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Abstract Many studies have documented racial, socioeconomic, geographic, and other disparities for United States (US) patients with multiple myeloma pertaining to diagnosis and frontline management. In contrast, very little is known about disparities in the management of relapsed/refractory multiple myeloma (RRMM) despite a plethora of novel treatment options. In this review, we discuss the manifestations of disparities in RRMM and strategies to mitigate their impact. Immunomodulatory drugs can create disparities on many axes, for example inappropriately low dosing due to Duffy-null status as well as time toxicity and financial toxicity from logistical hurdles for socioeconomically vulnerable patients. Access to myeloma expertise at high-volume centers is a critical consideration given the disconnect between how drugs like carfilzomib and dexamethasone are prescribed in trials versus optimized in real-world practice to lower toxicities. Disparities in chimeric antigen receptor T-cell therapy and bispecific antibody therapy span across racial, ethnic, and socioeconomic lines in large part due to their limited availability outside of high-volume centers. Another insidious source of disparities is supportive care in RRMM, ranging from inadequate pain control in Black patients to limited primary care provider access in rural settings. We discuss the rationales and evidence base for several solutions aimed at mitigating these disparities: for example, (1) bidirectional co-management with community-based oncologists, (2) screening for risk factors based on social determinants of health, (3) strategies to build patient trust with regard to clinical trials, and (4) longitudinal access to a primary care provider. As the treatment landscape for RRMM continues to expand, these types of efforts by the field will help ensure that this landscape is equally accessible and traversable for all US patients.

Abstract We present a patient with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome who had a dramatic and sustained elevation in plasma vascular endothelial growth factor (VEGF) levels from 182 to 740 pg/mL while on lenalidomide‐dexamethasone therapy. Given his biochemical evidence of progression, second‐line daratumumab was added. In hindsight, a concurrent influenza A infection was the likely driver of his VEGF elevation rather than his underlying POEMS syndrome. Given the importance of longitudinal VEGF monitoring and the infectious risks of plasma cell therapies, our case highlights the need for caution with POEMS response assessments in the setting of a respiratory viral infection.

Abstract Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18–70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p

The present study explores the prospects of operational stability of dual fuel operation comprehensively, considering that; methanol and diesel are of two different kinds which exhibit different combustion processes. To this effect, investigating the stability of engine operation under such condition becomes important. In this investigation, the harshness of the operation and the non-repeatability of the combustion cycles are examined, which have been identified as the major stability indicator in many studies. Such stability indices are characterized in this study through a comprehensive set of parameters, including of maximum pressure rise rate (ROPRmax) and coefficient of variation of indicated mean effective pressure (COVIMEP); and of peak pressure (COVPP) and crank angle of 50% mass fraction burn (COVCA50). The experimental investigation is carried out under a split injection strategy by varying injection timings as well as injection mass percentages at predefined methanol injection durations. It is shown that the partially premixed mode under the split injection strategy exhibits significant potential in reducing the harshness of operation indicated by lower peak pressure rise and increasing the repeatability of the combustion cycles implied by the substantially lower scores of the considered parameters for mapping stability.

Traditional prognostic models for newly diagnosed patients with multiple myeloma (MM), including International Staging System criteria and number of high-risk chromosomal abnormalities, are based on disease characteristics at diagnosis. However, the identification of patients at risk of more rapidly progressive MM is inherently a dynamic assessment. In a subset of patients with MM, adverse disease biology only becomes evident after the failure of first-line therapy. We define this entity as functional high-risk MM (FHRMM), encompassing relapse within 18 months of treatment initiation and/or within 12 months of frontline autologous stem cell transplantation. FHRMM is not adequately captured by traditional prognostic models, and there is a need for better understanding of mechanisms or risk factors for early relapse or progression. In this review, we explore potential definitions of FHRMM before delving into its underlying drivers based on genetic, transcriptomic, and immune cell profiling studies. Emerging data suggest that specific features of both myeloma cells and immune cells can enable the FHRMM phenotype. We conclude our review by discussing ongoing and future studies that seek to identify and intervene upon patients with FHRMM preemptively.

