Multivariate genetic architecture reveals testosterone-driven sexual antagonism in contemporary humans.

Sex difference (SD) is ubiquitous in humans despite shared genetic architecture (SGA) between the sexes. A univariate approach, i.e., studying SD in single traits by estimating genetic correlation, does not provide a complete biological overview, because traits are not independent and are genetically correlated. The multivariate genetic architecture between the sexes can be summarized by estimating the additive genetic (co)variance across shared traits, which, apart from the cross-trait and cross-sex covariances, also includes the cross-sex-cross-trait covariances, e.g., between height in males and weight in females. Using such a multivariate approach, we investigated SD in the genetic architecture of 12 anthropometric, fat depositional, and sex-hormonal phenotypes. We uncovered sexual antagonism (SA) in the cross-sex-cross-trait covariances in humans, most prominently between testosterone and the anthropometric traits - a trend similar to phenotypic correlations. 27% of such cross-sex-cross-trait covariances were of opposite sign, contributing to asymmetry in the SGA. Intriguingly, using multivariate evolutionary simulations, we observed that the SGA acts as a genetic constraint to the evolution of SD in humans only when selection is sexually antagonistic and not concordant. Remarkably, we found that the lifetime reproductive success in both the sexes shows a positive genetic correlation with anthropometric traits, but not with testosterone. Moreover, we demonstrated that genetic variance is depleted along multivariate trait combinations in both the sexes but in different directions, suggesting absolute genetic constraint to evolution. Our results indicate that testosterone drives SA in contemporary humans and emphasize the necessity and significance of using a multivariate framework in studying SD.

3D reconstruction of the mouse cochlea from scRNA-seq data suggests morphogen-based principles in apex-to-base specification.

In the mammalian auditory system, frequency discrimination depends on numerous morphological and physiological properties of the organ of Corti, which gradually change along the apex-to-base (tonotopic) axis of the organ. For example, the basilar membrane stiffness changes tonotopically, thus affecting the tuning properties of individual hair cells. At the molecular level, those frequency-specific characteristics are mirrored by gene expression gradients; however, the molecular mechanisms controlling tonotopic gene expression in the mouse cochlea remain elusive. Through analyzing single-cell RNA sequencing (scRNA-seq) data from E12.5 and E14.5 time points, we predicted that morphogens, rather than a cell division-associated mechanism, confer spatial identity in the extending cochlea. Subsequently, we reconstructed the developing cochlea in 3D space from scRNA-seq data to investigate the molecular pathways mediating positional information. The retinoic acid (RA) and hedgehog pathways were found to form opposing apex-to-base gradients, and functional interrogation using mouse cochlear explants suggested that both pathways jointly specify the longitudinal axis.

Influence of super-optimal light intensity on the acetic acid uptake and microalgal growth in mixotrophic culture of Chlorella sorokiniana in bubble-column photobioreactors.

This study seeks to determine the influence of super-optimal light intensity on acetic acid uptake and its associated impact on the cellular composition of Chlorella sorokiniana in a semi-batch mixotrophic cultivation setup. Unicellular green microalga Chlorella sorokiniana is grown in a 1L bubble-column photobioreactor at light intensities from 6000 to 14,000 lx (≈81 to 189 µmol.photons.m-2.s-1). We find that microalgal acetic acid utilization reduces as illumination increases from an optimal 10,000 lx (≈135 µmol.photons.m-2.s-1) to a super-optimal zone (>10000 lx). This lowers microalgal growth (2.75 g/L) and acetic acid intake, which peak at 6 mL/L (10000 lx) and drop to 2 and 1 mL/L at 12,000 and 14,000 lx, respectively. Concurrently, the maximum lipid yield decreases from 0.66 g/L (10000 lx) to 0.54 g/L (12000 lx) and 0.42 g/L (14000 lx). Hence, super-optimal illumination not only disturbs phototrophy but also affects the heterotrophic component, creating an imbalance between the two.

Functional inhibition of RECQL5 helicase elicits non-homologous end joining response and sensitivity of breast cancers to PARP inhibitor.

