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Objectives To investigate the effect of adjunct micro-interventional pre-treatment for nucleus disassembly on the surgical efficiency of non-cavitating lensectomy during cataract surgery. Methods and analysis 12 surgeons performed 512 consecutive cataract extractions using a sonic cavitation-free lensectomy with or without adjunct pre-treatment for nucleus disassembly. There were 2 interventional arms including (1) lensectomy without adjunct pre-treatment and (2) lensectomy with micro-interventional miLOOP pre-treatment. Results Successful lensectomy was achieved in all eyes using cavitation-free sonic lensectomy. Average baseline cataract density was 2.28 and 2.39 in the three groups, respectively. Compared to no pre-treatment, nucleus evacuation time was 24% (p = < 0.001) faster with micro-interventional nucleus disassembly. Irrigation/aspiration (I/A) time was 14% faster with the micro-interventional pre-treatment (p = < 0.001). Irrigation fluid use was 24% less with micro-interventional. There was a low rate of capsular tear of 1 case across 512 cases with no other unanticipated complications. Conclusion Micro-interventional pre-treatment for nucleus disassembly was associated with improved lensectomy time and fluidic efficiency compared to no pre-treatment. Non-cavitating lensectomy with the miCOR lens pen achieved effective fragmentation and extraction in all grades of cataract.

Purpose: Manufacturing MSMEs are in need to identify new ideas and work on ideas to implement them into their process to create new or improved products. Innovation management is a prerequisite and has a direct effect on a firm’s performance. Innovation allows firms to secure a market position and create value by making new customers. This study attempts to find the relationship between innovative capabilities and the firm’s performance in manufacturing MSMEs and how the commercial capabilities of the firm moderate the relationship.   Theoretical Framework: Several studies have been reviewed to identify the relationship between innovation, firm performance, and commercial capabilities. A necessitated gap in the literature was identified and the factors were established.   Design/Methodology/approach: This study was done among the manufacturing MSMEs in India. A structured questionnaire was circulated to the top performing MSMEs in every state of India and the responses were collected through email. A total of 384 responses were collected at the end of the data collection period. The scale of the measure was adopted and it has measured reliability and validity scores to get to be used in this study.   Findings: The results of the study showed that the innovative capability of manufacturing MSMEs has a significant positive relationship with the firm’s performance. The moderation analysis showed that the manufacturing capability and marketing capability significantly moderate the relationship between innovative capability and a firm’s performance.   Research, Practical & Social Implications: This study provides the managers of the manufacturing MSMEs to rely on investment in innovation however they are moderately influenced by networking, R&D, and commercial capabilities of the business.   Originality/Value: Contributes to the existing body of knowledge theoretically and empirically by including diverse demographic respondents the results obtained were unique and universally applicable.

This paper studies the network model in SLN by applying the methodology of social network to a widely accepted, real-life user interactive network scenario. The data and experiments are based on micro-blogging (Sina Weibo). Results show that the statistic properties of SLN are in close analogy with that of social network. Contrary to our normal understanding, some nodes with too much semantics (especially under one category) are in decreased chances of having links from newly added nodes.

The authors have often use uniform distribution to describe diversity of agent values. And this description often used in agent simulation, which mimics real society on computer which they call an artificial society. In this article, they show that, an agent simulation under uniform distribution may cause wide divergence of final convergent consensus points, though they give a fixed initial macro consensus value to an artificial society facing an alternative decision. Because intuitive observation provides a same convergent value of final consensus for a given initial value of macro consensus, they call this uncertainty or divergence of the final consensus the pitfall of agent simulation. Through numerous simulations, they found that, the divergent final consensus have some order and the mechanism of the uncertainty were unveiled in this article.

Mitochondrial abnormalities have been noted in lupus, but the causes and consequences remain obscure. Autophagy-related genes ATG5 , ATG7 and IRGM have been previously implicated in autoimmune disease. We reasoned that failure to clear defective mitochondria via mitophagy might be a foundational driver in autoimmunity by licensing mitochondrial DNA–dependent induction of type I interferon. Here, we show that mice lacking the GTPase IRGM1 (IRGM homolog) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired the execution of mitophagy with cell-specific consequences. In fibroblasts, mitochondrial DNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-dependent type I interferon, whereas in macrophages, lysosomal Toll-like receptor 7 was activated. In vivo, Irgm1 –/– tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology was abolished and lung pathology was attenuated by cGAS and STING deletion, pancreatic pathology remained unchanged. These findings reveal fundamental connections between mitochondrial quality control and tissue-selective autoimmune disease. Fessler and colleagues report that loss of the IFN-γ-induced GTPase IRGM1 results in autoinflammatory disease. Deficient IRGM1 activity led to defective lysosomal maturation and impaired mitophagy, prompting the release of cytosolic mtDNA and thereby activating the cGAS–STING pathway.

