Computational Strategies in Drug Discovery: Leveraging Subtractive Genomic Analysis for Target Identification.

The utilization of In-silico subtractive genomic analysis has emerged as an important and essential method in modern drug discovery and development since it significantly improves the process of identifying and validating potential targets for discovering novel therapeutic compounds to treat severe infections caused by Antimicrobial-resistant (AMR) - pathogenic species. This review provides a complete overview of the methodology, advantages, disadvantages, and prospects, associated with subtractive genomic research in the context of drug discovery and development. The initial phase of analysis encompasses the retrieval of data, which serves as a foundation for the subsequent data mining process in Phase 1. After data mining, Phase 2 utilizes subtractive channels for the target's non-homology and essentiality analysis. Phase 3 of the study aims to provide a comprehensive understanding of prospective targets by their qualitative characterization. Further, Phase 4 of the study emphasizes on conducting structure-based analyses, which involves the determination, refinement, evaluation, and validation of three-dimensional structures of the target proteins, along with their active site prediction and selection of the novel therapeutic compounds against that active site on the obtained targets through virtual screening and docking studies by utilizing various databases and servers. The therapeutic compounds obtained can be then validated by in vitro and in vivo testing, thereby establishing a connection between the computational predictions and real applications.

Which trap is best? Alternatives to outdoor human landing catches for malaria vector surveillance: a meta-analysis.

BACKGROUND: Human landing catches (HLC) are an entomological collection technique in which humans are used as attractants to capture medically relevant host-seeking mosquitoes. The use of this method has been a topic of extensive debate for decades mainly due to ethical concerns. Many alternatives to HLC have been proposed; however, no quantitative review and meta-analysis comparing HLC to outdoor alternative trapping methods has been conducted. METHODS: A total of 58 comparisons across 12 countries were identified. We conducted a meta-analysis comparing the standardized mean difference of Anopheles captured by HLC and alternative traps. To explain heterogeneity, three moderators were chosen for analysis: trap type, location of study, and species captured. A meta-regression was fit to understand how the linear combination of moderators helped in explaining heterogeneity. The possibility of biased results due to publication bias was also explored. RESULTS: Random-effects meta-analysis showed no statistically significant difference in the mean difference of Anopheles collected. Moderator analysis was conducted to determine the effects of trap type, geographical location of study, and the species of Anopheles captured. On average, tent-based traps captured significantly more Anopheles than outdoor HLC (95% CI: [- .9065, - 0.0544]), alternative traps in Africa captured on average more mosquitoes than outdoor HLC (95% CI: [- 2.8750, - 0.0294]), and alternative traps overall captured significantly more Anopheles gambiae s.l. than outdoor HLC (95% CI: [- 4.4613, - 0.2473]) on average. Meta-regression showed that up to 55.77% of the total heterogeneity found can be explained by a linear combination of the three moderators and the interaction between trap type and species. Subset analysis on An. gambiae s.l. showed that light traps specifically captured on average more of this species than HLC (95% CI: [- 18.3751, - 1.0629]). Publication bias likely exists. With 59.65% of studies reporting p-values less than 0.025, we believe there is an over representation in the literature of results indicating that alternative traps are superior to outdoor HLC. CONCLUSIONS: Currently, there is no consensus on a single "magic bullet" alternative to outdoor HLC. The diversity of many alternative trap comparisons restricts potential metrics for comparisons to outdoor HLC. Further standardization and specific question-driven trap evaluations that consider target vector species and the vector control landscape are needed to allow for robust meta-analyses with less heterogeneity and to develop data-driven decision-making tools for malaria vector surveillance and control.

Clinico-Epidemiological Profile of Dialysis Services in Karnataka, India - A Multicentric Exploratory Study.