Summary The damage caused by stink bugs that feed on agricultural crops accounts for such significant losses that transgenic plant resistance to stink bugs would be highly desirable. As the level of toxicity of the Bacillus thuringiensis‐derived, ETX/Mtx2 pesticidal protein Mpp83Aa1 is insufficient for practical use against the southern green stink bug Nezara viridula, we employed two disparate approaches to isolate peptides NvBP1 and ABP5 that bind to specific proteins (alpha amylase and aminopeptidase N respectively) on the surface of the N. viridula gut. Incorporation of these peptides into Mpp83Aa1 provided artificial anchors resulting in increased gut binding, and enhanced toxicity. These peptide‐modified pesticidal proteins with increased toxicity provide a key advance for potential future use against N. viridula when delivered by transgenic plants to mitigate economic loss associated with this important pest.

Abstract Renal dysfunction in patients with acute myeloid leukemia (AML) can be multifactorial. We present the case of a 72‐year‐old male with relapsed myelomonocytic AML who presented with transient acute kidney injury (AKI) and severe persistent electrolyte derangements. In the setting of nephrotic‐range proteinuria and electrolyte wasting without significant albuminuria or glucosuria, a diagnosis of lysozymuria was made. Lysozymuria is a rare paraneoplastic complication of AML and chronic myelomonocytic leukemia characterized by lysozyme. This represents the first case of lysozymuria presenting primarily with refractory electrolyte derangements rather than severe AKI. Lysozymuria portends a poor clinical prognosis even with aggressive management.

Abstract Paraneoplastic coagulopathies are uncommon in patients with lymphoma. We report the first case of an acquired coagulopathy in a patient with isolated primary central nervous system lymphoma (PCNSL) demonstrating large‐cell histology. In our patient, a paraneoplastic factor VII inhibitor significantly delayed a diagnostic lumbar puncture despite fresh frozen plasma and inactivated prothrombin complex concentrate. While her coagulopathy was effectively overcome with recombinant activated factor VIIa and subsequently with lymphoma‐directed therapy, her delayed diagnosis likely contributed to a poor outcome. Our case highlights the importance of rapidly identifying and correcting paraneoplastic coagulopathies when PCNSL is suspected.

Abstract Hematologic malignancy outcomes have remarkably improved in the past decade with further advancement expected in future years. However, the detrimental effects of financial toxicity (FT) on patients with hematologic malignancies, because of both diagnoses and subsequent treatments, have not been studied comprehensively. We performed a systematic review of all studies reporting FT as a primary or secondary outcome among adult or pediatric patients with hematological malignancies. A total of 55 studies met the inclusion criteria for analysis. Across studies, 20–50% of patients reported some form of FT, including loss of work productivity, food and transportation costs, and depletion of savings. Younger age, lower-income level, unemployment, and rural residence were the most commonly identified risk factors for FT. Two studies looked at survival outcomes, with one reporting improvement in survival with a decrease in financial toxicity. However, significant heterogeneity in FT definitions was found between countries and payor systems. Only half of the studies (51%, n = 28) used validated survey instruments such as the COST assessment. The present systematic review identified that FT is common in patients with hematological malignancies and may be associated with poorer outcomes. However, studies of FT generally use non-standardized methods with cross-sectional analyses rather than longitudinal, prospective assessments. Further work is needed to standardize FT reporting and investigate measures to alleviate FT among patients with hematologic malignancies.

Autologous chimeric antigen receptor T-cell (CAR-T) therapies targeting B-cell maturation antigen (BCMA) have revolutionized the field of multiple myeloma in the same way that the Ford Model T revolutionized the original CAR world a century ago. However, we are only beginning to understand how to improve the efficacy and usability of these cellular therapies. In this review, we explore three automotive analogies for innovation with BCMA CAR-T therapies: stronger engines, better mileage, and hassle-free delivery. Firstly, we can build stronger engines in terms of BCMA targeting: improved antigen binding, tools to modulate antigen density, and armoring to better reach the antigen itself. Secondly, we can improve “mileage” in terms of response durability through ex vivo CAR design and in vivo immune manipulation. Thirdly, we can implement hassle-free delivery through rapid manufacturing protocols and off-the-shelf products. Just as the Model T set a benchmark for car manufacturing over 100 years ago, idecabtagene vicleucel and ciltacabtagene autoleucel have now set the starting point for BCMA CAR-T therapy with their approvals. As with any emerging technology, whether automotive or cellular, the best in innovation and optimization is yet to come.

