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Abstract Quantitative experiments are essential for investigating, uncovering, and confirming our understanding of complex systems, necessitating the use of effective and robust experimental designs. Despite generally outperforming other approaches, the broader adoption of model-based design of experiments (MBDoE) has been hindered by oversimplified assumptions and computational overhead. To address this, we present PARameter SEnsitivity Clustering (PARSEC), an MBDoE framework that identifies informative measurable combinations through parameter sensitivity (PS) clustering. We combined PARSEC with a new variant of Approximate Bayesian Computation-based parameter estimation for rapid, automated assessment and ranking of experiment designs. Using two kinetic model systems with distinct dynamical features, we show that PARSEC-based experiments improve the parameter estimation of a complex system. By its inherent formulation, PARSEC can account for experimental restrictions and parameter variability. Moreover, we demonstrate that there is a strong correlation between sample size and the optimal number of PS clusters in PARSEC, offering a novel method to determine the ideal sampling for experiments. This validates our argument for employing parameter sensitivity in experiment design and illustrates the potential to leverage both model architecture and system dynamics to effectively explore the experimental design space.

Abstract In this study, we analyze the dynamics of the interaction between dark matter and curvature-driven dark energy in viable f(R) gravity models using the framework of dynamical system analysis. We incorporate this interaction by introducing a source term in their respective continuity equations, given by $$Q = \frac{\kappa ^2 \alpha }{3\,H}\tilde{\rho }_\textrm{m}\rho _\textrm{curv}$$ Q = κ 2 α 3 H ρ ~ m ρ curv , and examine two f(R) gravity models that comply with local gravity constraints and cosmological viability criteria. Our findings reveal subtle modifications to fixed points and their stability criteria when compared to the conventional dynamical analysis of f(R) gravity models without matter-curvature interactions as proposed and examined in prior literature. We determine the parameter limits associated with the stability criteria of critical points of the dynamical system for both the models. Additionally, the introduction of interaction reveals variations in the dynamical aspects of cosmic evolution, contingent on the range of values for the relevant model parameters. These results are consistent with the observed features of cosmic evolution within specific limits of the f(R) models parameters and the coupling parameter $$\alpha $$ α . We also examine the evolutionary dynamics of the universe in the interacting scenario through cosmological and cosmographic parameters. Our analysis demonstrates that the interacting scenario comprehensively accounts for all the observed phases of the universe’s evolution and also results in a stable late-time cosmic acceleration. Additionally, we’ve studied how the coupling parameter affects evolutionary dynamics, particularly its impact on the matter-to-curvature energy density ratio. Our findings suggest that the chosen form of interaction can also address the cosmic coincidence problem.

Aims To identify the patterns of psychiatric help seeking behaviour among patients with psychotic illness presenting to mental health institute in Pakistan. Methods This Descriptive, Cross-Sectional Design comprised of a sample of 103 patients with psychotic diseases, chosen via non-probability – consecutive sampling at Outpatient Department of Sir Cowasjee Jehangir Institute of Psychiatry, Hyderabad. The relatives of psychotic patients who were between 18 and 65 years of age with either gender and living with at least one family member were interviewed after taking informed written consent. An anonymous self-structured questionnaire containing inquiries pertaining to basic biodata, sociodemographic details, psychiatric diagnosis and disease particulars, pattern of help seeking and time and reasons for delay. Results The mean age of the sample stood at 32 years (±9.5 SD). 1/3 of the sample comprised of male patients while only 24% were comprised of female population. The mean time elapsed after first episode psychosis till interview was 82 ± 32 months (7 years) while mean delay in help seeking to any helper was reported to be 41 ± 17 months (3.5 years). Majority of the patients approached first to faith healers (Aamil Baba, Witch Doctor, Pir, Religious Leader, Molvi, Imam or Religious Cleric) while only 1/5 of the patients approached to psychiatrists for treatment of first psychotic episode. The mean time duration to approach to psychiatrist after first episode psychosis was reported to be 73 ± 38 months (around 6 years). Conclusion The study showed that most frequent source of health care for psychiatric patients were faith healers (Aamil Baba, Witch Doctor, Pir, Religious Leader, Molvi, Imam or Religious Cleric) as compared with one-third who went to qualified healthcare providers like psychiatrists or physicians. There is a huge delay in proper help seeking among psychiatric patients. Health education aiming at increasing awareness among general population regarding treatment options for psychiatric illness is recommended to improve the quality of life of people living in our locality.