Introduction: New challenges in dialysis care delivery confront caregivers with the rise in dialysis numbers. There are significant lacunae in the knowledge and efficient application of dialysis therapy in the absence of a dialysis registry. This multicentric study was conducted by the Nephrology Association of Karnataka to systematically study patient demographics and dialysis characteristics in Karnataka state, India, as a basis for a statewide dialysis registry. Material and Methods: Data were collected from the consenting dialysis centers after institutional ethics board clearances. Residents of Karnataka state, who were confirmed prevalent patients with end-stage renal disease, on either maintenance hemodialysis (HD) or peritoneal dialysis were included. Demographic data of patients and details of dialysis as well as dialysis facilities were collected on an online platform. Statistical analysis was done using SPSS software Version 16. Results: Thirty-two centers contributed to the data of 2,050 patients (males 70.3%, mean age 53.49 ± 14.09 years). Most patients were on HD (95.3%). Diabetes was the commonest cause of chronic kidney disease. About 72% of patients had temporary venous catheters as initial vascular access. In all, 1,156 patients (59.9%) were on thrice weekly HD. Around 65% of the centers were in private hospitals. The majority (90%) of the centers reused dialyzers, 56% reprocessed dialyzers mechanically, and 66% tested viral serology quarterly. Conclusions: This study was one of the initial attempts to capture dialysis data across Karnataka, and it offers useful insight into the existing dialysis demographics and care delivery. Participation of more centers and continued effort to form a dialysis registry for deriving meaningful clinico-epidemiological insight are desirable.

Alphabetical ordering of author surnames in academic publishing: A detriment to teamwork.

INTRODUCTION: In academia, many institutions use journal article publication productivity for making decisions on tenure and promotion, funding grants, and rewarding stellar scholars. Although non-alphabetical sequencing of article coauthoring by the spelling of surnames signals the extent to which a scholar has contributed to a project, many disciplines in academia follow the norm of alphabetical ordering of coauthors in journal publications. By assessing business academic publications, this study investigates the hypothesis that author alphabetical ordering disincentivizes teamwork and reduces the overall quality of scholarship. METHODS: To address our objectives, we accessed data from 21,353 articles published over a 20-year period across the four main business subdisciplines. The articles selected are all those published by the four highest-ranked journals (in each year) and four lower-ranked journals (in each year) for accounting, business technology, marketing, and organizational behavior. Poisson regression and binary logistic regression were utilized for hypothesis testing. RESULTS: This study finds that, although team size among business scholars is increasing over time, alphabetical ordering as a convention in journal article publishing disincentivizes author teamwork. This disincentive results in fewer authors per publication than for publications using contribution-based ordering of authors. Importantly, article authoring teamwork is related to article quality. Specifically, articles written by a single author typically are of lesser quality than articles published by coauthors, but the number of coauthors exhibits decreasing returns to scale-coauthoring teams of one to three are positively related to high-quality articles, but larger teams are not. Alphabetical ordering itself, however, is positively associated with quality even though it inhibits teamwork, but journal article coauthoring has a greater impact on article quality than does alphabetical ordering. CONCLUSIONS: These findings have important implications for academia. Scholars respond to incentives, yet alphabetical ordering of journal article authors conflicts with what is beneficial for the progress of academic disciplines. Based on these findings, we recommend that, to drive the highest-quality research, teamwork should be incentivized-all fields should adopt a contribution-based journal article author-ordering convention and avoid author ordering based upon the spelling of surnames. Although this study was undertaken using articles from business journals, its findings should generalize across all academia.

Gelatinous foam needle tract embolization during CT guided percutaneous transthoracic lung biopsy: A practical and cost effective approach in the community hospital setting.

Gelatinous foam (GelFoam, Pfizer, Inc, New York, NY) is a low cost, readily available material with a wide range of procedural applications. A novel implementation during computed tomography (CT) guided percutaneous lung biopsy to reduce the rates of pneumothorax leading to further intervention with chest tube placement. We present the imaging and outcome of a patient undergoing this procedure in a community hospital setting.

Co-pyrolysis of lignin and plastics using red clay as catalyst in a micro-pyrolyzer.

