scJVAE: A novel method for integrative analysis of multimodal single-cell data.

The study of cellular decision-making can be approached comprehensively using multimodal single-cell omics technology. Recent advances in multimodal single-cell technology have enabled simultaneous profiling of more than one modality from the same cell, providing more significant insights into cell characteristics. However, learning the joint representation of multimodal single-cell data is challenging due to batch effects. Here we present a novel method, scJVAE (single-cell Joint Variational AutoEncoder), for batch effect removal and joint representation of multimodal single-cell data. The scJVAE integrates and learns joint embedding of paired scRNA-seq and scATAC-seq data modalities. We evaluate and demonstrate the ability of scJVAE to remove batch effects using various datasets with paired gene expression and open chromatin. We also consider scJVAE for downstream analysis, such as lower dimensional representation, cell-type clustering, and time and memory requirement. We find scJVAE a robust and scalable method outperforming existing state-of-the-art batch effect removal and integration methods.

Multi-source domain adaptation of social media data for disaster management.

Labeled data scarcity at the time of an ongoing disaster has encouraged the researchers to use the labeled data from some previous disaster for training and transferring the knowledge to the current disaster task using Domain Adaptation (DA). However, often labeled data from more than one previous disaster may be available. As all deep learning models are data-hungry and perform better if fed with more annotated data, it is advisable to use data from multiple sources for training a Deep Convolutional Neural Network (DCNN). One of the easiest ways is to simply combine the data from multiple sources and use it for training. However, this arrangement is not that straightforward. The models trained on the combined data from various sources do not perform well on the target, mainly due to distribution discrepancies between multiple sources. This has motivated us to explore the challenging area of multi-source domain adaptation for disaster management. The aim is to learn the domain invariant features and representations across the domains and transfer more related knowledge to solve the target task with improved accuracy than single-source or combined-source domain adaptation. This study proposes a Multi-Source Domain Adaptation framework for Disaster Management (MSDA-DM) to classify disaster images posted on social media based on unsupervised DA with adversarial training. The empirical results obtained confirm that the proposed model MSDA-DM performs better than single-source DA by up to 10.83% and combined-source DA by up to 5.06% in terms of F1-score for different sets of source and target disaster domains. We also compare our model with current state-of-the-art models. The main challenge of multi-source DA is the choice of the relevant sources taken for training since, unlike single-source DA that handles only source-target distribution drift, the multi-source DA network has to address both source-target and source-source distribution drifts.

Establishment of effective and safe recipient preparation for germ-cell transplantation with intra-testicular busulfan treatment in pre-pubertal Barbari goats.

The busulfan, an alkylating agent, suppresses endogenous spermatogenesis in recipient testes. However, considering a wide variation in the effects of busulfan among animal species, its dosage and route of infusion need optimization to prepare effective and safe recipients. Thus, the current study aimed to create a suitable recipient goat model for germ cell (Gc) transplantation through a single intra-testicular (i.t.) busulfan infusion under ultrasonographic (USG) guidance. As observed through the infusion of trypan blue under USG guidance into mediastinum testis (MT) of pre-pubertal Barbari bucks, 3-5 mL of trypan blue solution could fill almost 80% of seminiferous tubules. Thereafter, in Experiment-1, the effect of different busulfan doses (mg/kg) i.e. 0 [negative control, Group (Gr) 1; 0 mg/kg-MT], 1 (Gr 2; 1 mg/kg-MT), 2 (Gr 3; 2 mg/kg-MT), and 3 (Gr 4; 3 mg/kg-MT) were studied. Further, in Experiment-2, sterilizing effects of busulfan infusion through two different routes [MT or cavum vaginale (CV)] were compared. Following i.t. busulfan treatment, no adverse physiological effects or body weight loss were detected. The histological analyses demonstrate a dose-dependent depletion of Gc with almost complete loss of Gc and spermatogenic activities in Gr 3 and 4, and extensive fibrosis in Gr 4. A considerable suppression of spermatogenesis marked with devoid of endogenous spermatogonial population and absence of significant (P > 0.05) effect on key hematological variables were observed in 2 mg/kg-MT Gr. These findings coupled with the results of significant (P < 0.05) down-regulation of marker genes of undifferentiated spermatogonia (THY-1 and PLZF), Gc pluripotency (UCHL-1, OCT-4, and DDX-4), and adhesion (E-cadherin and ß-integrin); up-regulation of apoptotic genes (ID - 4 and BCL-6), and unchanged expression of Sertoli cell marker (vimentin), confirmed the safe and efficient depletion of endogenous Gc in 2 mg/kg-MT Gr. Furthermore, the effect of busulfan infusion on scrotal-testicular biometry, endocrine variables (plasma cortisol and testosterone), and Gc removal was more evident when busulfan was infused into MT than into CV. Overall, the results demonstrated that 2.0 mg/kg is an optimal single dose of busulfan when infused into the MT under USG guidance for the preparation of pre-pubertal recipient bucks. Overall, this study provides a basis to prepare suitable recipients through providing an available niche for efficient Gc transplantation in goats.

