Neural signal propagation atlas of Caenorhabditis elegans.

Establishing how neural function emerges from network properties is a fundamental problem in neuroscience1. Here, to better understand the relationship between the structure and the function of a nervous system, we systematically measure signal propagation in 23,433 pairs of neurons across the head of the nematode Caenorhabditis elegans by direct optogenetic activation and simultaneous whole-brain calcium imaging. We measure the sign (excitatory or inhibitory), strength, temporal properties and causal direction of signal propagation between these neurons to create a functional atlas. We find that signal propagation differs from model predictions that are based on anatomy. Using mutants, we show that extrasynaptic signalling not visible from anatomy contributes to this difference. We identify many instances of dense-core-vesicle-dependent signalling, including on timescales of less than a second, that evoke acute calcium transients-often where no direct wired connection exists but where relevant neuropeptides and receptors are expressed. We propose that, in such cases, extrasynaptically released neuropeptides serve a similar function to that of classical neurotransmitters. Finally, our measured signal propagation atlas better predicts the neural dynamics of spontaneous activity than do models based on anatomy. We conclude that both synaptic and extrasynaptic signalling drive neural dynamics on short timescales, and that measurements of evoked signal propagation are crucial for interpreting neural function.

Inhibitory feedback from the motor circuit gates mechanosensory processing in Caenorhabditis elegans.

Animals must integrate sensory cues with their current behavioral context to generate a suitable response. How this integration occurs is poorly understood. Previously, we developed high-throughput methods to probe neural activity in populations of Caenorhabditis elegans and discovered that the animal's mechanosensory processing is rapidly modulated by the animal's locomotion. Specifically, we found that when the worm turns it suppresses its mechanosensory-evoked reversal response. Here, we report that C. elegans use inhibitory feedback from turning-associated neurons to provide this rapid modulation of mechanosensory processing. By performing high-throughput optogenetic perturbations triggered on behavior, we show that turning-associated neurons SAA, RIV, and/or SMB suppress mechanosensory-evoked reversals during turns. We find that activation of the gentle-touch mechanosensory neurons or of any of the interneurons AIZ, RIM, AIB, and AVE during a turn is less likely to evoke a reversal than activation during forward movement. Inhibiting neurons SAA, RIV, and SMB during a turn restores the likelihood with which mechanosensory activation evokes reversals. Separately, activation of premotor interneuron AVA evokes reversals regardless of whether the animal is turning or moving forward. We therefore propose that inhibitory signals from SAA, RIV, and/or SMB gate mechanosensory signals upstream of neuron AVA. We conclude that C. elegans rely on inhibitory feedback from the motor circuit to modulate its response to sensory stimuli on fast timescales. This need for motor signals in sensory processing may explain the ubiquity in many organisms of motor-related neural activity patterns seen across the brain, including in sensory processing areas.

A high-throughput method to deliver targeted optogenetic stimulation to moving C. elegans populations.

We present a high-throughput optogenetic illumination system capable of simultaneous closed-loop light delivery to specified targets in populations of moving Caenorhabditis elegans. The instrument addresses three technical challenges: It delivers targeted illumination to specified regions of the animal's body such as its head or tail; it automatically delivers stimuli triggered upon the animal's behavior; and it achieves high throughput by targeting many animals simultaneously. The instrument was used to optogenetically probe the animal's behavioral response to competing mechanosensory stimuli in the the anterior and posterior gentle touch receptor neurons. Responses to more than 43,418 stimulus events from a range of anterior-posterior intensity combinations were measured. The animal's probability of sprinting forward in response to a mechanosensory stimulus depended on both the anterior and posterior stimulation intensity, while the probability of reversing depended primarily on the anterior stimulation intensity. We also probed the animal's response to mechanosensory stimulation during the onset of turning, a relatively rare behavioral event, by delivering stimuli automatically when the animal began to turn. Using this closed-loop approach, over 9,700 stimulus events were delivered during turning onset at a rate of 9.2 events per worm hour, a greater than 25-fold increase in throughput compared to previous investigations. These measurements validate with greater statistical power previous findings that turning acts to gate mechanosensory evoked reversals. Compared to previous approaches, the current system offers targeted optogenetic stimulation to specific body regions or behaviors with many fold increases in throughput to better constrain quantitative models of sensorimotor processing.

Endogenous Glucocorticoid Signaling in the Regulation of Bone and Marrow Adiposity: Lessons from Metabolism and Cross Talk in Other Tissues.

