Mental health markers and protective factors in students with symptoms of physical pain across WEIRD and non-WEIRD samples - a network analysis.

BACKGROUND: Studies conducted in Western societies have identified variables associated with chronic pain, but few have done so across cultures. Our study aimed to clarify the relationship between specific mental health markers (i.e., depression, anxiety, posttraumatic stress disorder [PTSD], perceived stress) as well as specific protective factors (i.e., social support and self-efficacy) related to physical pain among university students across non-WEIRD and WEIRD samples. METHOD: A total of 188 university students (131 women and 57 men) were included in the study. We used network analysis to ascertain mental health markers especially central to the experience of physical pain. RESULTS: No statistically significant difference was found between mental health markers (i.e., depression, anxiety, perceived stress, and PTSD) and protective factors (i.e., social support and self-efficacy) associated with physical pain symptoms for Swiss students versus Indian students (M = 0.325, p = .11). In addition, networks for Swiss versus Indian students did not differ in global strength (S = 0.29, p = .803). Anxiety was the most central mental health marker, and social support was the most important protective factor related to physical pain in both countries. However, for Swiss students, perceived stress, and for Indian students, PTSD symptoms were central mental health markers related to physical pain. CONCLUSION: Our results identify factors that may serve as important treatment targets for pain interventions among students of both countries before it becomes chronic.

Impact of Patient Education Formats on Treatment Adherence and Denture Hygiene in Edentulous Patients: A Comparative Study.

BACKGROUND Effective communication and patient education are important in geriatric dental care. Memory decline complicates patient adherence. This study aimed to compare verbal, audio, and video patient education material (PEM) and adherence to dental prosthetic management in edentulous patients. MATERIAL AND METHODS 90 completely/partially edentulous patients (aged 40 to 70 years), were divided (simple random) into three groups (Gp) of 30 each . A total of 68 instructions were organized into 9 learning categories. For GpVi, a 20 minute video was shot using a Sony camera (PD170), with two actors depicting related PEM information. Patients were recalled after 1 day and 7days, to recall the PEM instructions. A Denture plaque Index (DPI) determined the efficiency of the instructions at both time intervals. Frequencies, means and standard deviations were derived for each group and then compared using Chi square, paired and unpaired t test and a Neuman-Keul post hoc pairwise test. All significant differences were kept at probability t value of ≤0.05. RESULTS PEM instructions related to patient individuality, proper tongue position and miscellaneous showed poor patient recall. At 1 day interval, audio was found to have better recall than video and verbal in 5 PEM instruction categories. At 7 day interval, video showed better recall than other two groups (P≤0.05). Despite improvements in patients recall, DPI revealed better denture hygiene maintenance in patients receiving instructions through video format (P≤0.05). CONCLUSIONS For all categories, no single media was considered to be sufficient, audio produced early better recall while video influenced long term recall and better denture hygiene maintenance.

Implicit angry faces interfere with response inhibition and response adjustment.

Cognitive control enables people to adjust their thoughts and actions according to the current task demands. Response inhibition and response adjustment are two key aspects of cognitive control. Here, we examined how the implicit processing of emotional information influences these two functions with the help of the double-step saccade task. Each trial had either a single target or two sequential targets. Upon a single target onset, participants were required to make a quick saccade, but upon two target onsets, participants were instructed to inhibit their initial saccades and redirect their gaze to the second target. In three experiments, we manipulated the emotional information of the first and second targets. We found that irrelevant emotional information of the first target impaired response inhibition compared to non-emotional information (geometric shapes) of the first target. When non-emotional information (geometric shape) came as the first target, irrelevant angry emotional faces as the second target interfered with both response inhibition and response adjustment compared to irrelevant happy and neutral faces. We explain these results with previous findings that processing faces with irrelevant angry facial expressions take up many attentional resources, leaving fewer resources available for ongoing activities such as response inhibition and response adjustment.

Relationship of anemia with COVID-19 deaths: A retrospective cross-sectional study.

