Protein bioelectronics: a review of what we do and do not know.

We review the status of protein-based molecular electronics. First, we define and discuss fundamental concepts of electron transfer and transport in and across proteins and proposed mechanisms for these processes. We then describe the immobilization of proteins to solid-state surfaces in both nanoscale and macroscopic approaches, and highlight how different methodologies can alter protein electronic properties. Because immobilizing proteins while retaining biological activity is crucial to the successful development of bioelectronic devices, we discuss this process at length. We briefly discuss computational predictions and their connection to experimental results. We then summarize how the biological activity of immobilized proteins is beneficial for bioelectronic devices, and how conductance measurements can shed light on protein properties. Finally, we consider how the research to date could influence the development of future bioelectronic devices.

A rigorous statistical framework for spatio-temporal pollution prediction and estimation of its long-term impact on health.

In the United Kingdom, air pollution is linked to around 40000 premature deaths each year, but estimating its health effects is challenging in a spatio-temporal study. The challenges include spatial misalignment between the pollution and disease data; uncertainty in the estimated pollution surface; and complex residual spatio-temporal autocorrelation in the disease data. This article develops a two-stage model that addresses these issues. The first stage is a spatio-temporal fusion model linking modeled and measured pollution data, while the second stage links these predictions to the disease data. The methodology is motivated by a new five-year study investigating the effects of multiple pollutants on respiratory hospitalizations in England between 2007 and 2011, using pollution and disease data relating to local and unitary authorities on a monthly time scale.

Quantifying the impact of current and future concentrations of air pollutants on respiratory disease risk in England.

BACKGROUND: Estimating the long-term health impact of air pollution in a spatio-temporal ecological study requires representative concentrations of air pollutants to be constructed for each geographical unit and time period. Averaging concentrations in space and time is commonly carried out, but little is known about how robust the estimated health effects are to different aggregation functions. A second under researched question is what impact air pollution is likely to have in the future. METHODS: We conducted a study for England between 2007 and 2011, investigating the relationship between respiratory hospital admissions and different pollutants: nitrogen dioxide (NO2); ozone (O3); particulate matter, the latter including particles with an aerodynamic diameter less than 2.5 micrometers (PM2.5), and less than 10 micrometers (PM10); and sulphur dioxide (SO2). Bayesian Poisson regression models accounting for localised spatio-temporal autocorrelation were used to estimate the relative risks (RRs) of pollution on disease risk, and for each pollutant four representative concentrations were constructed using combinations of spatial and temporal averages and maximums. The estimated RRs were then used to make projections of the numbers of likely respiratory hospital admissions in the 2050s attributable to air pollution, based on emission projections from a number of Representative Concentration Pathways (RCP). RESULTS: NO2 exhibited the largest association with respiratory hospital admissions out of the pollutants considered, with estimated increased risks of between 0.9 and 1.6% for a one standard deviation increase in concentrations. In the future the projected numbers of respiratory hospital admissions attributable to NO2 in the 2050s are lower than present day rates under 3 Representative Concentration Pathways (RCPs): 2.6, 6.0, and 8.5, which is due to projected reductions in future NO2 emissions and concentrations. CONCLUSIONS: NO2 concentrations exhibit consistent substantial present-day health effects regardless of how a representative concentration is constructed in space and time. Thus as concentrations are predicted to remain above limits set by European Union Legislation until the 2030s in parts of urban England, it will remain a substantial health risk for some time.

Electron transport via a soluble photochromic photoreceptor.

Electron transport properties via a photochromic biological photoreceptor have been studied in junctions of monolayer assemblies in solid-state configurations. The photoreceptor studied was a member of the LOV domain protein family with a bound flavin chromophore, and its photochemically inactive mutant due to change of a crucial cysteine residue by a serine. The photochemical properties of the protein were maintained in dry, solid state conditions, indicating that the proteins in the junctions were assembled in native state-like conditions. Significant current magnitudes (>20 µA at 1.0 V applied bias) were observed with a mechanically deposited gold pad (area ∼0.002 cm2) as top electrode. The current magnitudes are ascribed to electrode-cofactor coupling originating from the apparent perpendicular orientation of the protein's cofactor embedded between the electrodes, and its proximity to the electrodes. Temperature independent electron transport across the protein monolayers demonstrated that solid-state electron transport is dominated by tunneling. Modulation of the observed current by illumination of the wildtype protein suggested conformation-dependent electron conduction efficiency across the solid-state protein junctions.