PURPOSE OF REVIEW: The development of adiposity in the bone marrow, known as marrow adipose tissue (MAT), is often associated with musculoskeletal frailty. Glucocorticoids, which are a key component of the biological response to stress, affect both bone and MAT. These molecules signal through receptors such as the glucocorticoid receptor (GR), but the role of the GR in regulation of MAT is not yet clear from previous studies. The purpose of this review is to establish and determine the role of GR-mediated signaling in marrow adiposity by comparing and contrasting what is known against other energy-storing tissues like adipose tissue, liver, and muscle, to provide better insight into the regulation of MAT during times of metabolic stress (e.g., dietary challenges, aging). RECENT FINDINGS: GR-mediated glucocorticoid signaling is critical for proper storage and utilization of lipids in cells such as adipocytes and hepatocytes and proteolysis in muscle, impacting whole-body composition, energy utilization, and homeostasis through a complex network of tissue cross talk between these systems. Loss of GR signaling in bone promotes increased MAT and decreased bone mass. GR-mediated signaling in the liver, adipose tissue, and muscle is critical for whole-body energy and metabolic homeostasis, and both similarities and differences in GR-mediated GC signaling in MAT as compared with these tissues are readily apparent. It is clear that GC-induced pathways work together through these tissues to affect systemic biology, and understanding the role of bone in these patterns of tissue cross talk may lead to a better understanding of MAT-bone biology that improves treatment strategies for frailty-associated diseases.

Simulation study on comprehensive sensing enhancement of BlueP/MoS2- and BlueP/WS2-based fluoride fiber surface plasmon resonance sensors: analysis founded on damping, field, and optical power.

Two-dimensional (2D) heterostructure-based fluoride fiber surface plasmon resonance (SPR) sensor designs are simulated and analyzed while emphasizing figure of merit (FOM) enhancement in the near-infrared (NIR) spectral region. Through simultaneous optimization of NIR wavelength and Ag layer thickness, exceptionally large FOM values of 15,650.75 RIU-1 and 12,409.30 RIU-1 are achieved for BlueP/MoS2-based and BlueP/WS2-based fiber SPR sensors, respectively. The results are explained in terms of tunable radiation damping, power loss, and corresponding field enhancement. These FOM values are significantly greater than recently reported sensors. The BlueP/MoS2-based sensor with 48.8 nm Ag film and at 738.4 nm wavelength provides an all-round large FOM.

Azo-dyes based small bifunctional molecules for metal chelation and controlling amyloid formation.

Chemical tools are needed to discover new effective drugs for tackling multifaceted complex neurodegenerative diseases like Alzheimer's disease (AD). Multifunctional nature of two compounds, 5-((4-nitro-phenyl)diazenyl)quinolin-8-ol (HL1) and 4-((4-nitrophenyl)diazenyl)benzene-1,3-diol (HL2) is reported w.r.t. their ability to bind Cu2+ ions and amyloid aggregates related to AD. HL1 and HL2 have half congo-red type azo-stilbene structural framework incorporated with metal chelating groups, designed to chelate metal ions from metal-amyloid species. Metal binding studies of HL1 and HL2 are established by the methods of Job's Plot, UV-vis spectra with metal ions and stability constant determination. In addition, their metal complexes are isolated, purity checked by elemental analysis, spectroscopically characterized and their structural analyses were obtained from DFT based calculations including binding energy determination. Chicken egg white Lysozyme (CEWL) was used as a model peptide for fibrillation studies. HL1 is found as an excellent colorimetric sensor for amyloid fibrils. Inhibitory effect of HL1 and HL2 and their isolated metal complexes L1-Cu and L2-Cu on CEWL fibrillation was studied using ThT and ANS fluorescence assay along with TEM imaging. In addition, the cell toxicity studies on these compounds suggest that although azo dyes may be non-toxic but having a nitro-substitution lead to significant cell toxicity. Overall, these results suggest that this new class of multifunctional small molecules can interact with amyloids as well as metal ions and could be potential anti-aggregation metal chelating agents.

Evaluation of 64Cu-Based Radiopharmaceuticals that Target Aß Peptide Aggregates as Diagnostic Tools for Alzheimer's Disease.