In the current study, low-density polyethylene and polystyrene were co-pyrolyzed with dealkaline lignin in a micro-reactor at 500 °C with and without low-cost red clay catalyst. The products were analyzed with GC-MS/FID to quantify phenolic compounds, alkanes and alkenes. The synergistic effect between plastics and lignin was studied by comparing the carbon yield of compounds from co-pyrolysis with that from individual pyrolysis. The co-pyrolysis of lignin and polystyrene was also performed at 600, 700 and 800 °C to examine the effect of pyrolysis temperature. The study explores a novel approach to enhance lignin depolymerization with red clay catalyst while utilizing waste plastics.

Endovascular Repair of Renal Artery Anastomotic Pseudoaneurysm Following Living Donor Kidney Transplant.

Renal artery anastomotic pseudoaneurysms, an uncommon complication of transplantation, may result in aneurysm rupture and loss of allograft. We report the case of 50-year-old female with back pain 3 weeks post renal transplantation. CT scan revealed transplant renal artery anastomotic pseudoaneurysm arising from anastomosis of two renal arteries joined together to form a single renal artery that was joined to the aorta. Successful endovascular treatment was achieved with covered stents, resulting in preserved renal function. Follow-up ultrasound at one-day post procedure and CT at 2 months revealed satisfactory renal perfusion with no pseudoaneurysm. Endovascular treatment of transplant renal artery pseudoaneurysms with covered stent and ostial flare balloon technology may be preferred in patients with extensive prior pelvic surgery, as illustrated in this case.

GI hemorrhage arising from splenic artery: intraprocedure cone-beam CT as problem-solving tool to aide in safe catheterization of offending vessel.

We present the case of a 67-year-old female with melena and hypotension who was found to have a bleeding splenic artery pseudoaneurysm subjacent to a large gastric ulcer on computed tomographic angiography. The lesion was angiographically occult on standard anteroposterior and oblique projections. The offending vessel was identified on intraprocedure cone-beam computed tomography (CT). This case illustrates the value of intraprocedure cone-beam CT as a problem-solving tool for the interventional radiologist.

PET/CT presentation of primary effusion lymphoma-like lymphoma unrelated to human herpes virus 8, a rare NHL subtype.

We present a 71-year-old female with human herpes virus 8 (HHV8)-unrelated primary effusion lymphoma (PEL)-like lymphoma. Dyspnea and pericardial effusion led to pericardiocentesis, diagnosing diffuse large B-cell lymphoma. She underwent positron emission tomography/computed tomography (PET/CT), which demonstrated hypermetabolic pericardial, pleural, and ascites fluid without lymphadenopathy elsewhere. Malignant fluid in the absence of lymphadenopathy is a hallmark of PEL. PEL is associated with immunodeficiency states such as acquired immunodeficiency syndrome (AIDS) and infectious agents such as HHV8. Our patient had no such history and had not received immunosuppressive chemotherapy. We present the PET/CT findings of this rare case of HHV8-unrelated PEL-like lymphoma.

Effect of iterative reconstruction algorithms on peripheral MDCT angiography virtual histology plaque volumes: have we been overestimating disease burden?

Our objective was to compare plaque volumes of multidetector computed tomographic images reconstructed using adaptive statistical iterative reconstruction (ASIR), model-based iterative reconstruction (MBIR), and filtered back projection (FBP). We reviewed 25 patients for a total of 50 extremities imaged on the same scanner. Calcified plaque FBP volume (3468.2 ± 2634.8 mm(3)) was higher than ASIR (2548.1 ± 2166.5 mm(3)). Calcified plaque FBP volume was higher than MBIR (mean=2345.7 ± 1935.4 mm(3)). Our findings suggest that traditional FBP methods overestimate disease compared to newer reconstruction methods.

Implementation and evaluation of a performance improvement intervention to address physician documentation deficiencies in abdominal ultrasound.

