Title: How Is the Infraorbital Nerve Block Performed?
Category: Procedures and Tests
Created: 4/21/2020 12:00:00 AM
Last Editorial Review: 4/21/2020 12:00:00 AM

Title: How Do You Give a Mental Nerve Block?
Category: Procedures and Tests
Created: 4/21/2020 12:00:00 AM
Last Editorial Review: 4/21/2020 12:00:00 AM

Title: How Long Does a Retrobulbar Block Last?
Category: Procedures and Tests
Created: 4/24/2020 12:00:00 AM
Last Editorial Review: 4/24/2020 12:00:00 AM

Title: Baby Boom After Pandemic Lockdowns? Maybe Not
Category: Health News
Created: 5/8/2020 12:00:00 AM
Last Editorial Review: 5/8/2020 12:00:00 AM

Researchers conducted nearly 1,500 online interviews and found that nearly 82% of those surveyed said they didn't plan to conceive during the coronavirus pandemic.

Title: Get Ready for Clocks to 'Spring Ahead'
Category: Health News
Created: 3/6/2020 12:00:00 AM
Last Editorial Review: 3/6/2020 12:00:00 AM

There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor–targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1–targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic "class" effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC₅₀ and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1–targeted combination therapy for Ewing sarcoma.

ABSTRACT

In the absence of a vaccine, multidrug-resistant Neisseria gonorrhoeae has emerged as a major human health threat, and new approaches to treat gonorrhea are urgently needed. N. gonorrhoeae pili are posttranslationally modified by a glycan that terminates in a galactose. The terminal galactose is critical for initial contact with the human cervical mucosa via an interaction with the I-domain of complement receptor 3 (CR3). We have now identified the I-domain galactose-binding epitope and characterized its galactose-specific lectin activity. Using surface plasmon resonance and cellular infection assays, we found that a peptide mimic of this galactose-binding region competitively inhibited the N. gonorrhoeae-CR3 interaction. A compound library was screened for potential drugs that could similarly prohibit the N. gonorrhoeae-CR3 interaction and be repurposed as novel host-targeted therapeutics for multidrug-resistant gonococcal infections in women. Two drugs, methyldopa and carbamazepine, prevented and cured cervical cell infection by multidrug-resistant gonococci by blocking the gonococcal-CR3 I-domain interaction.

IMPORTANCE Novel therapies that avert the problem of Neisseria gonorrhoeae with acquired antibiotic resistance are urgently needed. Gonococcal infection of the human cervix is initiated by an interaction between a galactose modification made to its surface appendages, pili, and the I-domain region of (host) complement receptor 3 (CR3). By targeting this crucial gonococcal–I-domain interaction, it may be possible to prevent cervical infection in females. To this end, we identified the I-domain galactose-binding epitope of CR3 and characterized its galactose lectin activity. Moreover, we identified two drugs, carbamazepine and methyldopa, as effective host-targeted therapies for gonorrhea treatment. At doses below those currently used for their respective existing indications, both carbamazepine and methyldopa were more effective than ceftriaxone in curing cervical infection ex vivo. This host-targeted approach would not be subject to N. gonorrhoeae drug resistance mechanisms. Thus, our data suggest a long-term solution to the growing problem of multidrug-resistant N. gonorrhoeae infections.

ABSTRACT

The obligatory intracellular pathogen Ehrlichia chaffeensis lacks most factors that could respond to oxidative stress (a host cell defense mechanism). We previously found that the C terminus of Ehrlichia surface invasin, entry-triggering protein of Ehrlichia (EtpE; EtpE-C) directly binds mammalian DNase X, a glycosylphosphatidylinositol-anchored cell surface receptor and that binding is required to induce bacterial entry and simultaneously to block the generation of reactive oxygen species (ROS) by host monocytes and macrophages. However, how the EtpE-C–DNase X complex mediates the ROS blockade was unknown. A mammalian transmembrane glycoprotein CD147 (basigin) binds to the EtpE-DNase X complex and is required for Ehrlichia entry and infection of host cells. Here, we found that bone marrow-derived macrophages (BMDM) from myeloid cell lineage-selective CD147-null mice had significantly reduced Ehrlichia-induced or EtpE-C-induced blockade of ROS generation in response to phorbol myristate acetate. In BMDM from CD147-null mice, nucleofection with CD147 partially restored the Ehrlichia-mediated inhibition of ROS generation. Indeed, CD147-null mice as well as their BMDM were resistant to Ehrlichia infection. Moreover, in human monocytes, anti-CD147 partially abrogated EtpE-C-induced blockade of ROS generation. Both Ehrlichia and EtpE-C could block activation of the small GTPase Rac1 (which in turn activates phagocyte NADPH oxidase) and suppress activation of Vav1, a hematopoietic-specific Rho/Rac guanine nucleotide exchange factor by phorbol myristate acetate. Vav1 suppression by Ehrlichia was CD147 dependent. E. chaffeensis is the first example of pathogens that block Rac1 activation to colonize macrophages. Furthermore, Ehrlichia uses EtpE to hijack the unique host DNase X-CD147-Vav1 signaling to block Rac1 activation.