Positron emission tomography (PET) imaging agents that detect amyloid plaques containing amyloid beta (Aß) peptide aggregates in the brain of Alzheimer's disease (AD) patients have been successfully developed and recently approved by the FDA for clinical use. However, the short half-lives of the currently used radionuclides 11C (20.4 min) and 18F (109.8 min) may limit the widespread use of these imaging agents. Therefore, we have begun to evaluate novel AD diagnostic agents that can be radiolabeled with 64Cu, a radionuclide with a half-life of 12.7 h, ideal for PET imaging. Described herein are a series of bifunctional chelators (BFCs), L1-L5, that were designed to tightly bind 64Cu and shown to interact with Aß aggregates both in vitro and in transgenic AD mouse brain sections. Importantly, biodistribution studies show that these compounds exhibit promising brain uptake and rapid clearance in wild-type mice, and initial microPET imaging studies of transgenic AD mice suggest that these compounds could serve as lead compounds for the development of improved diagnostic agents for AD.

Coordination Chemistry of Bifunctional Chemical Agents Designed for Applications in 64Cu PET Imaging for Alzheimer's Disease.

Positron emission tomography (PET) is emerging as one of the most important diagnostic tools for brain imaging, yet the most commonly used radioisotopes in PET imaging, 11C and 18F, have short half-lives, and their usage is thus somewhat limited. By comparison, the 64Cu radionuclide has a half-life of 12.7 h, which is ideal for administering and imaging purposes. In spite of appreciable research efforts, high-affinity copper chelators suitable for brain imaging applications are still lacking. Herein, we present the synthesis and characterization of a series of bifunctional compounds (BFCs) based on macrocyclic 1,4,7-triazacyclononane and 2,11-diaza[3.3](2,6)pyridinophane ligand frameworks that exhibit a high affinity for Cu2+ ions. In addition, these BFCs contain a 2-phenylbenzothiazole fragment that is known to interact tightly with amyloid ß fibrillar aggregates. Determination of the protonation constants (pKa values) and stability constants (log ß values) of these BFCs, as well as characterization of the isolated copper complexes using X-ray crystallography, electron paramagnetic resonance spectroscopy, and electrochemical studies, suggests that these BFCs exhibit desirable properties for the development of novel 64Cu PET imaging agents for Alzheimer's disease.

Hydrogen peroxide test for intraoperative bile leak detection.

BACKGROUND: Bile leakage (BL) is a common complication following liver surgery, ranging from 3 to 27% in different series. To reduce the incidence of post-operative BL various BL tests have been applied since ages, but no method is foolproof and every method has their own limitations. In this study we used a relatively simpler technique to detect the BL intra-operatively. Topical application of 1.5% diluted hydrogen peroxide (H2O2) was used to detect the BL from cut surface of liver and we compared this with conventional saline method to know the efficacy. METHODS: A total of 31 patients included all patients who underwent liver resection and donor hepatectomies as part of Living Donor Liver Transplantation. After complete liver resection, the conventional saline test followed by topical diluted 1.5% H2O2 test was performed on all. RESULTS: A BL was demonstrated in 11 patients (35.48%) by the conventional saline method and in 19 patients (61.29%) by H2O2 method. Statistically compared by Wilcoxon signed-rank test showed significant difference (P = 0.014) for minor liver resections group and (P = 0.002) for major liver resections group. CONCLUSION: The topical application of H2O2 is a simple and effective method of detection of BL from cut surface of liver. It is an easy, non-invasive, cheap, less time consuming, reproducible, and sensitive technique with no obvious disadvantages.

Pulsed hydrogen-deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aß) peptide aggregation.

Probing the conformational changes of amyloid beta (Aß) peptide aggregation is challenging owing to the vast heterogeneity of the resulting soluble aggregates. To investigate the formation of these aggregates in solution, we designed an MS-based biophysical approach and applied it to the formation of soluble aggregates of the Aß42 peptide, the proposed causative agent in Alzheimer's disease. The approach incorporates pulsed hydrogen-deuterium exchange coupled with MS analysis. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as observed previously by fluorescence methods. Unlike those approaches, pulsed hydrogen-deuterium exchange does not require modified Aß42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aß42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of soluble species is affected by temperature and Cu(2+) ions. This MS approach has sufficient structural resolution to allow interrogation of Aß aggregation in physiologically relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic soluble peptide aggregates.

Neutral, cationic, and anionic low-spin iron(III) complexes stabilized by amidophenolate and iminobenzosemiquinonate radical in N,N,O ligands.

