodulation may selectively improve cognitive processing in older adults with symptoms of depression and/or anxiety. Clinical Trials Registration: www.clinicaltrials.gov, NCT04558177.

DMPC/Chol liposomal copper CX5461 is therapeutically superior to a DSPC/Chol formulation.

CX5461, a compound initially identified as an RNA polymerase inhibitor and more recently as a G-quadruplex binder, binds copper to form a complex. Our previous publication showed that the complexation reaction can be leveraged to formulate copper-CX5461 inside liposomes, improving the apparent solubility of CX5461 by over 500-fold and reducing the elimination of CX5461 from the plasma compartment following intravenous administration. In mouse models of acute myeloid leukemia, the resulting formulation was more effective than the free drug solution of CX5461 (pH 3.5) currently used in clinical trials. However, the gains observed with the liposomal formulation were minimal, despite significant increases in circulation half-life. Since the formulation technology used relied on liposomes and the fate of most compounds associated with liposomes is dependent on liposomal lipid composition, the studies described here were designed to evaluate how simple changes in lipid composition could affect therapeutic activity. The previously reported formulation method was simplified to ensure an easy scale-up process. In the modified method, pre-measured solid CX5461 was added to copper-containing liposomes prior to an incubation at 60 °C, which enabled copper-CX5461 complexation inside DSPC/Chol or DMPC/Chol liposomes. Efficacy was determined in BRCA-normal (BxPC3) and BRCA-deficient (Capan-1) models of pancreatic cancer. Both liposomal formulations enhanced the circulation lifetime of CX5461 compared to the free drug solution (pH 3.5). Unlike most compounds that are loaded using a transmembrane pH-gradient, the dissociation of CX5461 from liposomes prepared using the copper complexation method were comparable for DSPC/Chol and DMPC/Chol liposomes, in vitro and in vivo. Nonetheless, copper CX5461 prepared using DMPC/Chol liposomes exhibited superior efficacy. The reason for the improved activity of DMPC/Chol copper-CX5461 was not readily explained by the release data and may be due to the fact that DMPC/Chol liposomes are less stable following localization in the tumor. The results indicate that the therapeutic effects of copper-CX5461 will be dependent on liposomal lipid composition and that liposomal CX5461 should exhibit superior benefits when used to treat BRCA-deficient cancers.

Working memory load modulates the auditory "What" and "Where" neural networks.

Working memory for sound identity (What) and sound location (Where) has been associated with increased neural activity in ventral and dorsal brain regions, respectively. To further ascertain this domain specificity, we measured fMRI signals during an n-back (n=1, 2) working memory task for sound identity or location, where stimuli selected randomly from three semantic categories (human, animal, and music) were presented at three possible virtual locations. Accuracy and reaction times were comparable in both "What" and "Where" tasks, albeit worse for the 2-back than for the 1-back condition. The analysis of fMRI data revealed greater activity in ventral and dorsal brain regions during sound identity and sound location, respectively. More importantly, there was an interaction between task and working memory load in the inferior parietal lobule (IPL). Within the right IPL, there were two sub-regions modulated differentially by working memory load: an anterior ventromedial region modulated by location load and a posterior dorsolateral region modulated by category load. These specific changes in neural activity as a function of working memory load reveal domain-specificity within the parietal cortex.