Background and Aims: With the second wave of COVID-19, India lost close to three lakh people within the span of a few months. In this study, we aimed to investigate the impact of anemia on the severity of COVID-19 based on the hemoglobin (Hb) concentration of the patients noted at the time of admission to the intensive care unit (ICU), to mark Hb as a prognostic marker of disease severity for the future. Material and Methods: Retrospective data was collected from 784 patients admitted to the COVID adult ICU between March and June 2021. Patients were identified as anemic and non-anemic based on the World Health Organization (WHO) guidelines. Chi-squared test was applied to see the relationship of anemia with the patient deaths. Results: Among the 784 patients, 507 succumbed to COVID-19. Of these, 49.3% had varying degrees of anemia. Significant correlation of anemia with death due to COVID-19 was found in males and females (P = 0.002106 and P = 0.033071, respectively) and in patients without any other comorbidities except anemia (P = 0.002020). This suggests that anemia is independently an important parameter that plays a role in severity of COVID-19. Conclusion: Upon observing a significant correlation between anemia and COVID-19 severity, it can be stated that anemia should be considered as an independent prognostic risk factor for COVID-19 and that hemoglobin can be used for risk stratification in patients under home or hospital care.

Mechanism for IL-15-Driven B Cell Chronic Lymphocytic Leukemia Cycling: Roles for AKT and STAT5 in Modulating Cyclin D2 and DNA Damage Response Proteins.

Clonal expansion of B cell chronic lymphocytic leukemia (B-CLL) occurs within lymphoid tissue pseudofollicles. IL-15, a stromal cell-associated cytokine found within spleens and lymph nodes of B-CLL patients, significantly boosts in vitro cycling of blood-derived B-CLL cells following CpG DNA priming. Both IL-15 and CpG DNA are elevated in microbe-draining lymphatic tissues, and unraveling the basis for IL-15-driven B-CLL growth could illuminate new therapeutic targets. Using CpG DNA-primed human B-CLL clones and approaches involving both immunofluorescent staining and pharmacologic inhibitors, we show that both PI3K/AKT and JAK/STAT5 pathways are activated and functionally important for IL-15→CD122/ɣc signaling in ODN-primed cells expressing activated pSTAT3. Furthermore, STAT5 activity must be sustained for continued cycling of CFSE-labeled B-CLL cells. Quantitative RT-PCR experiments with inhibitors of PI3K and STAT5 show that both contribute to IL-15-driven upregulation of mRNA for cyclin D2 and suppression of mRNA for DNA damage response mediators ATM, 53BP1, and MDC1. Furthermore, protein levels of these DNA damage response molecules are reduced by IL-15, as indicated by Western blotting and immunofluorescent staining. Bioinformatics analysis of ENCODE chromatin immunoprecipitation sequencing data from cell lines provides insight into possible mechanisms for STAT5-mediated repression. Finally, pharmacologic inhibitors of JAKs and STAT5 significantly curtailed B-CLL cycling when added either early or late in a growth response. We discuss how the IL-15-induced changes in gene expression lead to rapid cycling and possibly enhanced mutagenesis. STAT5 inhibitors might be an effective modality for blocking B-CLL growth in patients.

Mechanistic Insights into CpG DNA and IL-15 Synergy in Promoting B Cell Chronic Lymphocytic Leukemia Clonal Expansion.