Poly (ADPRibose) Polymerase inhibitor (PARPi) are clinically approved for the treatment of BRCA-mutated hereditary breast and ovarian cancers with homologous recombination (HR) deficiency, based on synthetic lethality concept. However, ∼90% of breast cancers are BRCA-wild type; they repair PARPi mediated damage through HR, leading to intrinsic de novo resistance. Hence, there is an unmet need of exploring novel targets in HR-proficient aggressive breast cancers for PARPi treatment. RECQL5 physically interacts and disrupts RAD51 from pre-synaptic filaments, aiding HR resolution, replication fork protection and preventing illegitimate recombination. In the current investigation, we show that targeted inhibition of HR by stabilization of RAD51-RECQL5 complex by a pharmacological inhibitor of RECQL5 (4a; 1,3,4-oxadiazole derivative) in the presence of PARPi [talazoparib (BMN673)] leads to abolition of functional HR with uncontrolled activation of NHEJ repair. This was assessed by GFP based NHEJ reporter assay, KU80 recruitment and in vitro NHEJ based plasmid ligation assay. Concomitant treatment with talazoparib and 4a generates copious amounts of replication stress, prolonged cell cycle arrest, extensive double strand breaks (DSBs) and mitotic catastrophe, leading to sensitization of HR-proficient breast cancers. Suppression of NHEJ activity abolishes 4a-mediated sensitization of breast cancers to PARPi treatment. Imperatively, 4a was ineffective against normal mammary epithelial cells, which expresses low RECQL5 vis-à-vis breast cancer cells. Moreover, functional inhibition of RECQL5 suppresses metastatic potential of breast cancer cells in response to PARPi. Together, we identified RECQL5 as a novel pharmacological target for expanding PARPi based treatment horizon for HR-proficient cancers.

Design and Synthesis of BODIPY-Hetero[5]helicenes as Heavy-Atom-Free Triplet Photosensitizers for Photodynamic Therapy of Cancer.

Designing heavy-atom-free triplet photosensitizers (PSs) is a challenge for the efficient photodynamic therapy (PDT) of cancer. Helicenes are twisted polycyclic aromatic hydrocarbons (PAHs) with an efficient intersystem crossing (ISC) that is proportional to their twisting angle. But their difficult syntheses and weak absorption profile in the visible spectral region restrict their use as heavy-atom-free triplet PSs for PDT. On the other hand, boron-containing PAHs, BODIPYs are highly recognized for their outstanding optical properties. However, planar BODIPY dyes has low ISC and thus they are not very effective as PDT agents. We have designed and synthesized fused compounds containing both BODIPY and hetero[5]helicene structures to develop red-shifted chromophores with efficient ISC. One of the pyrrole units of the BODIPY core was also replaced by a thiazole unit to further enhance the triplet conversion. All the fused compounds have helical structure, and their twisting angles are also increased by substitutions at the boron centre. The helical structures of the BODIPY-hetero[5]helicenes were confirmed by X-ray crystallography and DFT structure optimization. The designed BODIPY-hetero[5]helicenes showed superior optical properties and high ISC with respect to [5]helicene. Interestingly their ISC efficiencies increase proportionally with their twisting angles. This is the first report on the relationship between the twisting angle and the ISC efficiency in twisted BODIPY-based compounds. Theoretical calculations showed that energy gap of the S1 and T1 states decreases in BODIPY-hetero[5]helicene as compared to planar BODIPY. This enhances the ISC rate in BODIPY-hetero[5]helicene, which is responsible for their high generation of singlet oxygen. Finally, their potential applications as PDT agents were investigated, and one BODIPY-hetero[5]helicene showed efficient cancer cell killing upon photo-exposure. This new design strategy will be very useful for the future development of heavy-atom-free PDT agents.

Histone deacetylase 1 regulates haloperidol-induced motor side effects in aged mice.