Lacosamide in monotherapy in BTRE (brain tumor-related epilepsy): results from an Italian multicenter retrospective study.

PURPOSE: Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients. METHODS: We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints). RESULTS: Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence. CONCLUSIONS: This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

Complications and mortality associated with olecranon fractures in the elderly: a retrospective cohort comparison from a large level one trauma centre.

Background: Olecranon fractures in the elderly have an increasing incidence. This retrospective study aims to identify the complications and survivorship of these patients. Methods: All patients >70 years old treated for an olecranon fracture at our institution were identified between 2007 and 2019. Loss of reduction and/or metalwork loosening was recorded. Also noted were wound healing problems, deep/superficial infections, and any subsequent treatment including return to surgery and/or removal of metalwork. Results: From a total of 177 cases, 28 presented with concomitant fractures (16%), half of which were hip fractures. The largest treatment group underwent tension band wiring (n = 82, 46%, mean age 80.8 yrs). Twenty-one of these suffered failure of fixation (26%), all requiring return to surgery. The second largest treatment group underwent plating (n = 50 28%, mean age 80.1 yrs). Four of these suffered failure of fixation (8%), all requiring return to surgery. Forty-four patients were treated non-operatively (25%, mean age 83.8 yrs). Two patients suffered other complications (4.5%). Overall 1 year survivorship was 0.82. Discussion: Olecranon fractures in the elderly have higher than expected 1 year mortality rates. Operative management results in high complication rates, often requiring return to surgery for metalwork problems. Significant consideration of treatment options is required in this cohort.

Partnering for rotavirus vaccine introduction in India: A retrospective analysis.

BACKGROUND: The pre-existing partner network created in India for the delivery of polio vaccines was initially used to eradicate polio and later on embedded in the health systems network to promote routine immunization and other health interventions efficiently. The experience from this network offered lessons for strengthening the health care systems and provided a well-established network that could be utilized for other vaccine initiatives. It has also been established that successful partnerships between a broad range of stakeholders provide support, strengthen the health system, and accelerate vaccine innovation, introduction, access, logistics, and communication support. However, beyond polio eradication, there have not been too many documented success stories of vaccine introduction, which could be replicated in other new vaccine introductions and allied health initiatives. The authors have reviewed the successful and time-bound introduction of rotavirus vaccine (RVV) in India in the present article. METHODS: The review was conducted based on a partnership framework which analysed multiple factors-partnership prerequisites, partnership model, partnership process, and partnership performance, thereby providing a comprehensive insight into the successful utilization of partnership networks for rotavirus vaccine introduction under the Universal Immunization Program in India. RESULTS & CONCLUSION: The review also highlights the role of a lead agency in creating a fertile ground for lush, efficient, and effective partnerships amongst different stakeholders. The already existing RVV partnership framework reviewed by the authors can be successfully utilized for future new vaccine introductions.