Conjugated Cofactor Enables Efficient Temperature-Independent Electronic Transport Across ∼6 nm Long Halorhodopsin.

We observe temperature-independent electron transport, characteristic of tunneling across a ∼6 nm thick Halorhodopsin (phR) monolayer. phR contains both retinal and a carotenoid, bacterioruberin, as cofactors, in a trimeric protein-chromophore complex. This finding is unusual because for conjugated oligo-imine molecular wires a transition from temperature-independent to -dependent electron transport, ETp, was reported at ∼4 nm wire length. In the ∼6 nm long phR, the ∼4 nm 50-carbon conjugated bacterioruberin is bound parallel to the α-helices of the peptide backbone. This places bacterioruberin's ends proximal to the two electrodes that contact the protein; thus, coupling to these electrodes may facilitate the activation-less current across the contacts. Oxidation of bacterioruberin eliminates its conjugation, causing the ETp to become temperature dependent (>180 K). Remarkably, even elimination of the retinal-protein covalent bond, with the fully conjugated bacterioruberin still present, leads to temperature-dependent ETp (>180 K). These results suggest that ETp via phR is cooperatively affected by both retinal and bacterioruberin cofactors.

Why lead methylammonium tri-iodide perovskite-based solar cells require a mesoporous electron transporting scaffold (but not necessarily a hole conductor).

CH3NH3PbI3-based solar cells were characterized with electron beam-induced current (EBIC) and compared to CH3NH3PbI(3-x)Clx ones. A spatial map of charge separation efficiency in working cells shows p-i-n structures for both thin film cells. Effective diffusion lengths, LD, (from EBIC profile) show that holes are extracted significantly more efficiently than electrons in CH3NH3PbI3, explaining why CH3NH3PbI3-based cells require mesoporous electron conductors, while CH3NH3PbI(3-Clx ones, where LD values are comparable for both charge types, do not.

Odd-even effect in molecular electronic transport via an aromatic ring.

A distinct odd-even effect on the electrical properties, induced by monolayers of alkyl-phenyl molecules directly bound to Si(111), is reported. Monomers of H2C═CH-(CH2)n-phenyl, with n = 2-5, were adsorbed onto Si-H and formed high-quality monolayers with a binding density of 50-60% Si(111) surface atoms. Molecular dynamics simulations suggest that the binding proximity is close enough to allow efficient π-π interactions and therefore distinctly different packing and ring orientations for monomers with odd or even numbers of methylenes in their alkyl spacers. The odd-even alternation in molecular tilt was experimentally confirmed by contact angle, ellipsometry, FT-IR, and XPS with a close quantitative match to the simulation results. The orientations of both the ring plane and the long axis of the alkyl spacer are more perpendicular to the substrate plane for molecules with an even number of methylenes than for those with an odd number of methylenes. Interestingly, those with an even number conduct better than the effectively thinner monolayers of the molecules with the odd number of methylenes. We attribute this to a change in the orientation of the electron density on the aromatic rings with respect to the shortest tunneling path, which increases the barrier for electron transport through the odd monolayers. The high sensitivity of molecular charge transport to the orientation of an aromatic moiety might be relevant to better control over the electronic properties of interfaces in organic electronics.

Impact of right ventricular failure on the outcomes of acute inferior wall myocardial infarction.

Aim: Right ventricular failure (RVF) complicates 30-50% of cases with inferior wall myocardial infarctions (IWMI). Large-scale studies exploring the recent trends in morbidity and mortality of IWMI with RVF in the context of improved reperfusion strategies are currently lacking. Materials & methods: The International Classification of Diseases, Tenth Revision, Clinical Modification codes were used to query the National Inpatient Sample of 2018-2019 to yield IWMI admissions and stratified based on presence of RVF. The primary outcome was in-hospital mortality. Results: Out of the 182,485 weighed hospital admissions for IWMI, 1005 patients (0.6%) also had RVF. Patients with both IWMI and RVF had significantly higher mortality than patients with IWMI and no RVF (p < 0.001). Conclusion: RVF in patients with IWMI is an independent predictor of poor outcomes.