Introduction: The use of Ti6Al4V for orthopedic implants though widely accepted, is 10X stiffer than bone, that leads to stress shielding and aseptic loosening. Further, oral delivery demands significantly large dosage of drugs. To address these twin challenges, we have fabricated open cell porous scaffolds capable of sustained dual drug delivery. Drug delivery from open cell porous Ti6Al4V implants is a promising approach for in situ delivery in orthopedic and dental implant applications. Methodology: In this study, selective laser melting technology was used to fabricate open cell porous Ti6Al4V ELI scaffolds of 50 % volume fractions with Neovius architecture (NOCL). Electrochemical anodization was used to create micro and nano scale surface features for efficient drug loading. The two payloads: an osteogenic agent (Baicalein) and an anti-cancerous drug (Paclitaxel) were then loaded to different levels for differential release. An osteogenic agent was loaded in the nano reservoirs while paclitaxel was mixed with poloxamer and coated over the scaffold. Results: The mechanical stiffness of the designed NOCL lattices is approximately 1.29 ± 0.05 GPa, which is comparable to the human bone. This helps to reduce stress shielding effect. The scaffolds loaded with baicalein and paclitaxel yielded a sustained drug release profiles, releasing 57 % and 79 % of the pharmaceuticals over a 7-day period, respectively. Additionally, the baicalein-loaded nano reservoirs promote osteoblast differentiation in mesenchymal stem cells. As a result, bio-inspired 3D-printed open cell porous titanium scaffolds loaded with dual drugs offer a workable solution to the problems associated with orthopedic implants.

Pananterior urethral stricture involving the penile and bulbar urethra is a challenging urological condition in the Indian population. In India, Balanitis Xerotica Obliterans (BXO) or Lichen Sclerosus (LS) is the most common cause of pananterior urethral stricture. Various surgical techniques have been described in the literature for present condition, with varied outcomes. However, there is still a need for a simple and effective procedure to address this problem. Hereby, the authors present a case series that included five male patients with BXO and pananterior urethral stricture who underwent Detubularised Non Augmented (DNA) urethroplasty between January 2022 and December 2022. The median age of the patients was 45 years, with a mean stricture length of 13 cm. The median follow-up period was 11 months. During the procedure, a scroto-perineal incision was made, and the anterior urethra was ventrally cut open from the meatus to the junction of the stricturous and normal urethra. A right-sided Tunica Vaginalis (TV) flap was raised (left is left), and the cut-open anterior urethra was wrapped with the TV flap, creating a “controlled fistula” at the proximal end of the detubularised urethra. The average operative time was 1.5 hours. The success of the procedure was determined by a postoperative peak flow rate of 12 mL/sec or more, with no further need for urethral dilatation or direct vision internal urethrotomy. The procedure was successful in 4 out of 5 cases (80%). One patient developed a narrowed urethra during follow-up and required serial catheter upgradation for urethral dilatation. In conclusion, DNA urethroplasty was found to be a simple and effective treatment option for the notorious pananterior urethral stricture associated with BXO.

With the increasing demand for high-energy density motors for applications such as electric vehicles and aircraft propulsion, axial flux permanent magnet motors are promising. However, utmost care should be taken when designing an axial flux permanent magnet motor with a higher torque density because of thermal effects. To enhance the reliability and overall performance of a motor, efficient thermal management is important, because the torque density is restricted by maximum temperature. Therefore, this study comprehensively reviews different techniques used for the thermal modeling of motors. Computational fluid dynamics, the lumped parameter method, and finite element analysis were used to calculate the total heat transfer inside the motor. Various heat enhancement techniques for an axial flux permanent magnet motor have been presented, including core cooling (water jacket cooling, air cooling, and oil cooling) and winding cooling (direct slot cooling, end winding cooling, and fins). Finally, two case studies of an 8kW AFPM motor and a 65kW AFPM motor with a cooling arrangement are discussed.

Introduction: The Cancer Genome Atlas cohort of endometrial carcinoma (TCGA-UCEC) includes almost 40% TP53-mutants encompassing missense and truncated variants. TCGA revealed ‘POLE’, characterized by POLE gene bearing exonuclease domain mutation (EDM), as the prognostically best molecular profile. The worst profile was characterized by TP53-mutated Type 2 cancer requiring adjuvant therapy having cost implications in low-resource settings. We aimed to find more ‘POLE-like’ favourable subgroups by searching TCGA cohort, especially within TP53 mutated risk group, that could eventually avoid adjuvant treatment in resource-poor settings. Method: Our study was an in-silico survival analysis performed on the TCGA-UCEC dataset using SPSS statistical package. TP53 and POLE mutations, microsatellite instability (MSI), time-to-event and clinicopathological parameters were compared among 512 endometrial cancer cases. Deleterious POLE-mutations were identified by Polyphen2. Progression free survival was studied using Kaplan-Meier plots keeping original ‘POLE’ as comparator. Result: In presence of wild type (WT)-TP53, other deleterious POLE-mutations behaved like POLE-EDM. Only truncated and not missense TP53 benefitted from POLE/MSI overlap. However, TP53 missense mutation, Y220C, was found to be as favourable as ‘POLE’. Overlapping POLE, MSI and WT-TP53 also performed favourably. Truncated TP53 overlapped with POLE and/or MSI, TP53 Y220C alone and, WT-TP53 overlapped with POLE and MSI both, were named ‘POLE-like’ for prognostically behaving like the comparator ‘POLE’. Conclusion: Obesity being a lesser frequent event in low and middle-income countries (LMICs), relative proportion of women with lower BMI and Type 2 endometrial cancers may be high. Identification of ‘POLE-like’ groups may facilitate therapeutic de-escalation in some TP53-mutated cases - a novel option. Instead of 5% (POLE-EDM), potential beneficiary would then comprise 10% (POLE-like) of TCGA-UCEC.