IMPORTANCE Ehrlichia chaffeensis is an obligatory intracellular bacterium with the capability of causing an emerging infectious disease called human monocytic ehrlichiosis. E. chaffeensis preferentially infects monocytes and macrophages, professional phagocytes, equipped with an arsenal of antimicrobial mechanisms, including rapid reactive oxygen species (ROS) generation upon encountering bacteria. As Ehrlichia isolated from host cells are readily killed upon exposure to ROS, Ehrlichia must have evolved a unique mechanism to safely enter phagocytes. We discovered that binding of the Ehrlichia surface invasin to the host cell surface receptor not only triggers Ehrlichia entry but also blocks ROS generation by the host cells by mobilizing a novel intracellular signaling pathway. Knowledge of the mechanisms by which ROS production is inhibited may lead to the development of therapeutics for ehrlichiosis as well as other ROS-related pathologies.

In plants, water use efficiency (WUE) is a complex trait arising from numerous physiological and developmental characteristics. Here, we investigated the involvement of circadian regulation in long-term WUE in Arabidopsis (Arabidopsis thaliana) under light and dark conditions. Circadian rhythms are generated by the circadian oscillator, which provides a cellular measure of the time of day. In plants, the circadian oscillator contributes to the regulation of many aspects of physiology, including stomatal opening, rate of photosynthesis, carbohydrate metabolism, and developmental processes such as the initiation of flowering. We investigated the impact of the misregulation of numerous genes encoding various components of the circadian oscillator on whole plant, long-term WUE. From this analysis, we identified a role for the circadian oscillator in WUE. It appears that the circadian clock contributes to the control of transpiration and biomass accumulation. We also established that the circadian oscillator within guard cells can contribute to long-term WUE. Our experiments indicate that knowledge of circadian regulation will be important for developing crops with improved WUE.

Active matter, both synthetic and biological, demonstrates complex spatiotemporal self-organization and the emergence of collective behavior. A coherent rotational motion, the vortex phase, is of great interest because of its ability to orchestrate well-organized motion of self-propelled particles over large distances. However, its generation without geometrical confinement has been a...

Dependence of drug metabolism on dosing time has long been recognized. However, only recently are the underlying mechanisms for circadian drug metabolism being clarified. Diurnal rhythmicity in expression of drug-metabolizing enzymes is believed to be a key factor determining circadian metabolism. Supporting the notion that biological rhythms are generated and maintained by the circadian clock, a number of diurnal enzymes are under the control of the circadian clock. In general, circadian clock genes generate and regulate diurnal rhythmicity in drug-metabolizing enzymes via transcriptional actions on one or two of three cis-elements (i.e., E-box, D-box, and Rev-erb response element or RAR-related orphan receptor response element). Additionally, cycling or clock-controlled nuclear receptors such as hepatocyte nuclear factor 4α and peroxisome proliferator–activated receptor are contributors to diurnal enzyme expression. These newly discovered mechanisms for each of the rhythmic enzymes are reviewed in this article. We also discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity, which has direct implications for chronotherapeutics. Our discussion is also extended to two diurnal transporters (P-glycoprotein and multidrug resistance-associated protein 2) that have an important role in drug absorption. Although the experimental evidence is lacking in metabolism-based chronoefficacy, circadian genes (e.g., Rev-erbα) as drug targets are shown to account for diurnal variability in drug efficacy.

Site-specific arrest of RNA polymerases (RNAPs) is fundamental to several technologies that assess RNA structure and function. Current in vitro transcription “roadblocking” approaches inhibit transcription elongation by blocking RNAP with a protein bound to the DNA template. One limitation of protein-mediated transcription roadblocking is that it requires inclusion of a protein factor extrinsic to the minimal in vitro transcription reaction. In this work, we developed a chemical approach for halting transcription by Escherichia coli RNAP. We first established a sequence-independent method for site-specific incorporation of chemical lesions into dsDNA templates by sequential PCR and translesion synthesis. We then show that interrupting the transcribed DNA strand with an internal desthiobiotin-triethylene glycol modification or 1,N6-etheno-2'-deoxyadenosine base efficiently and stably halts Escherichia coli RNAP transcription. By encoding an intrinsic stall site within the template DNA, our chemical transcription roadblocking approach enables display of nascent RNA molecules from RNAP in a minimal in vitro transcription reaction.