What is this article about? Right ventricular failure (RVF) refers to a condition in which the right ventricle is unable to pump blood to the left side of the heart. Up to 30­50% of patients with heart attacks, commonly known as acute myocardial infarction, affecting the back or the inferior wall of the heart (IWMI) can develop RVF. Research studies assessing the outcomes of patients with IWMI and RVF were done either in a small number of patients or done during the time when the current standard of acute myocardial infarction care was not the standard of care. Therefore, we conducted a study to assess the clinical outcomes of patients with IWMI and RVF in contemporary times.What are the results? We found that among all patients with IWMI, only about 0.6% had evidence of RVF. However, these patients were older and much more likely to have a higher burden of chronic medical problems and were less likely to have received angioplasty to open blocked arteries when compared with patients with IWMI and no RVF. Patients with IWMI and RVF were noticed to have a higher rate of death during hospitalization.What do the results mean? Patients with IWMI and RVF, when compared with patients with IWMI and no RVF, had significantly higher rates of various complications and death.

GPTFX: A Novel GPT-3 Based Framework for Mental Health Detection and Explanations.

This paper introduces a novel approach GPTFX, an AI-based mental detection with GPT frameworks. This approach leverages GPT embeddings and the fine-tuning of GPT-3. This approach exhibits superior performance in both classifying mental health disorders and generating explanations with accuracy of around 87% in classification and Rouge-L of around 0.75. We utilized GPT embeddings with machine learning models for the classification of mental health disorders. Additionally, GPT-3 was fine-tuned for generating explanations related to the predictions made by these machine learning models. Notably, the proposed algorithm proves well-suited for real-time monitoring of mental health by deploying in AI-IoMT devices, as it has demonstrated greater reliability when compared to traditional algorithms.

Polarity-Induced Morphological Transformation with Tunable Optical Output of Terpyridine-Phenanthro[9,10-d]imidazole-Based Ligand and Its Zn(II) Complexes with I-V Characteristics.

Self-assembled nanostructures obtained from various functional π-conjugated organic molecules have been able to draw substantial interest due to their inherent optical properties, which are imperative for developing optoelectronic devices, multiple-color-emitting devices with color-tunable displays, and optical sensors. These π-conjugated molecules have proven their potential employment in various organic electronic applications. Therefore, the stimuli-responsive fabrication of these π-conjugated systems into a well-ordered assembly is extremely crucial to tuning their inherent optical properties for improved performance in organic electronic applications. To this end, herein, we have designed and synthesized a functional π-conjugated molecule (TP) having phenanthro[9,10-d]imidazole with terpyridine substitution at the 2 position and its corresponding metal complexes (TPZn and (TP)2Zn). By varying the polarity of the self-assembly medium, TP, TPZn, and (TP)2Zn are fabricated into well-ordered superstructures with morphological individualities. However, this medium polarity-induced self-assembly can tune the inherent optical properties of TP, TPZn, and (TP)2Zn and generate multiple fluorescence colors. Particularly, this property makes them useful for organic electronic applications, which require adjustable luminescence output. More importantly, in 10% aqueous-THF medium, TPZn exhibited H-type aggregation-induced white light emission and behaved as a single-component white light emitter. The experimentally obtained results of the solvent polarity-induced variation in optical properties as well as self-assembly patterns were further confirmed by theoretical investigation using density functional theory calculations. Furthermore, we investigated the I-V characteristics, both vertical and horizontal, using ITO and glass surfaces coated with TP, TPZn, and (TP)2Zn, respectively, and displayed maximum current density for the TPZn-coated surface with the order of measured current density TPZn > TP > (TP)2Zn. This observed order of current density measurements was also supported by a direct band gap calculation associated with the frontier molecular orbitals using the Tauc plot. Hence, solvent polarity-induced self-assembly behavior with adjustable luminescence output and superior I-V characteristics of TPZn make it an exceptional candidate for organic electronic applications and electronic device fabrication.

Improved Charge Transport across Bovine Serum Albumin-Au Nanoclusters' Hybrid Molecular Junction.