A novel reversible logic gate and its systematic approach to implement cost-efficient arithmetic logic circuits using QCA.

Quantum-dot cellular automata, is an extremely small size and a powerless nanotechnology. It is the possible alternative to current CMOS technology. Reversible QCA logic is the most important issue at present time to reduce power losses. This paper presents a novel reversible logic gate called the F-Gate. It is simplest in design and a powerful technique to implement reversible logic. A systematic approach has been used to implement a novel single layer reversible Full-Adder, Full-Subtractor and a Full Adder-Subtractor using the F-Gate. The proposed Full Adder-Subtractor has achieved significant improvements in terms of overall circuit parameters among the most previously cost-efficient designs that exploit the inevitable nano-level issues to perform arithmetic computing. The proposed designs have been authenticated and simulated using QCADesigner tool ver. 2.0.3.

Developmental neurotoxicity of monocrotophos and lead is linked to thyroid disruption.

AIM: A role of thyroid disruption in developmental neurotoxicity of monocrotophos (MCP) and lead is studied. MATERIALS AND METHODS: A total of 24 female rats after conception were randomized into four groups of six each and treated as follows: Group I - Sham was administered distilled water orally. Group II - A positive control was administered methyl methimazole at 0.02% orally in drinking water. Group III - MCP orally at 0.3 mg/kg and Group IV - Lead acetate at 0.2% orally in drinking water. The drug was administered from gestation day 3 through post-natal day 21 in all the groups. Acetylcholinesterase (AChE) inhibition, thyroid profile (thyroid stimulating hormone, T3 and T4), neurodevelopment (brain wet weights, DNA, RNA and protein), and neurobehavioral (elevated plus maze, photoactometry, and Morris water maze) parameters were assessed in pups. A histopathology of thyroid of dams and brain of progeny was conducted. RESULTS: Inhibition of AChE was <20%. Thyroid profile decreased in the treatment groups. Neurodevelopmental and neurobehavioral parameters did not reveal any significant changes. Thyroid architecture was affected significantly with MCP and lead. Cortical layers too were affected. The three layers of cerebellum either had abnormal arrangement or decreased cellularity in all treated groups relating to thyroid disruption. CONCLUSION: MCP and lead might have affected the development of cerebrum and cerebellum via thyroid disruption leading to developmental neurotoxicity.

Association of Periodontal Health with Orthodontic Appliances among Indian Patients.

BACKGROUND: To assess the association of periodontal status of the patients with and without orthodontic treatment. MATERIALS AND METHODS: This cross-sectional study was conducted among 520 patients (220 undergoing orthodontic procedure and 300 non-orthodontic patients). Periodontal health status was assessed using community periodontal index and loss of attachment. Data were analyzed using SPSS version 16 and level of significance used was 5% level. RESULT: Overall mean number of segments for bleeding component (Score 1) was 0.86 ± 0.708, that of calculus (Score 2) 0.30 ± 0.460, for shallow pockets (4-5 mm) (Score 3) 0.33 ± 0.744 and for deep pockets (6 mm or more) (Score 4) 0.38 ± 0.476. Patients with orthodontic appliances had poor periodontal status than the non-orthodontic patients (P < 0.05). CONCLUSION: Patients undergoing orthodontic treatment have increased the level of periodontal status as it leads to more retention of food debris. Hence, these patients should be motivated to maintain good oral hygiene.

Reprogramming homing endonuclease specificity through computational design and directed evolution.