B-cell receptor (BCR) signaling pathway components represent promising treatment targets in multiple B-cell malignancies including diffuse large B-cell lymphoma (DLBCL). In in vitro and in vivo model systems, a subset of DLBCLs depend upon BCR survival signals and respond to proximal BCR/phosphoinositide 3 kinase (PI3K) blockade. However, single-agent BCR pathway inhibitors have had more limited activity in patients with DLBCL, underscoring the need for indicators of sensitivity to BCR blockade and insights into potential resistance mechanisms. Here, we report highly significant transcriptional upregulation of C-X-C chemokine receptor 4 (CXCR4) in BCR-dependent DLBCL cell lines and primary tumors following chemical spleen tyrosine kinase (SYK) inhibition, molecular SYK depletion or chemical PI3K blockade. SYK or PI3K inhibition also selectively upregulated cell surface CXCR4 protein expression in BCR-dependent DLBCLs. CXCR4 expression was directly modulated by fork-head box O1 via the PI3K/protein kinase B/forkhead box O1 signaling axis. Following chemical SYK inhibition, all BCR-dependent DLBCLs exhibited significantly increased stromal cell-derived factor-1α (SDF-1α) induced chemotaxis, consistent with the role of CXCR4 signaling in B-cell migration. Select PI3K isoform inhibitors also augmented SDF-1α induced chemotaxis. These data define CXCR4 upregulation as an indicator of sensitivity to BCR/PI3K blockade and identify CXCR4 signaling as a potential resistance mechanism in BCR-dependent DLBCLs.

Oncolytic virotherapy can lead to systemic antitumor immunity, but the therapeutic potential of oncolytic viruses in humans is limited due to their insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). Here, we showed that locoregional oncolytic virotherapy upregulated the expression of PD-L1 in the TME, which was mediated by virus-induced type I and type II IFNs. To explore PD-1/PD-L1 signaling as a direct target in tumor tissue, we developed a novel immunotherapeutic herpes simplex virus (HSV), OVH-aMPD-1, that expressed a single-chain variable fragment (scFv) against PD-1 (aMPD-1 scFv). The virus was designed to locally deliver aMPD-1 scFv in the TME to achieve enhanced antitumor effects. This virus effectively modified the TME by releasing damage-associated molecular patterns, promoting antigen cross-presentation by dendritic cells, and enhancing the infiltration of activated T cells; these alterations resulted in antitumor T-cell activity that led to reduced tumor burdens in a liver cancer model. Compared with OVH, OVH-aMPD-1 promoted the infiltration of myeloid-derived suppressor cells (MDSC), resulting in significantly higher percentages of CD155⁺ granulocytic-MDSCs (G-MDSC) and monocytic-MDSCs (M-MDSC) in tumors. In combination with TIGIT blockade, this virus enhanced tumor-specific immune responses in mice with implanted subcutaneous tumors or invasive tumors. These findings highlighted that intratumoral immunomodulation with an OV expressing aMPD-1 scFv could be an effective stand-alone strategy to treat cancers or drive maximal efficacy of a combination therapy with other immune checkpoint inhibitors.

In Lysobacter enzymogenes OH11, RpfB1 and RpfB2 were predicted to encode acyl coenzyme A (CoA) ligases. RpfB1 is located in the Rpf gene cluster. Interestingly, we found an RpfB1 homolog (RpfB2) outside this canonical gene cluster, and nothing is known about its functionality or mechanism. Here, we report that rpfB1 and rpfB2 can functionally replace EcFadD in the Escherichia coli fadD mutant JW1794. RpfB activates long-chain fatty acids (n-C_16:0 and n-C_18:0) for the corresponding fatty acyl-CoA ligase (FCL) activity in vitro, and Glu-361 plays critical roles in the catalytic mechanism of RpfB1 and RpfB2. Deletion of rpfB1 and rpfB2 resulted in significantly increased heat-stable antifungal factor (HSAF) production, and overexpression of rpfB1 or rpfB2 completely suppressed HSAF production. Deletion of rpfB1 and rpfB2 resulted in increased L. enzymogenes diffusible signaling factor 3 (LeDSF3) synthesis in L. enzymogenes. Overall, our results showed that changes in intracellular free fatty acid levels significantly altered HSAF production. Our report shows that intracellular free fatty acids are required for HSAF production and that RpfB affects HSAF production via FCL activity. The global transcriptional regulator Clp directly regulated the expression of rpfB1 and rpfB2. In conclusion, these findings reveal new roles of RpfB in antibiotic biosynthesis in L. enzymogenes.