More than a hundred thousand dengue cases are diagnosed in India annually, and about half of the country's population carries dengue virus-specific antibodies. Dengue propagates and adapts to the selection pressures imposed by a multitude of factors that can lead to the emergence of new variants. Yet, there has been no systematic analysis of the evolution of the dengue virus in the country. Here, we present a comprehensive analysis of all DENV gene sequences collected between 1956 and 2018 from India. We examine the spatio-temporal dynamics of India-specific genotypes, their evolutionary relationship with global and local dengue virus strains, interserotype dynamics and their divergence from the vaccine strains. Our analysis highlights the co-circulation of all DENV serotypes in India with cyclical outbreaks every 3-4 years. Since 2000, genotype III of DENV-1, cosmopolitan genotype of DENV-2, genotype III of DENV-3 and genotype I of DENV-4 have been dominating across the country. Substitution rates are comparable across the serotypes, suggesting a lack of serotype-specific evolutionary divergence. Yet, the envelope (E) protein displays strong signatures of evolution under immune selection. Apart from drifting away from its ancestors and other contemporary serotypes in general, we find evidence for recurring interserotype drift towards each other, suggesting selection via cross-reactive antibody-dependent enhancement. We identify the emergence of the highly divergent DENV-4-Id lineage in South India, which has acquired half of all E gene mutations in the antigenic sites. Moreover, the DENV-4-Id is drifting towards DENV-1 and DENV-3 clades, suggesting the role of cross-reactive antibodies in its evolution. Due to the regional restriction of the Indian genotypes and immunity-driven virus evolution in the country, ~50% of all E gene differences with the current vaccines are focused on the antigenic sites. Our study shows how the dengue virus evolution in India is being shaped in complex ways.

Introduction: Caesarean techniques have evolved over time to increase their safety. Intra-abdominal closure of uterine incision seems more physiological. Exteriorisation makes repair easier with a better exposure. But this causes tension to the supporting structures attached to uterus and stretching of vasculature with the risk of intraoperative haematoma or aneurysm later on. Aim: To compare the in-situ repair Group and exteriorised repair group caesarean delivery under spinal anaesthesia regarding occurrence of intraoperative and postoperative complications of interest. Materials and Methods: A prospective interventional study was conducted in the Department of Obstetrics and Gynaecology at College of Medicine and Jawaharlal Nehru Memorial Hospital, West Bengal, India, over a period of two years from April 2014 to March 2016. Four hundred women undergoing caesarean section who fulfilled the inclusion and exclusion criteria were recruited in the study. They were randomly allocated into two study groups as per a computer generated random allocation table. In Group A (n=200) uterine incision was closed after uterus was exteriorised and in Group B (n=200) uterine incision was closed keeping it inside the abdomen. Intraoperative and postoperative parameters of interest such as nausea-vomiting, drop in pulse rate, incision closure time, drop in haemoglobin, blood transfusion rate, return of bowel sounds, febrile morbidity, surgical site infection, hospital stay etc., were noted and compared between the two groups. Numerical variables were expressed as mean and standard deviation and analysed using independent sample t-test. For qualitative variables frequency and percentage were calculated and analysed using Chi-square. Collected data was transferred and analysed using Statistical Package for Social Sciences (SPSS) version25. The p-value ≤0.05 was considered significant. Results: The demographic profiles like age, parity, gestational age etc. of both the groups were similar. There was a significant difference in uterine closure time (9±2.5 minutes in in-situ repair group vs. 10±2 minutes in exteriorisation and repair groups, respectively (p0.05). Mean drop of haemoglobin was more in the intraabdominal closure group (1.5±1.3 gm/dL) as compared to the group of closure after exteriorisation (1.4±1.3 gm/dL) though the difference was not significant statistically (p=0.44). Postpartum blood transfusion rate was 6.5% in exteriorised repair group and 9% in in-situ repair group (p=0.35). Postoperative morbidity like fever, surgical site infection, length of hospital stay was similar in both the groups. Conclusion: Choice of uterine closure method is operator dependent and either method of uterine closure is acceptable when practiced and skill is gained. Exteriorisation is advantageous when excessive bleeding is encountered. Though time taken for closure in in-situ group is statistically more it is similar practically. Bowel sounds returned earlier postoperatively in in-situ group.

IntroductionVPS45 belongs to the Sec1/Munc18 family of proteins, which interact with and regulate Qa-SNARE function during membrane fusion. We have shown previously that Arabidopsis thaliana VPS45 interacts with the SYP61/SYP41/VTI12 SNARE complex, which locates on the trans-Golgi network (TGN). It is required for SYP41 stability, and it functions in cargo trafficking to the vacuole and in cell expansion. It is also required for correct auxin distribution during gravitropism and lateral root growth.ResultsAs vps45 knockout mutation is lethal in Arabidopsis, we identified a mutant, vps45-3, with a point mutation in the VPS45 gene causing a serine 284-to-phenylalanine substitution. The VPS45-3 protein is stable and maintains interaction with SYP61 and SYP41. However, vps45-3 plants display severe growth defects with significantly reduced organ and cell size, similar to vps45 RNAi transgenic lines that have reduced VPS45 protein levels. Root hair and pollen tube elongation, both processes of tip growth, are highly compromised in vps45-3. Mutant root hairs are shorter and thicker than those of wild-type plants, and are wavy. These root hairs have vacuolar defects, containing many small vacuoles, compared with WT root hairs with a single large vacuole occupying much of the cell volume. Pollen tubes were also significantly shorter in vps45-3 compared to WT.DiscussionWe thus show that VPS45 is essential for proper tip growth and propose that the observed vacuolar defects lead to loss of the turgor pressure needed for tip growth.