BACKGROUND: Antipsychotic drugs prescribed to elderly patients with neuropsychiatric disorders often experience severe extrapyramidal side effects. Previous studies from our group suggest that changes in histone modifications during aging increase the risk for antipsychotic drug side effects, because co-administration of antipsychotics with class 1 histone deacetylase (HDAC) inhibitors could mitigate the severity of motor side effects in aged mice. However, which HDAC subtype contributes to the age-related sensitivity to antipsychotic drug side effects is unknown. METHODS: In this study, we overexpressed histone deacetylase type 1(HDAC1) in the striatum of 3-month-old mice and knocked down HDAC 1 in the striatum of 21-month-old mice by microinjection of AAV9-HDAC1-GFP or AAV9-CRISPR/Cas9-HDAC1-GFP vectors. Four weeks after the viral-vector delivery, the typical antipsychotic drug haloperidol was administered daily for 14 days, followed by motor function assessments through the open field, rotarod, and catalepsy behavioral tests. RESULTS: Young mice with overexpressed HDAC1 showed increased cataleptic behavior induced by haloperidol administration, which is associated with the increased HDAC1 level in the striatum. In contrast, aged mice with HDAC1 knocked down rescued locomotor activity, motor coordination, and decreased cataleptic behavior induced by haloperidol administration, which is associated with decreased HDAC1 level in the striatum. CONCLUSIONS: Our results suggest that HDAC1 is a critical regulator in haloperidol-induced severe motor side effects in aged mice. Repression of HDAC1 expression in the striatum of aged mice could mitigate typical antipsychotic drug-induced motor side effects.

Multiscale modelling of mixotrophic algal growth in pilot-scale photobioreactors and its application to microalgal cultivation using wastewater.

This multiscale model quantifies transport and reaction processes in mixotrophic microalgal growth at three characteristic length scales, namely, macro (photobioreactor), meso (algal cell), micro (organelles). The macro and the meso scale equations capture the temporal dynamics of the transport of CO2, O2, H+, organic carbon and nitrogen sources in the photobioreactor and the cell, respectively, while the micro scale quantifies the reaction rates of CO2 fixation and photorespiration in the chloroplast, and mitochondrial respiration. Our model is validated using our experiments (R2 = 0.96-0.99) on urea, CO2 (0.04-5%), and acetic acid-mediated mixotrophic cultivation of Chlorella sorokiniana for 138 h using municipal wastewater (with and without media) at 11,000 lx light in 25-liter pilot-scale bubble-column photobioreactors, which produces 0.47-2.74 g/L biomass with 22.8-29.6% lipids, while reducing the COD, ammonium, phosphate, nickel, and H+ concentrations by 65-89%. The alga assimilates the ammonium and the phosphates present in wastewater into amino acids and ATP, respectively. Our simulations quantify the autotrophic and heterotrophic components of mixotrophic biomass yield to find the optimal inlet CO2 concentration (of 3%) that synergizes autotrophic CO2 sequestration with heterotrophic assimilation of organic carbon, thereby maximizing both autotrophic and heterotrophic growths. Super-optimal levels of inlet CO2 acidify the stroma of the chloroplast, inhibit RuBisCo's enzymatic activity for CO2 fixation in the Calvin Cycle, decelerate carrier-mediated uptake of acetate, and reduce biomass yields. Our harvesting process drastically reduces the algal harvesting time to less than 29 min. This multiscale reaction-transport model provides a useful tool for further scaling up this pilot-scale technology that synergistically integrates CO2 sequestration and wastewater treatment with rapid microalgal cultivation (using municipal wastewater without autoclaving) and cost-effective harvesting.

Psychiatric morbidity and substance use in migrant workers: A population based study.