IMPORTANCE Understanding the biosynthetic and regulatory mechanisms of heat-stable antifungal factor (HSAF) could improve the yield in Lysobacter enzymogenes. Here, we report that RpfB1 and RpfB2 encode acyl coenzyme A (CoA) ligases. Our research shows that RpfB1 and RpfB2 affect free fatty acid metabolism via fatty acyl-CoA ligase (FCL) activity to reduce the substrate for HSAF synthesis and, thereby, block HSAF production in L. enzymogenes. Furthermore, these findings reveal new roles for the fatty acyl-CoA ligases RpfB1 and RpfB2 in antibiotic biosynthesis in L. enzymogenes. Importantly, the novelty of this work is the finding that RpfB2 lies outside the Rpf gene cluster and plays a key role in HSAF production, which has not been reported in other diffusible signaling factor (DSF)/Rpf-producing bacteria.

The impact on survival of steroids and TNFα blockade to treat immune-related toxicity from checkpoint blockade with ipilimumab, nivolumab/pembrolizumab, or combined ipilimumab and nivolumab was assessed using data from a large national database. Using steroids was associated with better survival than the use of TNFα-blocking antibodies such as infliximab.

See related article by Verheijden et al., p. 2268

Symmetric division of stem cells positive for gastrin receptor CCK2R is linked to gastric cancer.

Cho tôi hỏi bảng giá xây tô gạch bê tông siêu nhẹ bao nhiêu 1m2? Tô trần tô dầm tô cột? Hàng rào cao 3m xây bằng gạch block 10x20x40 dk 500x1000 giá bao nhiêu?

गुजरात से 1200 श्रमिकों को लेकर स्पेशल ट्रेन पहुंची कासगंज

भारतीय सिनेमा में बाहर से जितनी चकाचौंध दिखती है, अंदर जाकर उतना ही अंधेरा है। यहां पर स्टार किड्स के लिए रास्ता तो बहुत आसान है लेकिन जिनका इस इंडस्ट्री से कोई लेना देना नहीं रहा है

कोरोना वायरस की वजह से पूरे भारत में लॉकडाउन लागू है। इसके चलते लोगों को परेशानियां तो हो ही रही हैं। जो लोग अपने घर हैं और आसपास का माहौल कुछ हद तक ठीक है, वे तो फिर भी ठीक हैं। लेकिन, बाहर फंसे लोगों के लिए तो ये मुश्किलों भरा वक्त है।

कोरोना वायरस के चलते पूरे देश में जारी लॉकडाउन की वजह से 25 मार्च से बंद पड़े रेस्टोरेंट, क्लब और बार आदि को कर्नाटक सरकार ने राज्य में शराब की थोक कीमत पर बिक्री करने की अनुमति दे दी है।

गुरुग्राम के डीएलएफ स्थित कार्लटन एस्टेट सोसाइटी में आत्महत्या मामले में परिजनों और दोस्तों द्वारा कार्रवाई की मांग के बाद किशोरी अपने बचाव में आ गई है।

श्रम मंत्री हरक सिंह का कहना है कि 15 दिन के अंदर ही यह धनराशि श्रमिकों के खातों में पहुंच जाएगी

बिहार सरकार से डाकघर में खुले खाते में आर्थिक मदद की आस लगाए श्रमिक पोस्ट ऑफिस में इंडियन पोस्ट पेमेंट बैंकिंग (आईपीपीबी) का खाता खुलवाने पहुंच रहे हैं।

उत्तराखंड बोर्ड की परीक्षाएं इसी महीने हो सकती हैं। वहीं बोर्ड का रिजल्ट भी 10 जून से पहले घोषित किया जा सकता है।

कोरोना लॉकडाउन के दौरान पैदा हुई मुश्किलों को आसान करने के लिए देहरादून के युवाओं ने कुछ अलग किया है।

अस्थि विर्सजन से रोक हटने से कई लोगों ने राहत की सास ली है। वे अब श्मशान घाटों में रखीं परिजनों की अस्थियों को गंगा में विर्सजित कर सकेंगे।