Paralytic ileus is a condition where the intestine becomes paralysed in the absence of any mechanical obstruction. The common causes are intra-abdominal surgery, severe metabolic problems and drugs. Many anticancer drugs and targeted therapy drugs are important causes of this toxicity. Early diagnosis and appropriate management are essential because if prolonged and untreated it can lead to death in the same way as in acute mechanical obstruction. Capecitabine is an orally administered prodrug of 5-Fluorouracil (5-FU) routinely used in breast and colorectal cancer. Paralytic ileus is a rare but recognised serious side-effect of oral capecitabine. Hereby, authors present a case of 53-year-old male patient, who was a postoperative case of colon cancer and was treated by adjuvant capecitabine based chemotherapy and subsequently, developed capecitabine induced paralytic ileus. He was managed successfully by standard conservative measures, avoiding unnecessary laparotomy.

The study examines the troika of financial liberalisation–volatility–information asymmetry to explore the linkage between financial liberalisation and return volatility across the globe. The financial liberalisation phenomenon was studied across three phases: liberalisation, post-liberalisation, and liberalisation plus post-liberalisation. The results indicate that volatility surged during the liberalisation phase for emerging economies, whereas it significantly declined during the post-liberalisation period. A declining pattern of volatility was observed during the post-liberalisation phase for developed economies. The conditional and unconditional volatility measures were highest during the liberalisation phase for emerging economies, whereas both the volatility measures were higher during the combined liberalisation phase for developed economies. There was evidence of negative asymmetric shock that lowered the volatility in emerging economies, in developed economies, and at the aggregate level.

Human papillomavirus type-16 (HPV16) is classified into lineages, A, B, C and D and 10 sub-lineages portraying variable infectivity, persistence, and cytological outcomes, however, with geographical variations. Our objective was to delineate the distinctive features of lineages among cervical squamous cell carcinoma (SCC) in the eastern region of India. A total of 145 SCC cases and 24 non-malignant specimens, harboring episomal HPV16, were included. The presence of higher proportion of lineage A over D was observed among SCC cases (86.89% A1, 8.97% D1 and 4.14% D2), while only A1 sub-lineage viruses were found among control specimens. Among the A1 viruses, an association of variants in the E5 (Y44L, I65V), E6 (L83V) genes and LCR: C7577T with SCC, with combined Odd's ratio (95% CI) of 20.5(4.61–91.25) was observed. Network analyses revealed the presence of 10 clades of lineage A viruses comprising of 64 HPV16 genomes harboring the risk alleles. High episomal HPV16 DNA copy numbers (adjusted p-value= 0.0271) and E7 mRNA expression (p-value=0.000017) predominated in SCC with lineage A, over D. Our study highlights the distinctive modalities of oncogenicity among different HPV16 lineages.

Artificial membrane systems can serve as models to investigate molecular mechanisms of different cellular processes, including transport, pore formation, and viral fusion. However, the current, such as SUVs, GUVs, and the supported lipid bilayers suffer from issues, namely high curvature, heterogeneity, and surface artefacts, respectively. Freestanding membranes provide a facile solution to these issues, but current systems developed by various groups use silicon or aluminum oxide wafers for fabrication that involves access to a dedicated nanolithography facility and high cost while conferring poor membrane stability. Here, we report the development, characterization and applications of an easy-to-fabricate suspended lipid bilayer (SULB) membrane platform leveraging commercial track-etched porous filters (PCTE) with defined microwell size. Our SULB system offers a platform to study the lipid composition-dependent structural and functional properties of membranes with exceptional stability. With dye entrapped in PCTE microwells by SULB, we show that sphingomyelin significantly augments the activity of pore-forming toxin, Cytolysin A (ClyA) and the pore formation induces lipid exchange between the bilayer leaflets. Further, we demonstrate high efficiency and rapid kinetics of membrane fusion by dengue virus in our SULB platform. Our suspended bilayer membrane mimetic offers a novel platform to investigate a large class of biomembrane interactions and processes.