Malignant cell growth within patients with B cell chronic lymphocytic leukemia (B-CLL) is largely restricted to lymphoid tissues, particularly lymph nodes. The recent in vitro finding that TLR-9 ligand (oligodeoxynucleotide [ODN]) and IL-15 exhibit strong synergy in promoting B-CLL growth may be particularly relevant to growth in these sites. This study shows IL-15-producing cells are prevalent within B-CLL-infiltrated lymph nodes and, using purified B-CLL cells from blood, investigates the mechanism for ODN and IL-15 synergy in driving B-CLL growth. ODN boosts baseline levels of phospho-RelA(S529) in B-CLL and promotes NF-κB-driven increases in IL15RA and IL2RB mRNA, followed by elevated IL-15Rα and IL-2/IL-15Rß (CD122) protein. IL-15→CD122 signaling during a critical interval, 20 to 36-48 h following initial ODN exposure, is required for optimal induction of the cycling process. Furthermore, experiments with neutralizing anti-IL-15 and anti-CD122 mAbs indicate that clonal expansion requires continued IL-15/CD122 signaling during cycling. The latter is consistent with evidence of heightened IL2RB mRNA in the fraction of recently proliferated B-CLL cells within patient peripheral blood. Compromised ODN+IL-15 growth with limited cell density is consistent with a role for upregulated IL-15Rα in facilitating homotypic trans IL-15 signaling, although there may be other explanations. Together, the findings show that ODN and IL-15 elicit temporally distinct signals that function in a coordinated manner to drive B-CLL clonal expansion.

Priming by motivationally salient distractors produces hemispheric asymmetries in visual processing.

Stimuli that reliably herald the availability of rewards or punishers can acquire value associations, potentially imbuing them with emotional significance and attentional prioritization. Previous work has shown that an emotional stimulus (prime) presented just prior to an attention-demanding task disrupts performance in a lateralized manner that is independent of the prime's emotional valence. Here, we asked whether neutral stimuli with acquired value associations would similarly disrupt attention. In two experiments, adult participants first learned to associate specific face or chair stimuli with a high or low probability of either winning or losing points. These conditioned stimuli then served as primes in a speeded letter-search task. Primes with high versus low outcome probability, regardless of valence, slowed search for targets appearing in the left but not the right visual hemifield, mirroring previous results using emotional primes, and suggesting that motivational mechanisms that compete for control with non-emotional cognitive processes are right-lateralized in the human brain.

Plakinamine P, A Steroidal Alkaloid with Bactericidal Activity against Mycobacterium tuberculosis.

Tuberculosis is the leading cause of death due to infectious disease worldwide. There is an urgent need for more effective compounds against this pathogen to control the disease. Investigation of the anti-mycobacterial activity of a deep-water sponge of the genus Plakina revealed the presence of a new steroidal alkaloid of the plakinamine class, which we have given the common name plakinamine P. Its structure is most similar to plakinamine L, which also has an acyclic side chain. Careful dissection of the nuclear magnetic resonance data, collected in multiple solvents, suggests that the dimethyl amino group at the 3 position is in an equatorial rather than axial position unlike previously reported plakinamines. Plakinamine P was bactericidal against M. tuberculosis, and exhibited moderate activity against other mycobacterial pathogens, such as M. abscessus and M. avium. Furthermore, it had low toxicity against J774 macrophages, yielding a selectivity index (SI, or IC50/MIC) of 8.4. In conclusion, this work provides a promising scaffold to the tuberculosis drug discovery pipeline. Future work to determine the molecular target of this compound may reveal a pathway essential for M. tuberculosis survival during infection.

Effectiveness of Controlled Release Chlorhexidine Chip as an Adjunctive to Scaling and Root Planning for the Treatment of Chronic Periodontitis.

BACKGROUND: Chlorhexidine is considered one of the options for the management of periodontal diseases. This present study was conducted to assess the usefulness of controlled-release chlorhexidine chip in addition to scaling and root planning (SRP) while comparing with SRP alone in the treatment of chronic periodontitis clinically, microbiologically and radiographically. MATERIALS AND METHODS: This study included 20 patients age ranged from 30 to 55 years with chronic periodontitis. A total of 40 sites were selected. Two bilateral pockets with probing depth 4-6 mm were put in test and control groups in all subjects. SRP plus Periochip™ was used in the test group and SRP alone in the control group. In all subjects, all the analysis such as clinical parameters, the radiographic and anaerobic culture of P. gingivalis, T. denticola, and T. forsythia were performed and compared in both groups at baseline and 3 months interval. RESULTS: There was a significant improvement in all clinical and radiographic parameters in the test group in comparison to control group. Total colony counts also reduced significantly. At baseline, Tf was recovered from 15 test group sites and 16 control group sites, Pg from 14 test group and 14 control group sites, Td from 16 test group and 15 control group sites. At 3 months, Tf was recovered from 4 test group and 10 control group sites, Pg from 3 test group and 9 control group sites, Td from 4 test group and 8 control group site. CONCLUSION: Periochip™ placement as an adjunct to SRP, showed promising results when compared to SRP alone. CLINICAL SIGNIFICANCE: Periochip is considered the best treatment option in the treatment of chronic periodontitis.

Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates Targeting Mycobacterium tuberculosis and Mycobacterium abscessus.

Mycobacterium tuberculosis and the fast-growing species Mycobacterium abscessus are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant M. tuberculosis strains and the high level of intrinsic resistance of M. abscessus call for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), against M. abscessus and M. tuberculosis We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse M. tuberculosis and M. abscessus clinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target the M. tuberculosis gyrase. In vitro enzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against M. tuberculosis and M. abscessus that act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.

PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

Atomic model of the type III secretion system needle.

Pathogenic bacteria using a type III secretion system (T3SS) to manipulate host cells cause many different infections including Shigella dysentery, typhoid fever, enterohaemorrhagic colitis and bubonic plague. An essential part of the T3SS is a hollow needle-like protein filament through which effector proteins are injected into eukaryotic host cells. Currently, the three-dimensional structure of the needle is unknown because it is not amenable to X-ray crystallography and solution NMR, as a result of its inherent non-crystallinity and insolubility. Cryo-electron microscopy combined with crystal or solution NMR subunit structures has recently provided a powerful hybrid approach for studying supramolecular assemblies, resulting in low-resolution and medium-resolution models. However, such approaches cannot deliver atomic details, especially of the crucial subunit-subunit interfaces, because of the limited cryo-electron microscopic resolution obtained in these studies. Here we report an alternative approach combining recombinant wild-type needle production, solid-state NMR, electron microscopy and Rosetta modelling to reveal the supramolecular interfaces and ultimately the complete atomic structure of the Salmonella typhimurium T3SS needle. We show that the 80-residue subunits form a right-handed helical assembly with roughly 11 subunits per two turns, similar to that of the flagellar filament of S. typhimurium. In contrast to established models of the needle in which the amino terminus of the protein subunit was assumed to be α-helical and positioned inside the needle, our model reveals an extended amino-terminal domain that is positioned on the surface of the needle, while the highly conserved carboxy terminus points towards the lumen.

Exploitation of Mangrove Endophytic Fungi for Infectious Disease Drug Discovery.

There is an acute need for new and effective agents to treat infectious diseases. We conducted a screening program to assess the potential of mangrove-derived endophytic fungi as a source of new antibiotics. Fungi cultured in the presence and absence of small molecule epigenetic modulators were screened against Mycobacterium tuberculosis and the ESKAPE panel of bacterial pathogens, as well as two eukaryotic infective agents, Leishmania donovani and Naegleria fowleri. By comparison of bioactivity data among treatments and targets, trends became evident, such as the result that more than 60% of active extracts were revealed to be selective to a single target. Validating the technique of using small molecules to dysregulate secondary metabolite production pathways, nearly half (44%) of those fungi producing active extracts only did so following histone deacetylase inhibitory (HDACi) or DNA methyltransferase inhibitory (DNMTi) treatment.

Solution to Detect, Classify, and Report Illicit Online Marketing and Sales of Controlled Substances via Twitter: Using Machine Learning and Web Forensics to Combat Digital Opioid Access.