PURPOSE: For ultrasound reports to meet criteria for coding as abdomen complete (USABC), 8 elements are required: liver, bile ducts, gallbladder, spleen, kidneys, pancreas, inferior vena cava (IVC), and aorta. Failure to document all 8 results in coding as ultrasound abdomen limited. The purposes of our study were to identify deficiencies in documentation, implement a performance improvement intervention to address deficiencies, and evaluate the intervention. METHODS: In the first phase, 50 consecutive USABC reports performed as part of routine medical care were retrospectively analyzed for the presence or absence of the 8 elements required for USABC coding. Subsequently, education regarding current procedural terminology coding in abdominal ultrasound and standardized macros was provided to radiologists. In the second, postintervention phase, an additional 50 consecutive USABC reports were analyzed for the presence or absence of the 8 elements. RESULTS: In the first phase, none (0%) of 50 reports met criteria for USABC. The most commonly omitted elements were IVC (present in 2% of reports) and aorta (present in 6%). After intervention, there was an increase to 37 reports (74%) meeting criteria for USABC. The most commonly omitted elements were IVC (present in 76%) and aorta (present in 86%). Lack of 100% compliance was secondary to failure to update a macro and inaccurately scheduled studies (focused right lower quadrant/appendicitis study scheduled as USABC). CONCLUSIONS: We improved USABC documentation from 0% to 74%. Our compliance rate after intervention was similar to the 75.1% of previously published larger studies. Our study illustrates the efficacy of simple performance improvement interventions to improve abdominal ultrasound documentation.

The use of exploratory factor analysis in public health: a note on parallel analysis as a factor retention criterion.

PURPOSE: Exploratory factor analysis is used to identify latent factors for public health interventions. The most popular factor retention criterion, the eigenvalue greater than one (EVG1) rule, leads to the retention of more factors than warranted. The use of parallel analysis (PA) as a factor retention criterion is recommended. DESIGN: Environmental factors that are likely to affect the propensity of individuals to walk are identified. Results from PA are compared with those obtained by using the EVG1 rule. SETTING: Telephone survey data were collected from three communities (spanning 12 counties) in the Appalachian region. PARTICIPANTS: The sample was composed of adults between the ages of 40 and 65 years. There were 1019 completed surveys. MEASURES: The data on 14 variables, including measures of neighborhood safety, beauty, and access to walking facilities were collected. ANALYSIS: A principal components analysis was performed. The factors retained after using the EVG1 rule were compared with the factors retained after using PA. Varimax rotation was used to aid factor interpretation. RESULTS: The EVG1 rule led to the retention of nearly twice the number of latent factors as did the PA criterion. CONCLUSION: The use of the EVG1 rule in research may mislead policy makers to focus on trivial interventions. They are urged to use PA to obtain more parsimonious and externally valid interventions.

18F-FDG PET/CT of transitional cell carcinoma.

OBJECTIVE: The objective of this article is to provide a practical illustrated review of PET/CT in the imaging evaluation of transitional cell carcinoma. CONCLUSION: Local evaluation of the primary tumor in patients with transitional cell carcinoma on PET is often limited by the obscuring effect of excreted FDG, but assessment of metabolic activity may still be possible through close correlation with CT images. PET/CT may also be helpful in the detection of disease outside the bladder at nodal or more distant sites and in the assessment of recurrent disease.

Interposition grafting of popliteal artery cystic adventitial disease: case report.

Cystic adventitial disease of the popliteal artery is a rare cause of leg claudication occurring primarily in young adults. We report a case of a 41-year-old athletic man who presented with rapidly progressive left leg claudication. Using duplex ultrasound and magnetic resonance angiography, a diagnosis of popliteal artery cystic adventitial disease was made. The cystic popliteal artery was resected and replaced using a prosthetic interposition graft. At the 1.5-year follow-up, the cysts have recurred; however, the related symptoms have not. This is in contrast to a previously reported case of interposition saphenous vein grafting requiring resection due to invasion by recurrent cysts within 6 months.