Proteins, a highly complex substance, have been an essential element in living organisms, and various applications are envisioned due to their biocompatible nature. Apart from proteins' biological functions, contemporary research mainly focuses on their evolving potential associated with nanoscale electronics. Here, we report one chemical doping process in model protein molecules (BSA) to modulate their electrical conductivity by incorporating metal (gold) nanoclusters on the surface or within them. The as-synthesized Au NCs incorporated inside the BSA (Au 1 to Au 6) were optically well characterized with UV-vis, time-resolved photoluminescence (TRPL), X-ray photon spectroscopy, and high-resolution transmission electron microscopy techniques. The PL quantum yield for Au 1 is 6.8%, whereas that for Au 6 is 0.03%. In addition, the electrical measurements showed ∼10-fold enhancement of conductivity in Au 6 (8.78 × 10-3 S/cm), where maximum loading of Au NCs was predicted inside the protein matrix. We observed a dynamic behavior in the electrical conduction of such protein-nanocluster films, which could have real-time applications in preparing biocompatible electronic devices.

Impact of Pulmonary Hypertension in Patients With Hypertrophic Cardiomyopathy Presented With Cardiogenic Shock/Acute Decompensated Heart Failure.

There have been no studies focusing on how pulmonary hypertension (PH) affects inpatient outcomes in patients with hypertrophic cardiomyopathy (HCM) hospitalized for acute decompensated heart failure or cardiogenic shock. This study explores inpatient outcomes of patients with HCM, and concomitant PH compared to patients with HCM. Based on the National Inpatient Sample (NIS) 2016-2018, patients admitted with a primary diagnosis of acute decompensated heart failure or cardiogenic shock were selected. The patients diagnosed with concomitant HCM were identified and divided into 2 groups based on the presence or absence of PH. After propensity matching 1545 matched pairs were generated. Patients with PH had a higher prevalence of chronic kidney disease (P < 0.001), anemia (P < 0.001), coagulopathy (P < 0.001), atrial fibrillation (P = 0.031), and valvular disease (P < 0.001) (Table 1). The primary outcome (all-cause in-hospital mortality) occurred in 110 patients (2.6%) without PH and 95 patients (5.2%) with PH, which was not statistically significant after propensity matching (odds ratio [OR]:1.53; 95% confidence interval [CI]: 0.70-3.33; P = 0. 28) (Table 3). Patients with PH had a higher incidence of transient ischemic attack (TIA) (OR: 9.52; 95% CI: 3.38-26.78; P < 0.001)] and respiratory failure [(OR: 1.49; 95% CI:1.05-2.11; P = 0.027], although with no difference in requirement for mechanical ventilation (= 0.64), as compared to patients without PH. PH in patients with HCM is associated with increased morbidity, including increased risk of TIA and respiratory failure.

Characteristic noise features in light transmission across membrane protein undergoing photocycle.

We demonstrate a technique based on noise measurements which can be utilized to study dynamical processes in protein assembly. Direct visualization of dynamics in membrane protein system such as bacteriorhodopsin (bR) upon photostimulation are quite challenging. bR represents a model system where the stimulus-triggered structural dynamics and biological functions are directly correlated. Our method utilizes a pump-probe near field microscopy method in the transmission mode and involves analyzing the transmittance fluctuations from a finite size of molecular assembly. Probability density distributions indicating the effects of finite size and statistical correlations appear as a characteristic frequency distribution in the noise spectra of bR whose origin can be traced to photocycle kinetics. Valuable insight into the molecular processes were obtained from the noise studies of bR and its mutant D96N as a function of external parameters such as temperature, humidity or presence of an additional pump source.

Newer Horizon for Treatment of Acute Attack of Migraine: Lasmiditan and Ubrogepant.

Migraine is characterized by severe, intermittent headache attacks with associated symptoms including nausea, vomiting, phonophobia, and photophobia. Still Triptans (selective 5-HT1B/D agonists) are considered as the first-line therapy in acute attack of migraine. Recently two new drugs Lasmiditan and Ubrogepant were approved by United States Food and Drug Administration in acute attack of migraine with or without aura in adults. Lasmiditan is a highly selective 5-HT1F receptor agonist which demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed phase-3 trials, SAMURAI and SPARTAN. Ubrogepant is a novel small molecule oral calcitonin gene-related peptide receptor antagonist. The approval was supported by two pivotal phase-3, randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II) that evaluated the efficacy, safety, tolerability. Hopefully, these two drugs may soon be a new addition to the mounting armory of drugs against migraine and may fulfill a substantial unmet need.