Abstract In a recent multicenter analysis, long geographic distances predicted loss to follow‐up (LTF) among allogeneic hematopoietic cell transplantation (HCT) survivors. We hypothesized that lower frequencies of patient interactions (including in‐person appointments and telemedicine encounters) would predict LTF rather than long driving distances. However, in our retrospective single‐center analysis of 263 HCT survivors, the only predictors of LTF were residence in the furthest driving‐distance quartile and Medicaid insurance (but not annualized frequencies of patient interactions). Our findings suggest that telemedicine may not necessarily "rescue" long‐distance HCT survivors from LTF. Other solutions, for example patient‐specific partnerships with local providers, may be helpful.

Abstract Multiple myeloma patients undergoing autologous stem cell transplantation (ASCT) may receive benzodiazepine or zolpidem‐class (B/Z) medications despite their risks in older patients. Of 205 myeloma patients (36% aged 65+) who underwent ASCT at our institution between 2017 and 2018, we found that B/Z prescription rates for anxiety/insomnia rose significantly from 26% before ASCT to 38% at discharge and 39% at Day +100. B/Z initiation while hospitalized was a strong predictor of B/Z persistence at Day +100. Our findings highlight the role of these potentially inappropriate medications during hospitalizations for ASCT, a period where nonpharmacologic strategies for managing anxiety/insomnia may be feasible.

Abstract Background The fall armyworm (Spodoptera frugiperda (J.E. Smith)) is a highly polyphagous agricultural pest with long-distance migratory behavior threatening food security worldwide. This pest has a host range of > 80 plant species, but two host strains are recognized based on their association with corn (C-strain) or rice and smaller grasses (R-strain). The population genomics of the United States (USA) fall armyworm remains poorly characterized to date despite its agricultural threat. Results In this study, the population structure and genetic diversity in 55 S. frugiperda samples from Argentina, Brazil, Kenya, Puerto Rico and USA were surveyed to further our understanding of whole genome nuclear diversity. Comparisons at the genomic level suggest a panmictic S. frugiperda population, with only a minor reduction in gene flow between the two overwintering populations in the continental USA, also corresponding to distinct host strains at the mitochondrial level. Two maternal lines were detected from analysis of mitochondrial genomes. We found members from the Eastern Hemisphere interspersed within both continental USA overwintering subpopulations, suggesting multiple individuals were likely introduced to Africa. Conclusions Our research is the largest diverse collection of United States S. frugiperda whole genome sequences characterized to date, covering eight continental states and a USA territory (Puerto Rico). The genomic resources presented provide foundational information to understand gene flow at the whole genome level among S. frugiperda populations. Based on the genomic similarities found between host strains and laboratory vs. field samples, our findings validate the experimental use of laboratory strains and the host strain differentiation based on mitochondria and sex-linked genetic markers extends to minor genome wide differences with some exceptions showing mixture between host strains is likely occurring in field populations.

The yield of the crop is a complex function of a number of dependent traits, which makes yield prediction a statistically difficult task. A number of work on yield prediction using morphological characters already exists in the literature. Most of the work used statistical techniques such as linear regression and crop yield models, which assume a linear relationship between yield and the morphological traits; in actual practice, such a linear relationship is seldom achieved. With the advancement in the field of machine learning techniques, these methods can provide a viable alternative for dealing with nonlinear relationships for yield prediction. Globally, apples are the most consumed fruit. In this paper, attempts have been made to predict the yield of the apple crop using morphological traits. PCA was used for selection of the significant variables. These variables were later used as input variables in the ANN model with different hidden layers for predicting crop yield. The predictive performance of the model was evaluated using standard statistical tests. Sensitivity analysis was performed to find out the individual effects of each character on the apple yield. The study contributes to a better understanding of the complex relationships between crop yield and morphological traits.