उत्तराखंड में पूर्व सैनिकों के लिए अब सेना की कैंटीनों में शराब उपलब्ध कराई जाएगी।

प्रदेश के ऐसे लोग जो दूसरे राज्य में नौकरी या अन्य काम करते हैं और निजी वाहन से जाना चाहते हैं, वह http://smartcitydehradun.uk.gov.in/e-pass पर आवेदन कर ई-पास बनवा सकते हैं।

अन्य राज्यों में फंसे प्रवासियों को उत्तराखंड लाने के लिए अब 10 मई से स्पेशल ट्रेनें नहीं चलेगी। ये ट्रेन कब से चलेंगी अभी यह तारीख तय नहीं है।

लॉकडाउन के बीच जहां अपने भी मदद नहीं कर पा रहे हैं। ऐसे में महिला पुलिसकर्मी और एक युवक ने इंसानियत की मिसाल पेश की है।

लॉकडाउन के चलते स्कूल-कॉलेज बंद होने से समाज कल्याण की ओर से किया जाने वाला छात्रवृत्ति का भौतिक सत्यापन अधर में रह गया है।

Against The Clock is a series where we give an artist 10 minutes in the studio and see what they come up with. English-born, Shanghai-based producer Jamie Charlton is better known as Swimful. A member of the city’s SVBKVLT crew, he’s known for crafting melody-rich beats with elements of hip-hop, grime and dancehall, and collaborated with […]

The post Against The Clock: Swimful appeared first on FACT Magazine.

कोरोना वायरस को फैलने से रोकने के लिए पूरे देश में 17 मई तक लॉकडाउन लागू है। हिमाचल में लॉकडाउन के साथ कर्फ्यू भी लागू है।

हिमाचल में 15 जून से शुरू होने वाले सेब सीजन से पहले बागवानों के लिए मजदूरों का संकट खड़ा हो गया है।

A 3D printed grate can be used to make a smart window that blocks heat from sunlight out in the summer while letting it through in the winter, conserving energy

People in lockdown are no longer trying to use technology to get their old lives back and that's a good thing, says Annalee Newitz

पश्चिमी यूपी के विभिन्न जिलों में कोरोना दोबारा अपने पांव पसार रहा है वहीं संक्रमण को लेकर लोग अभी भी संजीदा नहीं हैं -

For the past two months, Katie Holliday has been cooped up alone in her Brooklyn apartment thinking longingly about an unlikely erogenous zone: the lower half of a stranger’s face. 

“I remember joking to my friend before all of this started, ‘Imagine if someone’s face becomes their most coveted body part?’” Holliday, who is 31, told The Daily Beast. “‘When someone removes their mask, is it a sign of trust? Is it like letting someone see you naked?’ I was kidding back then, but now it’s reality.”

Holliday doesn’t know exactly when it will be safe to start seeing people like she did before the pandemic began, but she’ll return to a singles scene unlike any other in history. “I’m picturing walking into a bar where everyone’s wearing masks,” she said. “I’ll meet someone whose face is covered. Are they cute or not? I don’t know!” 

Read more at The Daily Beast.

THE CORONAVIRUS lockdown is now causing serious damage to the UK's economy, Tory MP Steve Baker has warned - stressing he was now "gravely concerned" at the situation

CORONAVIRUS has forced people to re-evaluate their finances as income takes a hit and budgets are stretched. One of the first port of calls for change has been direct debits and new research reveals that some people may find themselves with more cash available once this all ends.

उत्तराखंड में कोरोना वायरस संक्रमण के मद्देनजर अब सिर्फ हरिद्वार जनपद ही रेड जोन में बचा है। स्वास्थ्य मंत्रालय ने ऊधमसिंह नगर और अल्मोड़ा जनपद को ग्रीन जोन घोषित कर दिया है।

हालात में सुधार के बावजूद रेड जोन में शामिल हरिद्वार जिले को लोगों को भी आज से बड़ी राहत मिलेगी।

हरिद्वार में ज्वालापुर के आंबेडकर नगर में भाजपा की ओर से बांटी गई राशन किट में मरा हुआ चूहा और कीड़े निकलने के प्रकरण ने तूल पकड़ लिया है।

लॉकडाउन के बीच दिल्ली से पैदल चलकर उत्तराखंड पहुंचे यूक्रेन के नागरिक को पुलिस ने हरिद्वार में पकड़ लिया। जैसे ही वह चिड़ियापुर चैकपोस्ट श्यामपुर पहुंचा तो वहां पुलिस ने चेकिंग के दौरान उसे रोक लिया।