Selumetinib: the first ever approved drug for neurofibromatosis-1 related inoperable plexiform neurofibroma.

Plexiform neurofibroma (PN) is one of the most striking clinical features of neurofibromatosis 1. Growth of PN can occur at any stage of life but mostly in childhood and during hormonal changes. They arise from multiple nerve fascicles and may transform into malignant peripheral nerve sheath tumors. There was previously no approved medical therapy for tumor shrinkage or regression. Surgery is not always possible due to inaccessible location, involvement of vital tissue, optimal timing, and incomplete removal. Recently, the US Food and Drug Administration approved selumetinib for pediatric patients, 2 years of age and older, with neurofibromatosis type 1 who have symptomatic, inoperable tumor. Neurofibromin, a 2818 amino acid long cytoplasmic protein, is the product of the NF1 gene. It inhibits the activity of Ras GTPase proteins. Lack of functional neurofibromin in patients with NF1 leads to dysregulated Ras and tumorigenesis. RAS MAPK pathway is hyper activated in NF1. Selumetinib is an inhibitor of MEK1 and MEK2 proteins, which play an important role in the MAPK signaling pathway related to tumor growth. Approval was based on one pivotal, single-arm, phase II trial. 70% of participants experienced confirmed partial response of tumor shrinkage, and 68% also had improvement of related complications, and other studies have also shown beneficial responses. The major limitation of this molecule regarding its mechanism of action is the dose-dependent effect of MEK inhibition in growth of neurofibroma. Long-term safety and efficacy studies are to be done in the future to establish selumetininb as a useful medicine.

Monitoring intermediate states of bacteriorhodopsin monolayers using near-field optical microscopy.

We demonstrate single-molecule-level features using near-field optical microscopy on bacteriorhodopsin (bR), a membrane protein that functions as a light-driven proton pump. The photophysical properties of bR are utilized in this imaging technique, using a combination of photoexcitation sources, to accurately identify the active regions and quantify the optical parameters. The studies of bR monolayers are carried out on inert quartz substrates as well as active conducting polymer (polyaniline) substrates. The substrate also plays an important role in the photocycle quantum efficiencies. We speculate on mechanisms governing the higher near-field absorption strength of bR molecules.

A Randomized Controlled Trial to Compare the Efficacy, Safety and Tolerability of Asenapine versus Olanzapine in Management of Schizophrenia.

OBJECTIVE: : Schizophrenia is a serious disease characterized by impairment in the perception or expression of reality, leading to occupational and social dysfunction. The use of antipsychotic medication is now universal in the first-line treatment of schizophrenia. This study was undertaken to compare the efficacy of asenapine with a standard atypical antipsychotic, olanzapine in treating this disease. METHODS: It was designed as a single blind, randomized, controlled, parallel group, single centre Phase IV trial of a newer atypical antipsychotic, asenapine versus existing standard atypical antipsychotic, olanzapine. Total 80 subjects were enrolled as per eligibility criteria.Each recruited subject received daily treatment with the trial medication (Olanzapine 10 mg or Asenapine 10 mg daily) for duration of 12 weeks. BPRS, CGI-S, CGI-I, Laboratory parameters and compliance was assessed and analyzed. Continuous variables were compared by t test and non-parametric data was analyzed by Mann-Whitney U test and Wilcoxon signed rank test. Likely categorical variables were analyzed by chi-square test or Fisher's exact test, as appropriate. RESULTS: The duration of schizophrenia at presentation was comparable in both the treatment groups. There was significant reduction of BPRS score between any two visits of each treatment groups. The decline in CGI-S and CGI-I scores was statistically significant (p < 0.001) when compared between visits of any of the both treatment arms. Adherence to treatment was excellent for all patients. CONCLUSION: Newer atypical antipsychotic asenapine is more effective than standard olanzapine in reducing the symptoms of schizophrenia in this study and further larger studies are to be done.