Problem/Relevance: Measuring the risk of an asset and the economic forces driving the price of the risk is a challenging task that preoccupied the asset pricing literature for decades. However, there exists no consensus on the integrated asset pricing framework among the financial economists in the contemporaneous asset pricing literature. Thus, we consider and study this research problem that has greater relevance in pricing the risks of an asset. In this backdrop, we develop an integrated equilibrium asset pricing model in an intertemporal (ICAPM) framework. Research Objective/Questions: Broadly we have two research objectives. First, we examine the joint dynamics of the human capital component and common factors in approximating the variation in asset return predictability. Second, we test whether the human capital component is the unaccounted and the sixth pricing factor of FF five-factor asset pricing model. Additionally, we assess the economic and statistical significance of the equilibrium six-factor asset pricing model. Methodology: The human capital component, market portfolio, size, value, profitability, and investment are the pricing factors of the equilibrium six-factor asset pricing model. We use Fama-French (FF) portfolios of 2 3, 5 5, 10 10 sorts, 2 4 4 sorts, and the Industry portfolios to examine the equilibrium six-factor asset pricing model. The Generalized method of moments (GMM) estimation is used to estimate the parameters of variant asset pricing models and Gibbons-Ross-Shanken test is employed to evaluate the performance of the variant asset pricing frameworks. Major Findings: Our approaches led to three conclusions. First, the GMM estimation result infers that the human capital component of the six-factor asset pricing model significantly priced the variation in excess return on FF portfolios of variant sorts and the Industry portfolios. Further, the sensitivity to human capital component priced separately in the presence of the market portfolios and the common factors. Second, the six-factor asset pricing model outperforms the CAPM, FF three-factor model, and FF five-factor model, which indicates that the human capital component is a significant pricing factor in asset return predictability. Third, we argue that the human capital component is the unaccounted asset pricing factor and equally the sixth-factor of the FF five-factor asset pricing model. The additional robustness test result confirms that the parameter estimation of the six-factor asset pricing model is robust to the alternative definitions of the human capital component. Implications: The empirical results and findings equally pose the more significant effects for the decision-making process of the rational investor, institutional managers, portfolio managers, and fund managers in formulating the better investment strategies, which can help in diversifying the aggregate risks.

We study the international stock returns across Europe, Asia Pacific, North America, US, Japan, Global, and Global excluding US. We find there are value premiums in average stock returns across the regions. There is momentum return in all the regions except for Japan. With the exception of Japan, profitability and investment premiums in average stock returns exist across the regions. Further, the value, momentum, and profitability premiums vary with the firm size and premiums decrease from smaller to bigger stocks excluding Japan. We examine whether empirical asset pricing models capture the value, momentum, profitability, and investment pattern in international average returns, and the integration of the asset prices across the regions. We reject the global integrated pricing approach. The performance of local Carhart four-factor model is relatively better than the variant models in approximating the returns on Japanese size-B/M and size-momentum portfolios. Similarly, the FF five-factor model performs better than the variant models in approximating the returns on Asia Pacific, North American, and Japanese size-profitability portfolios. In addition, FF five-factor model performs relatively better in approximating the returns on European and Japanese size-investment portfolios. Keywords: Asset pricing model, GRS test, Integrated pricing, International stock returns, Returns predictability, JEL classification: C53, F36, G12, O57

In this study, limestone (LS), kaolin (K) and bauxite residue (BR) were considered as potential raw meal ingredients for the preparation of ferrite-belite (cement) clinkers. A forecast of the mineralogical composition for the different clinker composition, based on the major oxides, i.e., CaO (C), SiO2 (S), Al2O3 (A) and Fe2O3 (F) was obtained using thermodynamic modelling (FactSage). A phase field schematic representation was established for the three-component raw meal. The data obtained therein were used to compute the Bogue equations for the ferrite-belite cements. Based on this assumption, i.e., only four simultaneous linear equations each containing four different variables (crystalline phases) were used to formulate Bogue type equations. It was established that with increasing LS content from 33 wt% to 64 wt% and BR content decreasing from 66 wt% to 35 wt%, CF was only present at an LS content between 33–47%, followed by gehlenite up to LS content of 53% and rankinite at a LS content of about 55 wt%. Moreover, C3A and lime were present in place of gehlenite and rankinite beyond LS content of 55 wt%. However, the belite and ferrite phases remained present throughout the entire clinker composition. Overall, this study provides the basic understanding required for the development of low carbon ferrite-belite clinkers.

Intimate interactions between photosynthetic and non-photosynthetic organisms require the orchestrated transfer of ions and metabolites between species. We review recent progress in identifying and characterizing the transport proteins involved in five mutualistic symbiotic interactions: lichens, Azolla–cyanobacteria, ectomycorrhiza, endomycorrhiza, and rhizobia–legumes. This review focuses on transporters for nitrogen and carbon and other solutes exchanged in the interactions. Their predicted functions are evaluated on the basis of their transport mechanism and prevailing transmembrane gradients of H+ and transported substrates. The symbiotic interactions are presented in the assumed order from oldest to most recently evolved.