Salmonella enterica serotype Typhimurium ( S . Typhimurium) causes acute gut inflammation by using its virulence factors to invade the intestinal epithelium and survive in mucosal macrophages. The inflammatory response enhances the transmission success of S . Typhimurium by promoting its outgrowth in the gut lumen through unknown mechanisms. Here we show that reactive oxygen species generated during inflammation react with endogenous, luminal sulphur compounds (thiosulphate) to form a new respiratory electron acceptor, tetrathionate. The genes conferring the ability to use tetrathionate as an electron acceptor produce a growth advantage for S . Typhimurium over the competing microbiota in the lumen of the inflamed gut. We conclude that S . Typhimurium virulence factors induce host-driven production of a new electron acceptor that allows the pathogen to use respiration to compete with fermenting gut microbes. Thus the ability to trigger intestinal inflammation is crucial for the biology of this diarrhoeal pathogen. A gut pathogen gains an edge The ability of the enteric pathogen Salmonella enterica serotype Typhimurium to use tetrathionate as a terminal electron acceptor has been used in the laboratory as a convenient means of enriching growth media containing this bacterium for many years. Tetrathionate respiration was thought to have little importance during infection, but to come into its own in free-living bacteria in environments containing tetrathionate, such as soil or decomposing carcasses. Now a possible role has been identified for this metabolism during intestinal infection. Acute intestinal inflammation induced by S. enterica Typhimurium virulence factors is shown to be accompanied by production of oxygen radicals in the gut lumen as part of the immune response. These oxygen radicals oxidize thiosulphate, the end product of hydrogen-sulphide detoxification by enterocytes, to tetrathionate. The pathogen can then use tetrathionate respiration during growth in the inflamed intestine, allowing it to out-compete other microbes that rely on anaerobic fermentation. Salmonella enterica serotype Typhimurium causes acute gut inflammation, which promotes the growth of the pathogen through unknown mechanisms. It is now shown that the reactive oxygen species generated during inflammation react with host-derived sulphur compounds to produce tetrathionate, which the pathogen uses as a terminal electron acceptor to support its growth. The ability to use tetrathionate provides the pathogen with a competitive advantage over bacteria that lack this property.

A new class of peptides, mambalgins, is isolated from the African snake the black mamba, which can abolish pain through inhibition of particular subtypes of acid-sensing ion channels expressed either in central or peripheral neurons. An alternative channel for pain relief This paper reports the isolation of a new class of peptides from the African black mamba snake that can abolish pain through the inhibition of particular subtypes of acid-sensing channel (ASIC) expressed either in central or peripheral neurons. These peptides — called mambalgins — are as effective as morphine when it comes to pain relief but are nontoxic in mice and do not induce tolerance or respiratory distress. Their effect differs from the analgesia associated with previously identified animal peptides that can block ASICs, whose action involves activation of the enkephalin system. Polypeptide toxins have played a central part in understanding physiological and physiopathological functions of ion channels 1 , 2 . In the field of pain, they led to important advances in basic research 3 , 4 , 5 , 6 and even to clinical applications 7 , 8 . Acid-sensing ion channels (ASICs) are generally considered principal players in the pain pathway 9 , including in humans 10 . A snake toxin activating peripheral ASICs in nociceptive neurons has been recently shown to evoke pain 11 . Here we show that a new class of three-finger peptides from another snake, the black mamba, is able to abolish pain through inhibition of ASICs expressed either in central or peripheral neurons. These peptides, which we call mambalgins, are not toxic in mice but show a potent analgesic effect upon central and peripheral injection that can be as strong as morphine. This effect is, however, resistant to naloxone, and mambalgins cause much less tolerance than morphine and no respiratory distress. Pharmacological inhibition by mambalgins combined with the use of knockdown and knockout animals indicates that blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b-containing channels in nociceptors is involved in the analgesic effect of mambalgins. These findings identify new potential therapeutic targets for pain and introduce natural peptides that block them to produce a potent analgesia.