A brownish-black complex [Fe(III)(L)2] (1) (S = 0), supported by two tridentate redox-active azo-appended o-amidophenolates [H2L = 2-(2-phenylazo)-anilino-4,6-di-tert-butylphenol], has been synthesized and structurally characterized. In CH2Cl2 1 displays two oxidative and two reductive 1e(-) redox processes at E1/2 values of 0.48 and 1.06 V and -0.42 and -1.48 V vs SCE, respectively. The one-electron oxidized form [1](+) isolated as a green solid [Fe(III)(L)2][BF4] (2) (S = 1/2) has been structurally characterized. Isolation of a dark ink-blue one-electron reduced form [1](-) has also been achieved [Co(III)(η(5)-C10H15)2][Fe(III)(L)2] (3) (S = 1/2). Mössbauer spectral parameters unequivocally establish that 1 is a low-spin (LS) Fe(III) complex. Careful analysis of Mössbauer spectral data of 2 and 3 at 200 and 80 K reveal that each complex has a major LS Fe(III) and a minor LS Fe(II) component (redox isomers): [Fe(III){(L(ISQ))(-•)}2](+) and [Fe(II){(L(IBQ))(0)}{(L(ISQ))(-•)}](+) (2) and [Fe(III){(L(AP))(2-)}2](-) and [Fe(II){(L(ISQ))(-•)}{(L(AP))(2-)}](-) (3). Notably, for both at 8 K mainly the major component exists. Broken-Symmetry (BS) Density Functional Theory (DFT) calculations at the B3LYP level reveals that in 1 the unpaired electron of LS Fe(III) is strongly antiferromagnetically coupled with a π-radical of o-iminobenzosemiquinonate(1-) (L(ISQ))(-•) form of the ligand, delocalized over two ligands providing 3- charge (X-ray structure). DFT calculations reveal that the unpaired electron in 2 is due to (L(ISQ))(-•) [LS Fe(III) (SFe = 1/2) is strongly antiferromagnetically coupled to one of the (L(ISQ))(-•) radicals (Srad = 1/2)] and 3 is primarily a LS Fe(III) complex, supported by two o-amidophenolate(2-) ligands. Time-Dependent-DFT calculations shed light on the origin of UV-vis-NIR spectral absorptions for 1-3. The collective consideration of Mössbauer, variable-temperature (77-298 K) electron paramagnetic resonance (EPR), and absorption spectral behavior at 298 K, and DFT results reveals that in 2 and 3 the valence-tautomerism is operative in the temperature range 80-300 K.

Small bifunctional chelators that do not disaggregate amyloid ß fibrils exhibit reduced cellular toxicity.

Multifunctional metal chelators that can modulate the amyloid ß (Aß) peptide aggregation and its interaction with metal ions such as copper and zinc hold considerable promise as therapeutic agents for Alzheimer's disease (AD). However, specific rather than systemic metal chelation by these compounds is needed in order to limit any side effects. Reported herein are two novel small bifunctional chelators, 2-[2-hydroxy-4-(diethylamino)phenyl]benzothiazole (L1) and 2-(2-hydroxy-3-methoxyphenyl)benzothiazole (L2), in which the metal-binding donor atoms are integrated within a molecular framework derived from the amyloid-binding fluorescent dye thioflavin T (ThT). The metal-binding properties of L1 and L2 were probed by pH spectrophotometric titrations to determine their pKa values and the corresponding metal complex stability constants, and the isolated metal complexes were structurally characterized. The amyloid-fibril-binding properties of L1 and L2 were investigated by fluorescence titrations and ThT competition assays. Interestingly, L1 and L2 do not lead to the formation of neurotoxic Aß42 oligomers in the presence or absence of metal ions, as observed by native gel electrophoresis, Western blotting, and transmission electron microscopy. In addition, L1 and L2 were able to reduce the cell toxicity of preformed Aß42 oligomers and of the copper-stabilized Aß42 oligomers. Given their ability to reduce the toxicity of soluble Aß42 and Cu-Aß42 species, L1 and L2 are promising lead compounds for the development of chemical agents that can control the neurotoxicity of soluble Aß42 species in AD.

An inhibitory acetylcholine receptor gates context dependent mechanosensory processing in C. elegans.