Homing endonucleases (HEs) can be used to induce targeted genome modification to reduce the fitness of pathogen vectors such as the malaria-transmitting Anopheles gambiae and to correct deleterious mutations in genetic diseases. We describe the creation of an extensive set of HE variants with novel DNA cleavage specificities using an integrated experimental and computational approach. Using computational modeling and an improved selection strategy, which optimizes specificity in addition to activity, we engineered an endonuclease to cleave in a gene associated with Anopheles sterility and another to cleave near a mutation that causes pyruvate kinase deficiency. In the course of this work we observed unanticipated context-dependence between bases which will need to be mechanistically understood for reprogramming of specificity to succeed more generally.

HMG-CoA reductase inhibitors in chronic kidney disease.

The incidence of chronic kidney disease (CKD) is on the rise in the USA. Cardiovascular events are the leading cause of death in this patient population, therefore reducing the risk of these events has become a major focus. The aim of this review is to assess current literature on the use of statins in CKD and end-stage renal disease. Cholesterol reduction is important in preventing the development and progression of coronary heart disease and its negative effects. Statins have been widely studied and proven to reduce cardiovascular risk in the general population. The information gained from trials has been extrapolated to special populations, including CKD, despite these patients often being excluded. However, recent studies have begun to focus on CKD, hemodialysis, and transplant patients and the use of cholesterol-lowering agents and the potential association with decreased cardiovascular events. In addition, due to the unique pharmacokinetic and pharmacodynamic changes that occur in these patients, choosing the appropriate cholesterol-lowering agent becomes important for both safety and efficacy. The complexity of CKD patients is an important consideration when choosing cholesterol-lowering medication. Patients with CKD are often on medications that may interact with many of the cholesterol-lowering agents. Ensuring drug interactions are minimized is essential to the prevention of adverse events from the medications.

Establishment of a comprehensive epilepsy center in pakistan: initial experiences, results, and reflections.

Background. Developing countries, home to 80% of epilepsy patients, do not have comprehensive epilepsy surgery programs. Considering these needs we set up first epilepsy surgery center in Pakistan. Methods. Seventeen teleconferences focused on setting up an epilepsy center at the Aga Khan University (AKU), Karachi, Pakistan were arranged with experts from the University of Alberta Hospital, Alberta, Canada and the University of West Virginia, USA over a two-year period. Subsequently, the experts visited the proposed center to provide hands on training. During this period several interactive teaching sessions, a nationwide workshop, and various public awareness events were organized. Results. Sixteen patients underwent surgery, functional hemispherectomy (HS) was done in six, anterior temporal lobectomy (ATL) in six, and neuronavigation-guided selective amygdalohippocampectomy (SAH) using keyhole technique in four patients. Minimal morbidity was observed in ATL and, SAH groups. All patients in SAH group (100%) had Grade 1 control, while only 5 patients (83%) in ATL group, and 4 patients (66%) in HS group had Grade 1 control according to Engel's classification, in average followups of 12 months, 24 months and 48 months for SAH, ATL, and HS, respectively. Conclusion. As we share our experience we hope to set a practical example for economically constrained countries that successful epilepsy surgery centers can be managed with limited resources.

Tension arachnoid cyst causing uncal herniation in a 60 year old: a rare presentation.

Arachnoid cysts are congenital benign cysts accounting for approximately 1% of all intracranial mass lesions. Uncal herniation due to arachnoid cyst is a rare mode of presentation. It is hypothesized that only tension arachnoid cyst could cause the life-threatening condition that results from a progressive deterioration and worsening of a simple and usually congenital arachnoid cyst, associated with the formation of a "ball valve" at the point of an opening on the cyst wall. To-date only one case of an arachnoid cyst causing Uncal herniation has been reported to the best of our knowledge. We present a rare case of uncal herniation in a 60-year-old lady caused by a giant left temporal arachnoid cyst. She presented to us in emergency room after experiencing headaches since last one week followed by vomiting, seizures, and altered state of consciousness. She was operated immediately and marsupialization of the arachnoid cyst was performed. She showed good recovery. Although arachnoid cyst is a benign slowly growing pathology, it can lead to Uncal herniation as a "tension" arachnoid cyst, possible due to "ball-valve" mechanism. Elective treatment should be considered to prevent progressive significant enlargement of cyst.