BackgroundFor patients with multiple myeloma receiving high-dose chemotherapy followed by autologous stem cell transplantation (SCT), acute life disruptions and symptom burden may lead to worsened quality of life (QOL) and increased emotional distress. Digital life coaching (DLC), whereby trained coaches deliver personalized well-being–related support via phone calls and SMS text messaging, has been shown to improve QOL among SCT survivors. However, DLC has not been investigated during the acute peri-SCT period, which is generally characterized by symptomatic exacerbations and 2-week hospitalizations. ObjectiveWe launched a single-arm pilot study to investigate the feasibility of patient engagement with DLC during this intensive period. MethodsWe approached English-speaking adult patients with multiple myeloma undergoing autologous SCT at our center. Enrolled patients received 16 weeks of virtual access to a life coach beginning on day −5 before SCT. Coaches used structured frameworks to help patients identify and overcome personal barriers to well-being. Patients chose the coaching topics and preferred communication styles. Our primary endpoint was ongoing DLC engagement, defined as bidirectional conversations occurring at least once every 4 weeks during the study period. Secondary endpoints were electronic patient-reported outcome assessments of QOL, distress, and sleep disturbances. ResultsOf the 20 patients who were screened, 17 (85%) chose to enroll and 15 (75%) underwent SCT as planned. Of these 15 patients (median age 65 years, range 50-81 years), 11 (73%) demonstrated ongoing DLC engagement. The median frequency of bidirectional conversations during the 3-month study period was once every 6.2 days (range 3.9-28 days). During index hospitalizations with median lengths of stay of 16 days (range 14-31 days), the median frequency of conversations was once every 5.3 days (range 2.7-15 days). Electronic patient-reported outcome assessments (94% adherence) demonstrated an expected QOL nadir during the second week after SCT. The prevalence of elevated distress was highest immediately before and after SCT, with 69% of patients exhibiting elevated distress on day −5 and on day +2. ConclusionsDLC may be feasible for older patients during intensive hospital-based cancer treatments such as autologous SCT for multiple myeloma. The limitations of our study include small sample size, selection bias among enrolled patients, and heterogeneity in DLC use. Based on the positive results of this pilot study, a larger phase 2 randomized study of DLC during SCT is underway to investigate the efficacy of DLC with regard to patient well-being. Trial RegistrationClinicalTrials.gov NCT04432818; https://clinicaltrials.gov/ct2/show/NCT04432818.

The western corn rootworm (WCR), Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae), is an economically important pest of corn (maize) in North America and Europe. Current management practices for WCR involve transgenic expression of insecticidal proteins to minimize larval feeding damage to corn roots. The evolution of resistant WCR populations to transgenic corn expressing insecticidal proteins (e.g. Cry3Bb1, Gpp34Ab1/Tpp35Ab1) necessitates efforts to discover and deploy new modes of action for WCR control. Here, we tested the hypothesis that the addition of short peptides selected for binding to the WCR gut would restore insecticidal activity of Cry3Bb1 to resistant insects. Phage display technology coupled with deep sequencing was used to identify peptides selected for binding to WCR brush border membrane vesicles and to recombinant putative receptors aminopeptidase and cadherin. The binding and specificity of selected peptides was confirmed by ELISA and pull-down assays, and candidate gut surface binding partners were identified. Although production of 284 novel Cry3Bb1 variants with these peptides did not restore activity against resistant WCR in artificial diet bioassays, 112 variants were active against susceptible insects. These results provided insights for the mechanism of Cry3Bb1 activity and toward engineering a new mode-of-action via receptor re-targeting in the context of protein structure and function.