An animal's current behavior influences its response to sensory stimuli, but the molecular and circuit-level mechanisms of this context-dependent decision-making is not well understood. In the nematode C. elegans, inhibitory feedback from turning associated neurons alter downstream mechanosensory processing to gate the animal's response to stimuli depending on whether the animal is turning or moving forward [1-3]. Until now, the specific neurons and receptors that mediate this inhibitory feedback were not known. We use genetic manipulations, single-cell rescue experiments and high-throughput closed-loop optogenetic perturbations during behavior to reveal the specific neuron and receptor responsible for receiving inhibition and altering sensorimotor processing. An inhibitory acetylcholine gated chloride channel comprised of lgc-47 and acc-1 expressed in neuron RIM receives inhibitory signals from turning neurons and performs the gating that disrupts the worm's mechanosensory evoked reversal response.

Olfactory learning alters navigation strategies and behavioral variability in C. elegans.

Animals adjust their behavioral response to sensory input adaptively depending on past experiences. The flexible brain computation is crucial for survival and is of great interest in neuroscience. The nematode C. elegans modulates its navigation behavior depending on the association of odor butanone with food (appetitive training) or starvation (aversive training), and will then climb up the butanone gradient or ignore it, respectively. However, the exact change in navigation strategy in response to learning is still unknown. Here we study the learned odor navigation in worms by combining precise experimental measurement and a novel descriptive model of navigation. Our model consists of two known navigation strategies in worms: biased random walk and weathervaning. We infer weights on these strategies by applying the model to worm navigation trajectories and the exact odor concentration it experiences. Compared to naive worms, appetitive trained worms up-regulate the biased random walk strategy, and aversive trained worms down-regulate the weathervaning strategy. The statistical model provides prediction with $>90 \%$ accuracy of the past training condition given navigation data, which outperforms the classical chemotaxis metric. We find that the behavioral variability is altered by learning, such that worms are less variable after training compared to naive ones. The model further predicts the learning-dependent response and variability under optogenetic perturbation of the olfactory neuron AWC$^\mathrm{ON}$. Lastly, we investigate neural circuits downstream from AWC$^\mathrm{ON}$ that are differentially recruited for learned odor-guided navigation. Together, we provide a new paradigm to quantify flexible navigation algorithms and pinpoint the underlying neural substrates.

Light evokes stereotyped global brain dynamics in Caenorhabditis elegans.

Stereotyped oscillations in population neural activity recordings from immobilized Caenorhabditis elegans have garnered interest for their striking low dimensionality and their evocative state-space trajectories or manifolds. Previously these oscillations have been interpreted as intrinsically driven global motor commands. Here we test whether these oscillations are intrinsic. We show that similar oscillations are evoked by high-intensity blue light commonly used for calcium imaging. Oscillations are reduced or absent and have a lower frequency when a longer imaging wavelength is used. Under the original blue light illumination, oscillations are reduced or have a lower frequency in animals that lack GUR-3, an endogenous light- and hydrogen-peroxide-sensitive gustatory receptor. Additional experiments with hydrogen peroxide are consistent with GUR-3's involvement. We therefore propose that blue light evokes global oscillations in part through the creation of reactive oxygen species that activate the hydrogen-peroxide-sensing receptor GUR-3.

Teaching an Old Drug a New Trick: Targeting Treatment Resistance in Genitourinary Cancers.

In the quest for improving the clinical outcome of patients with metastatic genitourinary cancers, including metastatic renal cell carcinoma (mRCC), the emphasis often is on finding new targeted therapies. However, two studies by Jordan et al. (Oncogenesis 2020) and Wang et al. (Cancer Cell Int 2022) demonstrate the feasibility of improving the efficacy of a modestly effective drug Sorafenib against mRCC by attacking a mechanism hijacked by RCC cells for inactivating Sorafenib. The studies also identified hyaluronic acid synthase -3 (HAS3) as a bonafide target of Sorafenib in RCC cells. The studies demonstrate that an over-the-counter drug Hymecromone (4-methylumbelliferone) blocks inactivation of Sorafenib in RCC cells and improves its efficacy against mRCC through the inhibition of HAS3 expression and HA signaling. In the broader context, improving the efficacy of "old and failed drugs" that have favorable safety profiles should increase the availability of effective treatments for patients with advanced cancers.

A bis-quinoline ruthenium(II) arene complex with submicromolar cytotoxicity in castration-resistant prostate cancer cells.