BACKGROUND: On December 6 and 7, 2017, the US Department of Health and Human Services (HHS) hosted its first Code-a-Thon event aimed at leveraging technology and data-driven solutions to help combat the opioid epidemic. The authors­an interdisciplinary team from academia, the private sector, and the US Centers for Disease Control and Prevention­participated in the Code-a-Thon as part of the prevention track. OBJECTIVE: The aim of this study was to develop and deploy a methodology using machine learning to accurately detect the marketing and sale of opioids by illicit online sellers via Twitter as part of participation at the HHS Opioid Code-a-Thon event. METHODS: Tweets were collected from the Twitter public application programming interface stream filtered for common prescription opioid keywords in conjunction with participation in the Code-a-Thon from November 15, 2017 to December 5, 2017. An unsupervised machine learning­based approach was developed and used during the Code-a-Thon competition (24 hours) to obtain a summary of the content of the tweets to isolate those clusters associated with illegal online marketing and sale using a biterm topic model (BTM). After isolating relevant tweets, hyperlinks associated with these tweets were reviewed to assess the characteristics of illegal online sellers. RESULTS: We collected and analyzed 213,041 tweets over the course of the Code-a-Thon containing keywords codeine, percocet, vicodin, oxycontin, oxycodone, fentanyl, and hydrocodone. Using BTM, 0.32% (692/213,041) tweets were identified as being associated with illegal online marketing and sale of prescription opioids. After removing duplicates and dead links, we identified 34 unique "live" tweets, with 44% (15/34) directing consumers to illicit online pharmacies, 32% (11/34) linked to individual drug sellers, and 21% (7/34) used by marketing affiliates. In addition to offering the "no prescription" sale of opioids, many of these vendors also sold other controlled substances and illicit drugs. CONCLUSIONS: The results of this study are in line with prior studies that have identified social media platforms, including Twitter, as a potential conduit for supply and sale of illicit opioids. To translate these results into action, authors also developed a prototype wireframe for the purposes of detecting, classifying, and reporting illicit online pharmacy tweets selling controlled substances illegally to the US Food and Drug Administration and the US Drug Enforcement Agency. Further development of solutions based on these methods has the potential to proactively alert regulators and law enforcement agencies of illegal opioid sales, while also making the online environment safer for the public.

Development of a dedicated phantom for multi-target single-isocentre stereotactic radiosurgery end to end testing.

PURPOSE: The aim of this project was to design and manufacture a cost-effective end-to-end (E2E) phantom for quantifying the geometric and dosimetric accuracy of a linear accelerator based, multi-target single-isocenter (MTSI) frameless stereotactic radiosurgery (SRS) technique. METHOD: A perspex Multi-Plug device from a Sun Nuclear ArcCheck phantom (Sun Nuclear, Melbourne, FL) was enhanced to make it more applicable for MTSI SRS E2E testing. The following steps in the SRS chain were then analysed using the phantom: magnetic resonance imaging (MRI) distortion, planning computed tomography (CT) scan and MRI image registration accuracy, phantom setup accuracy using CBCT, dosimetric accuracy using ion chamber, planar film dose measurements and coincidence of linear accelerator mega-voltage (MV), and kilo-voltage (kV) isocenters using Winston-Lutz testing (WLT). RESULTS: The dedicated E2E phantom was able to successfully quantify the geometric and dosimetric accuracy of the MTSI SRS technique. MRI distortions were less than 0.5 mm, or half a voxel size. The average MRI-CT registration accuracy was 0.15 mm (±0.31 mm), 0.20 mm (±0.16 mm), and 0.39 mm (±0.11 mm) in the superior/inferior, left/right and, anterior/posterior directions, respectively. The phantom setup accuracy using CBCT was better than 0.2 mm and 0.1°. Point dose measurements were within 5% of the treatment planning system predicted dose. The comparison of planar film doses to the planning system dose distributions, performed using gamma analysis, resulted in pass rates greater than 97% for 3%/1 mm gamma criteria. Finally, off-axis WLT showed MV/kV coincidence to be within 1 mm for off-axis distances up to 60 mm. CONCLUSION: A novel, versatile and cost-effective phantom for comprehensive E2E testing of MTSI SRS treatments was developed, incorporating multiple detector types and fiducial markers. The phantom is capable of quantifying the accuracy of each step in the MTSI SRS planning and treatment process.