Previous cross-sectional studies reported positive effects of meditation on the brain areas related to attention and executive function in the healthy elderly population. Effects of long-term regular meditation in persons with mild cognitive impairment (MCI) and Alzheimer’s disease dementia (AD) have rarely been studied. In this study, we explored changes in cortical thickness and gray matter volume in meditation-naïve persons with MCI or mild AD after long-term meditation intervention. MCI or mild AD patients underwent detailed clinical and neuropsychological assessment and were assigned into meditation or non-meditation groups. High resolution T1-weighted magnetic resonance images (MRI) were acquired at baseline and after 6 months. Longitudinal symmetrized percentage changes (SPC) in cortical thickness and gray matter volume were estimated. Left caudal middle frontal, left rostral middle frontal, left superior parietal, right lateral orbitofrontal, and right superior frontal cortices showed changes in both cortical thickness and gray matter volume; the left paracentral cortex showed changes in cortical thickness; the left lateral occipital, left superior frontal, left banks of the superior temporal sulcus (bankssts), and left medial orbitofrontal cortices showed changes in gray matter volume. All these areas exhibited significantly higher SPC values in meditators as compared to non-meditators. Conversely, the left lateral occipital, and right posterior cingulate cortices showed significantly lower SPC values for cortical thickness in the meditators. In hippocampal subfields analysis, we observed significantly higher SPC in gray matter volume of the left CA1, molecular layer HP, and CA3 with a trend for increased gray matter volume in most other areas. No significant changes were found for the hippocampal subfields in the right hemisphere. Analysis of the subcortical structures revealed significantly increased volume in the right thalamus in the meditation group. The results of the study point out that long-term meditation practice in persons with MCI or mild AD leads to salutary changes in cortical thickness and gray matter volumes. Most of these changes were observed in the brain areas related to executive control and memory that are prominently at risk in neurodegenerative diseases.

Phage display libraries have been used to isolate insect gut binding peptides for use as pathogen transmission blocking agents, and to provide artificial anchors for increased toxicity of bacteria-derived pesticidal proteins. Previously, phage clones displaying enriched peptides were sequenced by Sanger sequencing. Here we present a streamlined protocol for identification of insect gut binding peptides, using insect-appropriate feeding strategies, with next generation sequencing and tailored bioinformatics analyses. The bioinformatics pipeline is designed to eliminate poorly enriched and false positive peptides, and to identify peptides predicted to be stable and hydrophilic. In addition to developing streamlined protocols, we also sought to address whether candidate gut binding peptides can bind to insects from more than one order, which is an important consideration for safe, practical use of peptide-modified pesticidal proteins. To this end, we screened phage display libraries for peptides that bind to the gut epithelia of two pest insects, the Asian citrus psyllid, Diaphorina citri (Hemiptera) and beet armyworm, Spodoptera exigua (Lepidoptera), and one beneficial insect, the western honey bee, Apis mellifera (Hymenoptera). While unique peptide sequences totaling 13,427 for D. citri, 89,561 for S. exigua and 69,053 for A. mellifera were identified from phage eluted from the surface of the insect guts, final candidate pools were comprised of 53, 107 and 1423 peptides respectively. The benefits of multiple rounds of biopanning, along with peptide binding properties in relation to practical use of peptide-modified pesticidal proteins for insect pest control are discussed.

BackgroundTreatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitro and in animal model experiments.Methodology/principalLeishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK).FindingsThe in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug.Conclusions/significanceAll experiments affirmed the efficacy of suramin against L. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.

Abstract Objective The rapid emergence of drug resistant Leishmanial strains makes it imperative to continue the development of cheap and effective drugs against the parasite. Due to the absence of effective vaccines against leishmaniasis, current therapeutic measures exclusively rely on chemotherapy. Here we attempt, to identify novel antileishmanial from a list of known drugs determined from a previous bioinformatics study. Synergism between various drug combinations (involving netilmicin, suramin, paromomycin and curcumin) have been estimated to identify potent multidrug therapies to combat the disease. Results The drugs were screened against Leishmania promastigotes by utilizing the MTT assay and against intracellular amastigotes using murine Macrophage like tumor cell, RAW 264.7 as a host. In vitro drug interactions were tested for several drug combinations with a modified fixed ratio isobologram method against both Leishmania major and Leishmania donovani. This work reports the in vitro antileishmanial activity for the aminoglycoside netilmicin (for some Leishmania parasites) and the anti-trypanosomatid suramin. Synergism was also observed between paromomycin–suramin and netilmicin–curcumin.