The present study introduce the human capital component to the Fama and French five-factor model proposing an equilibrium six-factor asset pricing model. The study employs an aggregate of four sets of portfolios mimicking size and industry with varying dimensions. The first set consists of three set of six portfolios each sorted on size to B/M, size to investment, and size to momentum. The second set comprises of five index portfolios, third, a four-set of twenty-five portfolios each sorted on size to B/M, size to investment, size to profitability, and size to momentum, and the final set constitute thirty industry portfolios. To estimate the parameters of six-factor asset pricing model for the four sets of variant portfolios, we use OLS and Generalized method of moments based robust instrumental variables technique (IVGMM). The results obtained from the relevance, endogeneity, overidentifying restrictions, and the Hausman's specification, tests indicate that the parameter estimates of the six-factor model using IVGMM are robust and performs better than the OLS approach. The human capital component shares equally the predictive power alongside the factors in the framework in explaining the variations in return on portfolios. Furthermore, we assess the t-ratio of the human capital component of each IVGMM estimates of the six-factor asset pricing model for the four sets of variant portfolios. The t-ratio of the human capital of the eighty-three IVGMM estimates are more than 3.00 with reference to the standard proposed by Harvey et al. (2016). This indicates the empirical success of the six-factor asset-pricing model in explaining the variation in asset returns. Keywords: FF portfolio, Human capital, IVGMM approach, Return predictability, Six-factor asset pricing model, JEL classification: G12, C36, J24

We argue that the risk of an asset is measured by the covariance of an asset's return with the return on the aggregate market and human capital. The intertemporal and consumption-based CAPM, along with an extended version of CAPM framework examines the excess return on Fama and French portfolios sorted on size- BE/ME and momentum across the economies. The frequently used priced factors in anomaly literature include, Fama and French factors, momentum, dividend yield, bond market factors, saving, along with aggregate market and human capital component. Using unique panel data sets of emerging and developed economies, the panel regression, IV-GMM with random effects and PCA, finds the aggregate market and human capital are the strongest predictors of asset returns across the economies. Furthermore, the aggregate market and saving are strong predictors of asset return in emerging economies, whereas aggregate market and human capital emerge the best predictors of asset return in developed economies. Interestingly, human capital subsumes the predictive ability of Fama and French factors and becomes redundant along with momentum, dividend yield, and bond market factors.

Abstract Background The movement of plant roots within the soil is key to their ability to interact with the environment and maximize anchorage and nutrient acquisition. Directional growth of roots occurs by a combination of sensing external cues, hormonal signaling and cytoskeletal changes in the root cells. Roots growing on slanted, impenetrable growth medium display a characteristic waving and skewing, and mutants with deviations in these phenotypes assist in identifying genes required for root movement. Our study identifies a role for a trans-Golgi network-localized protein in root skewing. Results We found that Arabidopsis thaliana TNO1 (TGN-localized SYP41-interacting protein), a putative tethering factor localized at the trans-Golgi network, affects root skewing. tno1 knockout mutants display enhanced root skewing and epidermal cell file rotation. Skewing of tno1 roots increases upon microtubule stabilization, but is insensitive to microtubule destabilization. Microtubule destabilization leads to severe defects in cell morphology in tno1 seedlings. Microtubule array orientation is unaffected in the mutant roots, suggesting that the increase in cell file rotation is independent of the orientation of microtubule arrays. Conclusions We conclude that TNO1 modulates root skewing in a mechanism that is dependent on microtubules but is not linked to disruption of the orientation of microtubule arrays. In addition, TNO1 is required for maintenance of cell morphology in mature regions of roots and the base of hypocotyls. The TGN-localized SNARE machinery might therefore be important for appropriate epidermal cell file rotation and cell expansion during root growth.

Objective: To characterize the in vitro replication fitness, viral diversity, and phylogeny of dengue viruses (DENV) isolated from Indian patients. Methods: DENV was isolated from whole blood collected from patients by passaging in cell culture. Passage 3 viruses were used for growth kinetics in C6/36 mosquito cells. Parallel efforts also focused on the isolation of DENV RNA from plasma samples of the same patients, which were processed for next-generation sequencing. Results: It was possible to isolate 64 clinical isolates of DENV, mostly DENV-2. Twenty-five of these were further used for growth curve analysis in vitro, which showed a wide range of replication kinetics. The highest viral titers were associated with isolates from patients with dengue with warning signs and severe dengue cases. Full genome sequences of 21 DENV isolates were obtained. Genome analysis mapped the circulating DENV-2 strains to the Cosmopolitan genotype. Conclusions: The replication kinetics of isolates from patients with mild or severe infection did not differ significantly, but the viral titers varied by two orders of magnitude between the isolates, suggesting differences in replication fitness among the circulating DENV-2. Keywords: Dengue virus, Growth curve, Phylogenetics, Genotype, Mutations

Majorana fermions are predicted to arise at the ends of nanowire devices which combine superconductivity, strong spin-orbit coupling, and an external magnetic field. By manipulating networks of these devices with suitable gating, it has been suggested that braiding operations may be performed which act as logic operations, suitable for quantum computation. However, the unavoidable misalignment of the magnetic field in any realistic device geometry has raised questions about the feasibility of such braiding. In this paper, we numerically simulate braiding operations in devices with Y-junction and tuning-fork geometries using an experimentally motivated nanowire model. We study how the static and dynamical features vary with geometric parameters and identify parameter choices that optimize the probability of a successful braid. Notably, we find that there is an optimal Y-junction half-angle (about 20^{∘} for our parameter values), which balances two competing mechanisms that reduce the energy gap to excitations. In addition, we find that a tuning-fork geometry has significant advantages over a Y-junction geometry, as it substantially reduces the effect of dynamical phase oscillations that complicate the braiding process. Our results suggest that performing a successful braid is in principle possible with such devices and is within experimental reach.