Induction of FoxP3+CD4+25+ regulatory T cells following hemopoietic stem cell transplantation: role of bone marrow-derived facilitating cells.

The establishment of donor cell lineages following allogeneic bone marrow transplantation is frequently associated with the development of graft-vs-host disease (GVHD). The identification of cell populations that are capable of supporting allogeneic stem cell (SC) engraftment and the induction of tolerance without inducing GVHD could expand the use of this therapy. CD8(+)TCR(-) facilitating cells (FC) have been shown to promote allogeneic SC engraftment with resulting transplantation tolerance across complete MHC barriers without inducing GVHD. Although donor reconstitution in SC plus FC recipients is associated with the induction of regulatory T cell-associated factors, it is not known whether an induction of regulatory T cells and subsequent tolerance is a direct effect of the FC. The current study demonstrates that 1) SC plus FC transplantation results in the induction of donor CD4(+)25(+) regulatory T cells and that FC are present in the spleen of recipients before the induction of these cells, 2) activation of FC with CpG-oligodeoxynucleotide promotes CD4(+)25(-) T cell differentiation into CD4(+)25(+) regulatory T cells in vitro, as demonstrated by cytokine and forkhead/winged helix transcription factor (FoxP3) gene and protein expression, and 3) direct contact between FC and CD4(+)25(-) T cells is required for FoxP3(+)CD4(+)25(+) regulatory T cell induction and is dependent on CD86 expression on FC. This is the first report to demonstrate a mechanism for FC in the induction of regulatory T cells following allogeneic SC plus FC transplantation. The transplantation of donor FC may provide an alternative approach to permit clinical SC engraftment and induction of transplantation tolerance in the future.

Facilitating cells: novel promoters of stem cell alloengraftment and donor-specific transplantation tolerance in the absence of GVHD.

Bone marrow transplantation (BMT) is the treatment of choice for many hematological malignancies and immunopathologies. Unfortunately, success is often impeded by engraftment failure and graft-versus-host disease (GVHD). A rare bone marrow population known as the facilitating cell (FC) has been identified which facilitates stem cell engraftment and circumvents these obstacles in murine experimental models. This review discusses the identification and characterization of this rare population and provides an emerging portrait of FC origin, ontogeny and function. The promotion of durable stem cell engraftment in MHC disparate recipients, GVHD inhibition and tolerance induction by the FC suggests that future therapies in hematopoietic cell transplantation and tolerance induction for solid organ transplants may be significantly improved through the application of FC transplantation.

Reconstitution of allogeneic hemopoietic stem cells: the essential role of FcR gamma and the TCR beta-chain-FCp33 complex.

Transplantation of purified allogeneic hemopoietic stem cells (SC) alone is characterized by a decreased risk of graft-vs-host disease but increased incidence of engraftment failure. It has been established that the facilitating cell (FC) promotes allogeneic SC reconstitution and results in donor-specific transplantation tolerance across MHC disparities, without graft-vs-host disease. Although the requirements for this facilitating function are not well-characterized, it is known that facilitation is dependent on FC expression of a unique heterodimer consisting of the TCR beta-chain (TCRbeta) and a 33-kDa protein, FCp33. The current study confirms that CD3epsilon and TCRbeta expression are present on the FC at the time of transplantation and demonstrates that the majority of cells in the FC population express the TCR signaling molecule, FcRgamma, rather than the more conventional CD3zeta receptor. Of particular significance, we have now demonstrated that FC-mediated allogeneic SC reconstitution is critically dependent on FcRgamma expression and that FcRgamma coprecipitates with the TCRbeta-FCp33 heterodimer. The mandatory requirement of TCRbeta and FcRgamma for FC function provides the first evidence of a previously undescribed role for FcRgamma in the facilitation of allogeneic SC reconstitution and establishes that FcRgamma is part of the TCRbeta-FCp33 complex uniquely expressed on FC.