The formation of keto-enamine based crystalline, porous polymers in water is investigated for the first time. Facile access to the Schiff base reaction in water has been exploited to synthesize stable porous structures using the principles of Dynamic Covalent Chemistry (DCC). Most credibly, the water-based Covalent Organic Frameworks (COFs) possess chemical as well as physical properties such as crystallinity, surface area and porosity, which is comparable to their solvothermal counterparts. The formation of COFs in water is further investigated by understanding the nature of the monomers formed using hydroxy and non-hydroxy analogues of the aldehyde. This synthetic route paves a new way to synthesize COFs using a viable, greener route by utilization of the DCC principles in conjunction with the keto–enol tautomerism to synthesize useful, stable and porous COFs in water.

P2X3 receptor channels expressed in sensory neurons are activated by extracellular ATP and serve important roles in nociception and sensory hypersensitization, making them attractive therapeutic targets. Although several P2X3 structures are known, it is unclear how physiologically abundant Ca2+-ATP and Mg2+-ATP activate the receptor, or how divalent cations regulate channel function. We used structural, computational and functional approaches to show that a crucial acidic chamber near the nucleotide-binding pocket in human P2X3 receptors accommodates divalent ions in two distinct modes in the absence and presence of nucleotide. The unusual engagement between the receptor, divalent ion and the γ-phosphate of ATP enables channel activation by ATP-divalent complex, cooperatively stabilizes the nucleotide on the receptor to slow ATP unbinding and recovery from desensitization, a key mechanism for limiting channel activity. These findings reveal how P2X3 receptors recognize and are activated by divalent-bound ATP, aiding future physiological investigations and drug development.

The fall armyworm (Spodoptera frugiperda, J.E. Smith) is a noctuid moth that is a major and ubiquitous agricultural pest in the Western Hemisphere. Infestations have recently been identified in several locations in Africa, indicating its establishment in the Eastern Hemisphere where it poses an immediate and significant economic threat. Genetic methods were used to characterize noctuid specimens infesting multiple cornfields in the African nation of Togo that were tentatively identified as fall armyworm by morphological criteria. Species identification was confirmed by DNA barcoding and the specimens were found to be primarily of the subgroup that preferentially infests corn and sorghum in the Western Hemisphere. The mitochondrial haplotype configuration was most similar to that found in the Caribbean region and the eastern coast of the United States, identifying these populations as the likely originating source of the Togo infestations. A genetic marker linked with resistance to the Cry1Fa toxin from Bacillus thuringiensis (Bt) expressed in transgenic corn and common in Puerto Rico fall armyworm populations was not found in the Togo collections. These observations demonstrate the usefulness of genetic surveys to characterize fall armyworm populations from Africa.

Currently, considerable interest exists with regard to the dissociation of close packed aminoacids within proteins, in the course of unfolding, which could result in either wet or dry moltenglobules. The progressive disjuncture of residues constituting the hydrophobic core ofcyclophilin from L. donovani (LdCyp) has been studied during the thermal unfolding of the molecule, by molecular dynamics simulations. LdCyp has been represented as a surface contactnetwork (SCN) based on the surface complementarity (Sm) of interacting residues within themolecular interior. The application of Sm to side chain packing within proteins make it a very sensitive indicator of subtle perturbations in packing, in the thermal unfolding of the protein. Network based metrics have been defined to track the sequential changes in the disintegration ofthe SCN spanning the hydrophobic core of LdCyp and these metrics prove to be highly sensitive compared to traditional metrics in indicating the increased conformational (and dynamical) flexibility in the network. These metrics have been applied to suggest criteria distinguishing DMG, WMG and transition state ensembles and to identify key residues involved in crucial conformational/topological events during the unfolding process.

Designing a wearable driver assist system requires extraction of relevant features from physiological signals like galvanic skin response and photoplethysmogram collected from automotive drivers during real-time driving. In the discussed case, four stress-classes were identified using cascade forward neural network (CASFNN) which performed consistently with minimal intra- and inter-subject variability. Task-induced stress-trends were tracked using Triggs’ Tracking Variable-based regression model with CASFNN configuration. The proposed framework will enable proactive initiation of rescue and relaxation procedures during accidents and emergencies.