Satisfaction and psychological after effects of legal abortion at a tertiary care teaching hospital of North India.

Psychological assessment using the Beck Depression Inventory II (BDI) on 196 eligible Medical Termination of Pregnancy (MTP) seekers showed that the depression rate prior to MTP was 12 (6.1%) and had increased to 21 (10.7%) 1 month after MTP. Risk factors included primipara, second-trimester abortion, MTP on humanitarian grounds (rape), foetal congenital anomalies and maternal illness. Psychological morbidity due to abortion greatly interferes with the interpersonal, spousal and mother-child relationships. This demands the need of counselling centres so that each MTP seeker could be counselled prior to and after MTP. Impact statement What is already known on this subject? The association between abortion and depression has already been established. But there is a scarcity of information about the association between the psychological morbidity of abortion seekers, prior to and after legal abortions at a tertiary hospital. What do the results of this study add? Our study has not only evaluated the depression rate, but also evaluated the various individual psychological parameters of women with mild mood disorders which might go unnoticed and which certainly interferes with their interpersonal relationships. What are the implications of these findings for clinical practice and/or further research? Early diagnosis and interventions could help these women to have sound interpersonal relations.

Homocysteine and vitamin B12: Other causes of neural tube defects in Eastern Uttar Pradesh and Western Bihar population.

BACKGROUND: Neural tube defects (NTDs) are congenital malformations with an incidence of 1-10/1000 live births. Homocysteine and vitamin B12 metabolism have been shown to be associated with NTDs. AIM: To investigate the status of maternal and neonate's folic acid, homocysteine, and vitamin B12 levels and their association with the risk of development of NTDs in the population of Eastern Uttar Pradeshand Western Bihar, India. MATERIALS AND METHODS: This study is a cross-sectional, retrospective study where 96 mothers who either had a first NTD child or had a history of NTD child in the family and 126 neonates with spina bifida were recruited during the period 2012-2015. Eighty-four control mothers whose previous and current pregnancies were normal, and 87 control neonates who had no defects and were within the same age range as the NTD affected neonates, recruited from the department of pediatric surgery, were enrolled in the study. Plasma concentrations of folic acid, vitamin B12, and homocysteine were compared between cases and controls. RESULTS: The folic acid level in the mothers and neonates was within the normal limit. A significant increase in the level of homocysteine in mothers with affected pregnancy and in neonate cases in comparison to control mothers was obseved. Further, a significant decrease in the level of vitamin B12 in mothers with NTD neonates and in the affected neonates was noted. A negative correlation was found between homocysteine and vitamin B12 levels in case and control mothers. CONCLUSION: A correlation of an increase in serum homocysteine with a decrease in vitamin B12 was seen in mothers of neonates with NTD. A similar observation as made in the neonates with NTDs. It may be suggested that maternal decrease in vitamin B12, in mothers who have normal folic acid may be associated with NTD in their children.

Selective Killing of Dormant Mycobacterium tuberculosis by Marine Natural Products.

The dormant phenotype acquired by Mycobacterium tuberculosis during infection poses a major challenge in disease treatment, since these bacilli show tolerance to front-line drugs. Therefore, it is imperative to find novel compounds that effectively kill dormant bacteria. By screening 4,400 marine natural product samples against dual-fluorescent M. tuberculosis under both replicating and nonreplicating conditions, we have identified compounds that are selectively active against dormant M. tuberculosis This validates our strategy of screening all compounds in both assays as opposed to using the dormancy model as a secondary screen. Bioassay-guided deconvolution enabled the identification of unique pharmacophores active in each screening model. To confirm the activity of samples against dormant M. tuberculosis, we used a luciferase reporter assay and enumerated CFU. The structures of five purified active compounds were defined by nuclear magnetic resonance (NMR) and mass spectrometry. We identified two lipid compounds with potent activity toward dormant and actively growing M. tuberculosis strains. One of these was commercially obtained and showed similar activity against M. tuberculosis in both screening models. Furthermore, puupehenone-like molecules were purified with potent and selective activity against dormant M. tuberculosis In conclusion, we have identified and characterized antimycobacterial compounds from marine organisms with novel activity profiles which appear to target M. tuberculosis pathways that are conditionally essential for dormancy survival.

TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells.

Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) reflects the clone's Ag receptor (BCR) and involves stroma-dependent B-CLL growth within lymphoid tissue. Uniformly elevated expression of TLR-9, occasional MYD88 mutations, and BCR specificity for DNA or Ags physically linked to DNA together suggest that TLR-9 signaling is important in driving B-CLL growth in patients. Nevertheless, reports of apoptosis after B-CLL exposure to CpG oligodeoxynucleotide (ODN) raised questions about a central role for TLR-9. Because normal memory B cells proliferate vigorously to ODN+IL-15, a cytokine found in stromal cells of bone marrow, lymph nodes, and spleen, we examined whether this was true for B-CLL cells. Through a CFSE-based assay for quantitatively monitoring in vitro clonal proliferation/survival, we show that IL-15 precludes TLR-9-induced apoptosis and permits significant B-CLL clonal expansion regardless of the clone's BCR mutation status. A robust response to ODN+IL-15 was positively linked to presence of chromosomal anomalies (trisomy-12 or ataxia telangiectasia mutated anomaly + del13q14) and negatively linked to a very high proportion of CD38(+) cells within the blood-derived B-CLL population. Furthermore, a clone's intrinsic potential for in vitro growth correlated directly with doubling time in blood, in the case of B-CLL with Ig H chain V region-unmutated BCR and <30% CD38(+) cells in blood. Finally, in vitro high-proliferator status was statistically linked to diminished patient survival. These findings, together with immunohistochemical evidence of apoptotic cells and IL-15-producing cells proximal to B-CLL pseudofollicles in patient spleens, suggest that collaborative ODN and IL-15 signaling may promote in vivo B-CLL growth.

Network analysis of psoriasis reveals biological pathways and roles for coding and long non-coding RNAs.

BACKGROUND: Psoriasis is an immune-mediated, inflammatory disorder of the skin characterized by chronic inflammation and hyperproliferation of the epidermis. Differential expression analysis of microarray or RNA-seq data have shown that thousands of coding and non-coding genes are differentially expressed between psoriatic and healthy control skin. However, differential expression analysis may fail to detect perturbations in gene coexpression networks. Sensitive detection of such networks may provide additional insight into important disease-associated pathways. In this study, we applied weighted gene coexpression network analysis (WGCNA) on RNA-seq data from psoriasis patients and healthy controls. RESULTS: RNA-seq was performed on skin samples from 18 psoriasis patients (pre-treatment and post-treatment with the TNF-α inhibitor adalimumab) and 16 healthy controls, generating an average of 52.3 million 100-bp paired-end reads per sample. Using WGCNA, we identified 3 network modules that were significantly correlated with psoriasis and 6 network modules significantly correlated with biologic treatment, with only 16 % of the psoriasis-associated and 5 % of the treatment-associated coexpressed genes being identified by differential expression analysis. In a majority of these correlated modules, more than 50 % of coexpressed genes were long non-coding RNAs (lncRNA). Enrichment analysis of these correlated modules revealed that short-chain fatty acid metabolism and olfactory signaling are amongst the top pathways enriched for in modules associated with psoriasis, while regulation of leukocyte mediated cytotoxicity and regulation of cell killing are amongst the top pathways enriched for in modules associated with biologic treatment. A putative autoantigen, LL37, was coexpressed in the module most correlated with psoriasis. CONCLUSIONS: This study has identified several networks of coding and non-coding genes associated with psoriasis and biologic drug treatment, including networks enriched for short-chain fatty acid metabolism and olfactory receptor activity, pathways that were not previously identified through differential expression analysis and may be dysregulated in psoriatic skin. As these networks are comprised mostly of non-coding genes, it is likely that non-coding genes play critical roles in the regulation of pathways involved in the pathogenesis of psoriasis.