In vivo imaging of activated endothelium using an anti-VCAM-1 magnetooptical probe.

It has been suggested that vascular cell adhesion molecule-1 (VCAM-1) could serve as an early marker for inflammation of the endothelium. The ability to noninvasively image VCAM-1 could thus be a useful tool to diagnose a number of inflammatory diseases at early stages. Here we demonstrate that magnetooptical nanoparticles conjugated to anti-VCAM-1 antibodies can be used to specifically detect VCAM-1 expression on endothelial cells in culture and in vivo. Elevated VCAM-1 expression was detected on cultured murine heart endothelial cells by both fluorescence and magnetic resonance, while only basal expression levels were detected on murine dermal endothelial cells. Intravital microscopy of a murine inflammatory model injected with the VCAM-1 targeted nanoparticles revealed specific labeling of the activated endothelium, with labeling kinetics yielding a maximum vessel wall signal 6 h after injection. In contrast, nontargeted nanoparticles did not exhibit any specific labeling of the endothelium. These studies suggest that the developed nanoparticle would be useful for MR and optical detection of activated endothelium.

Bone marrow-derived lin(-)c-kit(+)Sca-1+ stem cells do not contribute to vasculogenesis in Lewis lung carcinoma.

The development of tumor vasculature is thought to occur through two complementary processes: sprouting angiogenesis from preexisting blood vessels of the host, and vasculogenesis, which involves the spontaneous development of vessels through specific recruitment, differentiation, and vascular incorporation of circulating endothelial cells (EC), endothelial progenitor cells (EPC), or potentially bone marrow-derived cells. Recent reports, however, have challenged the belief that bone marrow-derived cells contribute to tumor neovascularization, claiming an exclusive role for sprouting angiogenesis in tumor blood vessel development. In the present study, we explored the recruitment behavior of bone marrow-derived lin(-)c-kit(+)Sca-1+ stem cells to subcutaneously implanted Lewis lung carcinoma in a syngeneic bone marrow transplantation model. We observed that although lin(-)c-kit(+)Sca-1+ and their derived cells demonstrate significant recruitment to carcinomas in vivo, they do not appear to functionally contribute to tumor neovascularization. Furthermore, our results support the hypothesis that new vessel formation in carcinomas occurs primarily through endothelialization from adjacent and preexisting vasculature.

PSGL-1 derived from human neutrophils is a high-efficiency ligand for endothelium-expressed E-selectin under flow.

P-selectin glycoprotein ligand-1 (PSGL-1) has been proposed as an important tethering ligand for E-selectin and is expressed at a modest level on human leukocytes. Sialyl Lewis x (sLe(x))-like glycans bind to E-selectin and are expressed at a relatively high level on circulating leukocytes. It is unclear whether PSGL-1 has unique biochemical attributes that contribute to its role as an E-selectin ligand. To probe this issue, we conjugated microspheres with either sLe(x) or PSGL-1 purified from myeloid cells (neutrophils and HL-60) and compared their adhesion to endothelial expressed E-selectin under defined shear conditions. We found that both sLe(x) and PSGL-1 microspheres adhere to 4 h of IL-1beta-activated human umbilical vein endothelial cells predominantly through E-selectin. Analysis of the adhesion revealed that the rate of initial tethering of the PSGL-1 microspheres to E-selectin was significantly greater than the rate of initial tethering of the sLe(x) microspheres despite the fact that the sLe(x) microspheres tested had higher ligand densities than the PSGL-1 microspheres. We also found that pretreatment of the PSGL-1 or sLe(x) microspheres with HECA-452 had no significant effect on initial tethering to E-selectin. These results support the hypotheses that 1) PSGL-1 is a high-efficiency tethering ligand for E-selectin, 2) ligand biochemistry can significantly influence initial tethering to E-selectin, and 3) PSGL-1 tethering to E-selectin can occur via non-HECA-452 reactive epitopes.