A mechanism-based whole-cell screening assay to identify inhibitors of protein export in Escherichia coli by the Sec pathway.

More than 20% of bacterial proteins are noncytoplasmic, and most of these pass through the SecYEG channel en route to the periplasm, cell membrane, or surrounding environment. The Sec pathway, encompassing SecYEG and several associated proteins (SecA, SecB, YidC, SecDFYajC), is of interest as a potential drug target because it is distinct from targets of current drugs, is essential for bacterial growth, and exhibits dissimilarities in eukaryotes and bacteria that increase the likelihood of selectively inhibiting the microbial pathway. As a step toward validating the pathway as a drug target, we have adapted a mechanism-based whole-cell assay in a manner suitable for high-throughput screening (HTS). The assay uses an engineered strain of Escherichia coli that accumulates beta-galactosidase (ß-gal) in its cytoplasm if translocation through SecYEG is blocked. The assay should facilitate rapid identification of compounds that specifically block the Sec pathway because widely, toxic compounds and nonspecific protein synthesis inhibitors prevent ß-gal production and thus do not register as hits. Testing of current antibiotics confirmed that they do not generally act through the Sec pathway. A mini-screen of 800 compounds indicated the assay's readiness for larger screening projects.

Traumatic retroclival epidural hematoma in pediatric patient-Case report and review of literature.

BACKGROUND: Retroclival epidural hematoma (REDH) is a very rare entity in the practical field of neurosurgery. Only a few cases have been reported in literature. The authors present to you case of a 12-year-old female, a victim of road traffic accident (RTA), who had presented to us with loss of consciousness and seizures. CASE DESCRIPTION: Magnetic resonance imaging revealed retroclival hematoma. She was managed on conservative grounds and discharged with assurance of multiple follow-up visits. CONCLUSION: Very few cases of REDH have been reported in pediatric population to date. It should be suspected in children with head and neck injuries who have been a victim of RTAs. Most likely underdiagnosed due to its rarity; therefore, MRI should be considered when the suspicion is high. Atlanto-occipital dislocation should always be kept under consideration in all cases, and therefore should be managed and monitored very cautiously. In this report, the authors also present concise review of the literature pertaining to the pathogenesis and management of this rare clinical entity which has a high likelihood to be encountered and underdiagnosed by neurosurgeons in Emergency Room.

Computational reprogramming of homing endonuclease specificity at multiple adjacent base pairs.

Site-specific homing endonucleases are capable of inducing gene conversion via homologous recombination. Reprogramming their cleavage specificities allows the targeting of specific biological sites for gene correction or conversion. We used computational protein design to alter the cleavage specificity of I-MsoI for three contiguous base pair substitutions, resulting in an endonuclease whose activity and specificity for its new site rival that of wild-type I-MsoI for the original site. Concerted design for all simultaneous substitutions was more successful than a modular approach against individual substitutions, highlighting the importance of context-dependent redesign and optimization of protein-DNA interactions. We then used computational design based on the crystal structure of the designed complex, which revealed significant unanticipated shifts in DNA conformation, to create an endonuclease that specifically cleaves a site with four contiguous base pair substitutions. Our results demonstrate that specificity switches for multiple concerted base pair substitutions can be computationally designed, and that iteration between design and structure determination provides a route to large scale reprogramming of specificity.

Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model.