Over 75% of crop species produce nectar and are dependent on pollinators to achieve maximum seed set, yet little is known about the mechanisms regulating nectar secretion. The phytohormone jasmonic acid (JA) is recognized to be involved in several plant processes including development and defense. JA was also recently shown to positively influence nectar secretion in both floral and extrafloral nectaries. For example, endogenous JA levels peak in flowers just prior to nectar secretion, but the details of how JA regulates nectar secretion have yet to be elucidated. We have found that the octadecanoid pathway does indeed play a role in the production and regulation of floral nectar in Arabidopsis. Null alleles for several JA biosynthesis and response genes had significantly reduced amounts of nectar, as well as altered expression of genes known to be involved in nectar production. We additionally identified crosstalk between the JA and auxin response pathways in nectaries. For example, the nectar-less JA synthesis mutant aos-2 showed no auxin response in nectaries, but both nectar production and the auxin response were restored upon exogenous JA and auxin treatment. Conversely, coi1-1, a JA-Ile-insensitive receptor mutant, displayed no auxin response in nectaries under any circumstance, even in older flowers that produced nectar. Surprisingly, opr3-1, a mutant for 12-oxophytodienoate reductase 3 [an enzyme further down the JA biosynthetic pathway that reduces 12-oxo phytodienoic acid (OPDA)], produced no nectar in newly opened flowers, but did secrete nectar in older flowers. Furthermore, a similar phenotype was observed in coi1-1. Cumulatively, these observations strongly suggest an indispensable role for an octadecanoic acid- and auxin-dependent, but JA- and COI1-dispensible, pathway in regulating nectar production in Arabidopsis.

Summary: Background: Although childhood trauma and violence against women are global public health issues, few population-based data from low-income and middle-income countries exist about the links between them. We present data from the UN Multi-country Study on Men and Violence in Asia and the Pacific, exploring the pathways between different forms of childhood trauma and violence against women. Methods: In this multicountry study, we interviewed multistage representative samples of men and women, aged 18–49 years, in Asia and the Pacific, using standardised population-based household surveys. Men were interviewed in six countries, and women in four. Respondents were asked questions about their perpetration or experience of intimate partner violence or non-partner sexual violence, childhood trauma, and harsh parenting (smacking their children as a form of discipline). We used maximum likelihood multivariate logit models to explore associations between childhood trauma and violence against women, and fitted path models to explore associations between experience and perpetration of child maltreatment. Findings: Between Jan 1, 2011, and Dec 1, 2012, 10 178 men and 3106 women completed interviews in this study, with between 815 and 1812 men per site and 477 and 1103 women per site. The proportion of men who experienced any childhood trauma varied between 59% (n=478, 95% CI 54·0–63·3; Indonesia rural site) and 92% (n=791, 89·4–93·8; Bougainville, Papua New Guinea). For women, the results ranged from 44% (n=272, 37·7–50·8; Sri Lanka) to 84% (n=725, 80·7–86·8; Bougainville, Papua New Guinea). For men, all forms of childhood trauma were associated with all forms of intimate partner violence perpetration. For women, all forms of childhood trauma were associated with physical intimate partner violence, and both physical and sexual intimate partner violence. There were significant, often gendered, pathways between men's and women's perpetration and experiences of childhood trauma, physical intimate partner violence, harsh parenting, and other factors. Interpretation: The data point to both a co-occurrence and a cycle of abuse, with childhood trauma leading to violence against women and further child maltreatment, which in turn increases the risk of experience or perpetration of violence during adulthood. Efforts to prevent both forms of violence would benefit from a meaningful integrated approach. Interventions should promote positive parenting, address inequality and the normalisation of violence across the life course, and transform men's power over women and children. Funding: Partners for Prevention. National studies were funded by the UN Population Fund in Bangladesh and China, UN Women in Cambodia and Indonesia, UN Develoment Programme in Papua New Guinea, and CARE in Sri Lanka.

Epigenetic alterations within human papillomavirus (HPV) and host cellular genomes are known to occur during cervical carcinogenesis. Our objective was to analyse the influence of (1) methylation within two immunostimulatory CpG motifs within HPV16 E6 and E7 genes around the viral late promoter and their correlation, if any, with expression deregulation of host receptor (TLR9) and DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) and (2) global DNA methylation levels within CpGs of the repetitive Alu sequences, on cervical cancer (CaCx) pathogenesis. Significantly higher proportions of CaCx samples portrayed methylation in immunostimulatory CpG motifs, compared to HPV16-positive non-malignant samples, with cases harbouring episomal HPV16 showing decreased methylation compared to those with viral integration. A significant linear trend of TLR9 upregulation was recorded in the order of HPV–negative controls