Solid-State Protein Junctions: Cross- Laboratory Study Shows Preservation of Mechanism at Varying Electronic Coupling.

Successful integration of proteins in solid-state electronics requires contacting them in a non-invasive fashion, with a solid conducting surface for immobilization as one such contact. The contacts can affect and even dominate the measured electronic transport. Often substrates, substrate treatments, protein immobilization, and device geometries differ between laboratories. Thus the question arises how far results from different laboratories and platforms are comparable and how to distinguish genuine protein electronic transport properties from platform-induced ones. We report a systematic comparison of electronic transport measurements between different laboratories, using all commonly used large-area schemes to contact a set of three proteins of largely different types. Altogether we study eight different combinations of molecular junction configurations, designed so that Ageoof junctions varies from 105 to 10-3 µm2. Although for the same protein, measured with similar device geometry, results compare reasonably well, there are significant differences in current densities (an intensive variable) between different device geometries. Likely, these originate in the critical contact-protein coupling (∼contact resistance), in addition to the actual number of proteins involved, because the effective junction contact area depends on the nanometric roughness of the electrodes and at times, even the proteins may increase this roughness. On the positive side, our results show that understanding what controls the coupling can make the coupling a design knob. In terms of extensive variables, such as temperature, our comparison unanimously shows the transport to be independent of temperature for all studied configurations and proteins. Our study places coupling and lack of temperature activation as key aspects to be considered in both modeling and practice of protein electronic transport experiments.

Rainfall trends and variation in the Maasai Mara ecosystem and their implications for animal population and biodiversity dynamics.

Rainfall exerts a controlling influence on the availability and quality of vegetation and surface water for herbivores in African terrestrial ecosystems. We analyse temporal trends and variation in rainfall in the Maasai Mara ecosystem of East Africa and infer their implications for animal population and biodiversity dynamics. The data originated from 15 rain gauges in the Mara region (1965-2015) and one station in Narok Town (1913-2015), in Kenya's Narok County. This is the first comprehensive and most detailed analysis of changes in rainfall in the region of its kind. Our results do not support the current predictions of the International Panel of Climate Change (IPCC) of very likely increases of rainfall over parts of Eastern Africa. The dry season rainfall component increased during 1935-2015 but annual rainfall decreased during 1962-2015 in Narok Town. Monthly rainfall was more stable and higher in the Mara than in Narok Town, likely because the Mara lies closer to the high-precipitation areas along the shores of Lake Victoria. Predominantly deterministic and persistent inter-annual cycles and extremely stable seasonal rainfall oscillations characterize rainfall in the Mara and Narok regions. The frequency of severe droughts increased and floods intensified in the Mara but droughts became less frequent and less severe in Narok Town. The timings of extreme droughts and floods coincided with significant periodicity in rainfall oscillations, implicating strong influences of global atmospheric and oceanic circulation patterns on regional rainfall variability. These changing rainfall patterns have implications for animal population dynamics. The increase in dry season rainfall during 1935-2015 possibly counterbalanced the impacts of resource scarcity generated by the declining annual rainfall during 1965-2015 in Narok Town. However, the increasing rainfall extremes in the Mara can be expected to create conditions conducive to outbreaks of infectious animal diseases and reduced vegetation quality for herbivores, particularly when droughts and floods persist over multiple years. The more extreme wet season rainfall may also alter herbivore space use, including migration patterns.

Tissue multifractality and hidden Markov model based integrated framework for optimum precancer detection.

We report the application of a hidden Markov model (HMM) on multifractal tissue optical properties derived via the Born approximation-based inverse light scattering method for effective discrimination of precancerous human cervical tissue sites from the normal ones. Two global fractal parameters, generalized Hurst exponent and the corresponding singularity spectrum width, computed by multifractal detrended fluctuation analysis (MFDFA), are used here as potential biomarkers. We develop a methodology that makes use of these multifractal parameters by integrating with different statistical classifiers like the HMM and support vector machine (SVM). It is shown that the MFDFA-HMM integrated model achieves significantly better discrimination between normal and different grades of cancer as compared to the MFDFA-SVM integrated model.