Interleukin-10 (IL-10) gene transfection of donor lungs prior to transplantation is an attractive strategy to reduce ischemia-reperfusion induced lung injury. However, experimental data with gene therapy in large animal models of lung transplantation are generally lacking. We have developed a simple clinically applicable technique for adenoviral-mediated gene delivery of human IL-10 to the lung of large animals that provides homogenous gene expression after 12-24 h of transfection. Using this technique of gene delivery, we have studied the dynamics of adenoviral gene delivery to the lung in the setting of lung transplantation. Although there is a persistent inflammatory response to the adenoviral vector, we achieved significant expression of human IL-10 in lung tissue before lung retrieval to obviate the deleterious impact of the adenoviral vector on the donor lung. The administration of adenoviral-mediated human IL-10 to the donor lung reduced ischemia-reperfusion injury and improved graft function after lung transplantation in this pig lung transplantation model. Transfection of adenoviral-mediated human IL-10 to the donor lung prevented the release of inflammatory cytokines such as IL-6 in lung tissue and plasma. We have demonstrated that IL-10 gene therapy has significant potential to prevent or treat the inflammatory response associated with ischemia-reperfusion injury in lung transplantation. In the future, IL-10 gene therapy could also be used for immunomodulation or tolerance induction.

Deprenyl stimulates the efflux of monoamines from the rat hypothalamus in vitro.

The direct effects of L-deprenyl, a monoamine oxidase inhibitor, on the hypothalamus of male Sprague-Dawley rats was investigated by measuring the efflux of norepinephrine (NE), dopamine (DA), serotonin (5-HT), dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) using a combination of high performance liquid chromatography with electrochemical detection and an in vitro incubation system. After measuring basal efflux by incubating the hypothalami with Krebs-Ringers Henseleit (KRH) alone during the first incubation period, hypothalami were incubated either with the medium, KRH alone (0 mM), or KRH containing 0.1, 1, and 10 mM L-deprenyl. During the third incubation period, hypothalami were again incubated with KRH alone to measure the residual effects if any. During the final incubation period, the hypothalami were stimulated with high K(+) KRH. Deprenyl produced a dose-dependent increase in the efflux of NE, DA, and 5-HT from the hypothalami. Neurotransmitter efflux returned to pretreatment levels when L-deprenyl was removed from the medium. In contrast to NE, DA, and 5-HT, the efflux of the metabolites DOPAC and 5-HIAA was inhibited in a dose-dependent fashion after incubation with L-deprenyl. Results from this study demonstrate that L-deprenyl is capable of stimulating the efflux of neurotransmitters in vitro by a direct action on the hypothalamus.

Dual signaling by the alpha(v)beta(3)-integrin activates cytosolic PLA(2) in bovine pulmonary artery endothelial cells.

Vitronectin, which ligates the alpha(v)beta(3)-integrin, increases both lung capillary permeability and lung endothelial Ca(2+). In stable monolayers of bovine pulmonary artery endothelial cells (BPAECs) viewed with confocal microscopy, multimeric vitronectin aggregated the apically located alpha(v)beta(3)-integrin. This caused arachidonate release that was inhibited by pretreating the monolayers with the anti-alpha(v)beta(3) monoclonal antibody (MAb) LM609. No inhibition occurred in the presence of the isotypic MAb PIF6, which recognizes the integrin alpha(v)beta(5). Vitronectin also caused membrane translocation and phosphorylation of cytosolic phospholipase A(2) (cPLA(2)) as well as tyrosine phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) 2. The cPLA(2) inhibitor arachidonyl trifluoromethylketone, the tyrosine kinase inhibitor genistein, and the MAPK kinase inhibitor PD-98059 all blocked the induced arachidonate release. PD-98059 did not inhibit the increase of cytosolic Ca(2+) or cPLA(2) translocation, although it blocked tyrosine phosphorylation of ERK2. Moreover, although the intracellular Ca(2+) chelator MAPTAM also inhibited arachidonate release, it did not inhibit tyrosine phosphorylation of ERK2. These findings indicate that ligation of apical alpha(v)beta(3) in BPAECs caused ERK2 activation and an increase of intracellular Ca(2+), both conjointly required for cPLA(2) activation and arachidonate release. This is the first instance of a tyrosine phosphorylation-initiated "two-hit" signaling pathway that regulates an integrin-induced proinflammatory response.