Abortive cycling is a universal feature of transcription initiation catalyzed by DNA-dependent RNA polymerases (RNAP). In bacteriophage T7 RNAP, mutation of proline 266 to leucine (P266L) in the C-linker region connecting the N-terminal promoter binding domain with the C-terminal catalytic domain drastically reduces short abortive products (4-7 nt) while marginally increasing long abortives (9-11 nt). Here we have investigated the transcription initiation pathway of P266L with the goal of understanding the mechanistic basis for short and long abortive synthesis. We show that the P266L mutation does not alter the affinity for the promoter, mildly affects promoter opening, and increases the +1/+2 GTP K(d) by 2-fold. However, unlike wild-type T7 RNAP that undergoes stepwise rotation of the promoter binding domain and DNA scrunching during initial transcription, the P266L mutant does not undergo coupled rotational/scrunching movements until 7 nt RNA synthesis. The lack of rotation/scrunching correlates with greater stabilities of the initiation complexes of the P266L and decreased short abortive products. The results indicate that the increased flexibility in the C-linker due to P266L mutation enables T7 RNAP to absorb the stress from the growing RNA:DNA hybrid thereby decreasing short abortive products. Increased C-linker flexibility, however, has an adverse effect of delaying the transition into elongation by 1-2 nt, which gives rise to long abortive products. However, a mutation in the upstream promoter region greatly decreases long abortive products in P266L reactions, rendering the combination of P266L and A-15C promoter a desirable pair for efficient in vitro transcription for RNA production. We conclude that the conformational rigidity in the C-linker region conferred by the proline at position 266 is responsible for the undesirable short abortive products, but the rigidity is critical for efficient promoter clearance and transition into elongation.

We tested the hypothesis that (i) synonymous variations within the coding regions, and (ii) variations within the non-coding regions of HPV, influence cervical cancer (CaCx) pathogenesis under the impact of intact HPV16 genomes. Whole genome sequence analysis of HPV16 isolates within 70 CaCx cases and 25 non-malignant samples revealed that synonymous variations were significantly higher within the E6 (p = 0.014), E5 (p = 0.001) and L2 (p = 0.0002) genes of HPV16 isolates within cases, compared to isolates within non-malignant samples. All of the 25 (100%) humanized codons identified within L2 ORF of the samples analyzed, were harbored by CaCx cases, while 8 out of 25 (32%) were harbored by HPV16 positive non-malignant samples (p = 3.87105E-07). L2 (mRNA and protein) expression was evident only among cases with episomal viral genomes and L2 mRNA expression correlated significantly with E2 gene copy numbers suggesting expression from all episomal genomes. Among such cases, Asian American (AA) isolates portrayed all of the humanized codons (100%; 4-6/sample) recorded within L2, which was significantly higher (p = 2.02E-7) compared to the European (E) isolates (22.8%; none or 1-2/sample). Additionally, majority of E variant isolates within cases (54/57; 94.7%) portrayed a variation (T4228C) within the short non-coding region (NCR2) between E5 and L2 genes, which portrays a weak promoter activity specific for L2 mRNA expression. This resulted in loss of 9 out of 14 miRNA binding sites (hsa-miR-548 family), despite the significant overexpression of miR548a-5p and miR548d-5p among such cases (28.64 and 36.25 folds, respectively), in comparison to HPV negative control samples. The findings exemplify the biological relevance of sequence variations in HPV16 genomes and highlight that episomal HPV16 in CaCx cases employ multiple mechanisms to sustain L2 expression, thereby justifying the potential role of L2 in such cancers, as opposed to those harboring viral integration.

This study was undertaken to decipher the interdependent roles of (i) methylation within E2 binding site I and II (E2BS-I/II) and replication origin (nt 7862) in the long control region (LCR), (ii) expression of viral oncogene E7, (iii) expression of the transcript (E7-E1/E4) that encodes E2 repressor protein and (iv) viral load, in human papillomavirus 16 (HPV16) related cervical cancer (CaCx) pathogenesis. The results revealed over-representation (p

Phenotypic behavior of a group of organisms can be studied using a range of molecular evolutionary tools that help to determine evolutionary relationships. Traditionally a gene or a set of gene sequences was used for generating phylogenetic trees. Incomplete evolutionary information in few selected genes causes problems in phylogenetic tree construction. Whole genomes are used as remedy. Now, the task is to identify the suitable parameters to extract the hidden information from whole genome sequences that truly represent evolutionary information. In this study we explored a random anchor (a stretch of 100 nucleotides) based approach (ABWGP) for finding distance between any two genomes, and used the distance estimates to compute evolutionary trees. A number of strains and species of Mycobacteria were used for this study. Anchor-derived parameters, such as cumulative normalized score, anchor order and indels were computed in a pair-wise manner, and the scores were used to compute distance/phylogenetic trees. The strength of branching was determined by bootstrap analysis. The terminal branches are clearly discernable using the distance estimates described here. In general, different measures gave similar trees except the trees based on indels. Overall the tree topology reflected the known biology of the organisms. This was also true for different strains of Escherichia coli. A new whole genome-based approach has been described here for studying evolutionary relationships among bacterial strains and species.