BACKGROUND: The prevalence of mental health problems and substance abuse in the migrant population is higher than the general population. AIMS AND OBJECTIVES: To assess the prevalence and pattern of mental health issues and substance use in the migrant population and highlight the association with the reverse migration of migrant workers. METHODOLOGY: The field staff visited the shelter homes for migrant population in four cities of Northern India (Chandigarh (UT), Bhatinda (Punjab), Panchkula (Haryana) and Jaipur (Rajasthan). After maintaining the social distance and wearing masks by the staff and migrants, written informed consent was taken for participation in the study. The socio-demographic details of reverse migrants were noted down and Hindi version of Patient Health Questionnaire (PHQ-9) for mental health problems and screening tool for pattern of substance abuse was administered. Geographically matched undisplaced were also administered these tools. RESULTS: A total of 275 reverse migrants and 276 undisplaced were included in the study. The prevalence of ever use for all the substances among reverse migrants was 44.4% (122/275) and among undisplaced, it was 45.3%. The prevalence of alcohol, tobacco and cannabis was higher than the general population. The prevalence of at least one diagnosis on PHQ-9 is 13.45% (reverse migrants 19.3% and undisplaced 7.6) and the prevalence of other depressive disorder is significantly higher in reverse migrants (17.1%) than undisplaced (4.0%). CONCLUSION: The study concludes that prevalence of mental health issues and substance abuse in migrant population is significantly higher than the general population and the prevalence of at least one diagnosis and other depressive disorder is significantly higher in reverse migrants than undisplaced.

Factors Leading to Reverse Migration Among Migrant Workers During the COVID-19 Pandemic: A Multicenter Study From Northwest India.

OBJECTIVE: To examine the various psychosocial factors associated with reverse migration among migrant workers during the coronavirus disease 2019 (COVID-19) lockdown in India. METHODS: A cross-sectional multicenter study was conducted at 4 sites in Northwest India. The migrant workers were recruited from various shelter homes, and information was gathered from reverse migrant workers and controls using various tools including a sociodemographic profile; knowledge, attitudes, and practices questionnaire; and reasons for migration and reverse migration questionnaires. A total of 275 reverse migrant workers and 276 controls participated in the study. RESULTS: There was a considerable difference between reverse migrant workers and controls regarding the question of whether it was safe to travel during lockdown (76.0% vs 26.4%, respectively). The most common route of spread of COVID-19 infection was through touching and sneezing, and symptoms were fever, dry cough, and sore throat in both groups. Reverse migrant workers had low self-esteem and were reluctant to participate in customs of their migration city. A large number of reverse migrant workers reported that they had no money to survive, worried about family back home at their village, felt pressured by family members to come back to the village, and had been terminated from their job. CONCLUSIONS: Reverse migrant workers had the attitude that it was safe to travel during the lockdown. About one-fifth of the reverse migrant workers reported no place to live and fear of getting an infection. The reverse migrant workers also reported feeling low and gloomy, restless, and uncertain about the future and fear of death. Lack of jobs was a major factor driving migrant workers from their native homes.

Photochemical hydrogen evolution from cobalt microperoxidase-11.

A photochemical system utilizing the semisynthetic biomolecular catalyst acetylated cobalt microperoxidase-11 (CoMP11-Ac) along with [Ru(bpy)3]2+ as a photosensitizer and ascorbic acid as an electron donor is shown to generate hydrogen from water in a visible light-driven reaction. The reductive quenching pathway facilitated by photoexcited [Ru(bpy)3]2+ overcomes the high overpotential observed for CoMP11-Ac in electrocatalysis, yielding turnover numbers ranging from 606 to 2390 (2 µM - 0.1 µM CoMP11-Ac). The longevity of CoMP11-Ac in the photochemical system, sustaining catalysis for over 20 h, is in contrast to its previously reported behavior in an electrochemical system where catalysis slows after 15 min. Proton reduction turnover number and rate are highest at a neutral pH, a rare feature among cobalt catalysts in similar photochemical systems, which typically function best under acidic conditions. Incorporating biomolecular components into the design of catalysts for photochemical systems may address the need for hydrogen generation from neutral-pH water sources.

Targeting RECQL5 Functions, by a Small Molecule, Selectively Kills Breast Cancer in Vitro and in Vivo.