A new Ru(II) arene chlorido organometallic complex [(η6-p-cymene)(L)RuCl]PF6 (named as pCYRuL) using 2-bis(quinolin-2-ylmethylene) hydrazine (L) was developed that exhibits potent anticancer activity against castration-resistant prostate cancer (CRPC) (IC50 = 0.71 µM), and it is 45 times more effective than the standard drug cisplatin (IC50 = 31.3 µM) in a castration-resistant human prostatic adenocarcinoma cell line (PC-3) but non-toxic in normal human kidney cells (HK2) as well as normal breast cells (MCF10A) and found that pCYRuL exerted anticancer activity via apoptosis induction and cell cycle arrest in the G2/M phase of PC-3 cells.

Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention.

The paucity of preclinical models that recapitulate COVID-19 pathology without requiring SARS-COV-2 adaptation and humanized/transgenic mice limits research into new therapeutics against the frequently emerging variants-of-concern. We developed virus-free models by C57BL/6 mice receiving oropharyngeal instillations of a SARS-COV-2 ribo-oligonucleotide common in all variants or specific to Delta/Omicron variants, concurrently with low-dose bleomycin. Mice developed COVID-19-like lung pathologies including ground-glass opacities, interstitial fibrosis, congested alveoli, and became moribund. Lung tissues from these mice and bronchoalveolar lavage and lung tissues from patients with COVID-19 showed elevated levels of hyaluronic acid (HA), HA-family members, an inflammatory signature, and immune cell infiltration. 4-methylumbelliferone (4-MU), an oral drug for biliary-spasm treatment, inhibits HA-synthesis. At the human equivalent dose, 4-MU prevented/inhibited COVID-19-like pathologies and long-term morbidity; 4-MU and metabolites accumulated in mice lungs. Therefore, these versatile SARS-COV-2 ribo-oligonucleotide oropharyngeal models recapitulate COVID-19 pathology, with HA as its critical mediator and 4-MU as a potential therapeutic for COVID-19.

Design and analysis of graphene- and germanium-based plasmonic probe with photonic spin Hall effect in THz frequency region for magnetic field and refractive index sensing.

In this work, we analyze the design of a graphene- and germanium-based plasmonic sensor with photonic spin Hall effect (PSHE) for detection of refractive index (RI) of a gas medium and magnetic field (B) applied to the graphene monolayer in THz frequency region. The PSHE phenomenon is studied in both conventional as well as modified weak measurements. The effect of gaseous medium thickness (d4), transverse magnetic (TM) mode's order, and amplified angle parameter (Δ) is studied on the sensor's performance. Parameters such as sensitivity, resolution, and figure of merit have been considered for sensor's performance evaluation. The results indicate that in the conventional weak measurements, for a TM1 mode (with d4 = 20 µm, B = 0, and Δ = 0.1°), an RI resolution of 2.32 × 10-12 RIU is achievable for gas medium in the range 1-1.1 RIU. In the modified weak measurements, for a TM3 mode (with d4 = 100 µm, B = 0, and Δ = 0.1°), the RI resolution close to 1.39 × 10-10 RIU is achievable for gas sensing. The same sensor design was also studied for magnetic field sensing while keeping the value of gaseous medium RI (n4) as 1. The results indicate that for a TM1 mode (with d4 = 20 µm and Δ = 0.1°), in the conventional weak measurements, a magnetic field resolution of 5.31 × 10-4 µT (i.e., 0.53 nT) is achievable for a range 0-1 T of B. Further, it is found that in contrast with the conventional case, the resolutions in the modified weak measurements are improved for large values of the Δ. Some of the results emerge better or comparable with the resolutions of RI and magnetic field measurement (5 × 10-9 RIU and 0.7 µT or 1.22 × 10-11 RIU and 1.46 × 10-2 µT) existing in the literature.

Bifunctional compounds for controlling metal-mediated aggregation of the aß42 peptide.

Abnormal interactions of Cu and Zn ions with the amyloid ß (Aß) peptide are proposed to play an important role in the pathogenesis of Alzheimer's disease (AD). Disruption of these metal-peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu(2+) and Zn(2+) and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward Aß species. Both compounds are efficient inhibitors of the metal-mediated aggregation of the Aß(42) peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble Aß(42) oligomers in the presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the Aß(42) peptide-in contrast to the Aß(40) peptide-the previously employed strategy of inhibiting Aß aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Aß(42) oligomers.