Clinical and preclinical data reveal that RECQL5 protein overexpression in breast cancer was strongly correlated with poor prognosis, survival, and therapeutic resistance. In the current investigation, we report design, synthesis, and specificity of a small molecule, 4a, which can preferentially kill RECQL5-expressing breast cancers but not RECQL5 knockout. Our stringent analysis showed that compound 4a specifically sensitizes RECQL5-expressing cancers, while it did not have any effect on other members of DNA RECQL-helicases. Integrated approaches of organic synthesis, biochemical, in silico molecular simulation, knockouts, functional mutation, and rescue experiments showed that 4a potently inhibits RECQL5-helicase activity and stabilizes RECQL5-RAD51 physical interaction, leading to impaired HRR and preferential killing of RECQL5-expressing breast cancer. Moreover, 4a treatment led to the efficient sensitization of cisplatin-resistant breast cancers but not normal mammary epithelial cells. Pharmacologically, compound 4a was orally effective in reducing the growth of RECQL5-expressing breast tumors (human xenograft) in NUDE-mice with no appreciable toxicity to the vital organs.

Light-driven hydrogen production with CdSe quantum dots and a cobalt glutathione catalyst.

A photocatalytic hydrogen (H2) production system is reported using glutathione (GSH)-capped CdSe QDs with a cobalt precatalyst, yielding 130 000 mol H2 per mol cobalt over 48 hours. Analysis of the reaction mixtures after catalysis indicates that the active catalyst is a labile complex of cobalt and GSH formed in situ.

Management of Lateral Malleolus Giant Cell Tumor using A Reverse Proximal Fibular Graft-A Case Report.

Introduction: A giant cell tumor is a locally aggressive non-cancerous tumor. It usually develops near a joint at the end of the bone. Most occur in the long bones of the legs and arms. Presently, we are considering a case of Ggiant cell tumor over lateral malleolar region with the line of management. Case Report: A 21-year-old male patient came with left ankle swelling over lateral malleolar region with subsequent episodes of pain during walking. Radiographic investigation suggestive of Ggiant cell tumour which was managed by en block resection of tumour with reconstruction of lateral malleolus using a proximal fibular graft, harvested from same side with protecting the neurovascular structures and used it as a newly reconstructed lateral malleolus with proper fixation. Conclusion: Post -operative functional outcome was estimated by using AOFAS score with radiographic evaluation of ankle mortis. Both implied a satisfactory outcome which conclude that though a giant cell tumour localized on the lateral malleolus are rare, but it can be managed by en bloc resection and restore the ankle biomechanics with a reverse proximal fibular graft.

Automatic Diagnosis of Cerebral Palsy Gait Using Computational Intelligence Techniques: A Low-Cost Multi-Sensor Approach.

Automatic diagnosing of Cerebral Palsy (CP) gait is crucial in quantitative evaluation of a therapeutic intervention. Existing systems for such gait assessment are expensive and require user intervention. This study proposes a low-cost gait assessment system equipped with multiple Kinect sensors. Forty subjects (20 CP patients and 20 normal) were recruited for the experiment. To remove outlier frames from the combined gait signal of multiple sensors a data driven algorithm was proposed. Different supervised classifiers along with extreme learning machine were investigated to diagnose CP gait. In addition, a feature level analysis was also performed. Several spatio-temporal features (i.e. step length, stride length, stride time, etc.) were extracted. The strength of walking ratio, a speed invariant feature, to detect CP gait was thoroughly analyzed. The proposed system outperformed state-of-the-art with ≈98% of accuracy (sensitivity: 100%, and specificity: 96.87%). Results indicate a substantial improvement in abnormality detection performance after outlier removal. Based on ReliefF feature ranking algorithm, walking ratio ranked the best among other classical gait features. Performance of all classifiers increased substantially using walking ratio as a feature. Extreme learning machine demonstrated a competing performance in all cases. The higher classification accuracy of this low-cost system using only a single feature makes it attractive for CP gait detection.

Relaxation in a phase-separating two-dimensional active matter system with alignment interaction.

Via computer simulations, we study kinetics of pattern formation in a two-dimensional active matter system. Self-propulsion in our model is incorporated via the Vicsek-like activity, i.e., particles have the tendency of aligning their velocities with the average directions of motion of their neighbors. In addition to this dynamic or active interaction, there exists passive inter-particle interaction in the model for which we have chosen the standard Lennard-Jones form. Following quenches of homogeneous configurations to a point deep inside the region of coexistence between high and low density phases, as the systems exhibit formation and evolution of particle-rich clusters, we investigate properties related to the morphology, growth, and aging. A focus of our study is on the understanding of the effects of structure on growth and aging. To quantify the latter, we use the two-time order-parameter autocorrelation function. This correlation, as well as the growth, is observed to follow power-law time dependence, qualitatively similar to the scaling behavior reported for passive systems. The values of the exponents have been estimated and discussed by comparing with the previously obtained numbers for other dimensions as well as with the new results for the passive limit of the considered model. We have also presented results on the effects of temperature on the activity mediated phase separation.

Enhancing the activity of photocatalytic hydrogen evolution from CdSe quantum dots with a polyoxovanadate cluster.

We report the improvement of photocatalytic proton reduction using molecular polyoxovanadate-alkoxide clusters as hole scavengers for CdSe quantum dots. The increased hydrogen production is explained by favorable charge interactions between reduced forms of the cluster and the charge on the quantum dots arising from the capping ligands.

Cryoelectron Tomography Reveals Nanoscale Organization of the Cytoskeleton and Its Relation to Microtubule Curvature Inside Cells.

Microtubules (MTs) are the most rigid elements of the cytoskeleton with in vitro persistence lengths (Lp) in the range of 1-6 mm. In cellular environments, however, MTs often appear strongly curved. This has been attributed to the forces acting upon them in situ where they are embedded in composite networks of different cytoskeletal elements. Hitherto, the nanoscale organization of these networks has remained largely uncharacterized. Cryo-electron tomography (cryo-ET) allowed to visualize and analyze the in situ structure of cytoskeletal networks in pristinely preserved cellular environments and at high resolution. Here, we studied the molecular organization of MTs and their interactions with the composite cytoskeleton in frozen-hydrated HeLa and P19 cells at different cell-cycle stages. We describe modulation of MT curvature correlated with the surrounding molecular architecture, and show that nanoscale defects occur in curved MTs. The data presented here contribute to constructing realistic models of cytoskeletal biomechanics.

Three-dimensional organization of the cytoskeleton: A cryo-electron tomography perspective.

Traditionally, structures of cytoskeletal components have been studied ex situ, that is, with biochemically purified materials. There are compelling reasons to develop approaches to study them in situ in their native functional context. In recent years, cryo-electron tomography emerged as a powerful method for visualizing the molecular organization of unperturbed cellular landscapes with the potential to attain near-atomic resolution. Here, we review recent works on the cytoskeleton using cryo-electron tomography, demonstrating the power of in situ studies. We also highlight the potential of this method in addressing important questions pertinent to the field of cytoskeletal biomechanics.

Accuracy of image data stream of a markerless motion capture system in determining the local dynamic stability and joint kinematics of human gait.

Assessment of gait parameters is commonly performed through the high-end motion tracking systems, which limits the measurement to sophisticated laboratory settings due to its excessive cost. Recently, Microsoft Kinect (v2) sensor has become popular in clinical gait analysis due to its low-cost. But, determining the accuracy of its RGB-D image data stream in measuring the joint kinematics and local dynamic stability remains an unsolved problem. This study examined the suitability of Kinect(v2) RGB-D image data stream in assessing those gait parameters. Fifteen healthy participants walked on a treadmill during which lower body kinematics were measured by a Kinect(v2) sensor and a optophotogrametric tracking system, simultaneously. Extended Kalman filter was used to extract the lower extremity joint angles from Kinect, while inverse kinematics was used for the gold standard system. For both systems, local dynamic stability was assessed using maximal Lyapunov exponent. Sprague's validation metrics, root mean square error (RMSE) and normalized RMSE were computed to confirm the difference between the joint angles time series of the two systems while relative agreement between them was investigated through Pearson's correlation coefficient (pr). Fisher's Exact Test was performed on maximal Lyapunov exponent to investigate the data independence while reliability was assessed using intraclass correlation coefficients. This study concludes that the RGB-D data stream of Kinect sensor is efficient in estimating joint kinematics, but not suitable for measuring the local dynamic stability.