Tissue homeostasis requires balanced self-renewal and differentiation of stem/progenitor cells, especially in tissues that are constantly replenished like the esophagus. Disruption of this balance is associated with pathological conditions, including eosinophilic esophagitis (EoE), in which basal progenitor cells become hyperplastic upon proinflammatory stimulation. However, how basal cells respond to the inflammatory environment at the molecular level remains undetermined. We previously reported that the bone morphogenetic protein (BMP) signaling pathway is critical for epithelial morphogenesis in the embryonic esophagus. Here, we address how this pathway regulates tissue homeostasis and EoE development in the adult esophagus. BMP signaling was specifically activated in differentiated squamous epithelium, but not in basal progenitor cells, which express the BMP antagonist follistatin. Previous reports indicate that increased BMP activity promotes Barrett's intestinal differentiation; however, in mice, basal progenitor cell-specific expression of constitutively active BMP promoted squamous differentiation. Moreover, BMP activation increased intracellular ROS levels, initiating an NRF2-mediated oxidative response during basal progenitor cell differentiation. In both a mouse EoE model and human biopsies, reduced squamous differentiation was associated with high levels of follistatin and disrupted BMP/NRF2 pathways. We therefore propose a model in which normal squamous differentiation of basal progenitor cells is mediated by BMP-driven NRF2 activation and basal cell hyperplasia is promoted by disruption of BMP signaling in EoE.

Dopamine (DA) plays a critical role in the brain, and the ability to directly measure dopaminergic activity is essential for understanding its physiological functions. We therefore developed red fluorescent G-protein-coupled receptor-activation-based DA (GRAB DA ) sensors and optimized versions of green fluorescent GRAB DA sensors. In response to extracellular DA, both the red and green GRAB DA sensors exhibit a large increase in fluorescence, with subcellular resolution, subsecond kinetics and nanomolar-to-submicromolar affinity. Moreover, the GRAB DA sensors resolve evoked DA release in mouse brain slices, detect evoked compartmental DA release from a single neuron in live flies and report optogenetically elicited nigrostriatal DA release as well as mesoaccumbens dopaminergic activity during sexual behavior in freely behaving mice. Coexpressing red GRAB DA with either green GRAB DA or the calcium indicator GCaMP6s allows tracking of dopaminergic signaling and neuronal activity in distinct circuits in vivo. Red and improved green versions of the genetically encoded dopamine sensor GRAB DA have been developed. These neurotransmitter sensors are used alone or in combination with, for example, calcium sensors in behaving fruit flies and rodents.

Clock neurons projecting from the suprachiasmatic nucleus activate a thirst-related brain area in mice to cause a surge in drinking just before sleep and thereby to prevent dehydration during the sleep period. Neural circuits driving anticipatory thirst It is vital for mammals to maintain their internal water equilibrium. The neurobiological mechanisms linking thirst response behaviour and fluid balance maintenance raise intriguing questions, given that these two components operate on different timescales. Two papers in this issue of Nature identify areas of the mouse brain that respond to and anticipate thirst. Zachary Knight and colleagues reveal a role for thirst-promoting neurons in the subfornical organ (SFO). During eating and drinking, feedback from the oral cavity to the SFO—one of the three sensory circumventricular organs of the brain—is integrated with information regarding blood composition, providing an indication of how oral consumption is likely to alter fluid balance, leading to behavioural adjustments. Charles Bourque and colleagues identify a projection from central clock neurons that drives anticipatory water intake just prior to sleep, regardless of physiological need. Without this specifically timed increase in water intake, animals suffered from dehydration near the end of a period of sleep. Circadian rhythms have evolved to anticipate and adapt animals to the constraints of the earth’s 24-hour light cycle 1 . Although the molecular processes that establish periodicity in clock neurons of the suprachiasmatic nucleus (SCN) are well understood, the mechanisms by which axonal projections from the central clock drive behavioural rhythms are unknown 2 , 3 , 4 . Here we show that the sleep period in mice (Zeitgeber time, ZT0–12) is preceded by an increase in water intake promoted entirely by the central clock, and not motivated by physiological need. Mice denied this surge experienced significant dehydration near the end of the sleep period, indicating that this water intake contributes to the maintenance of overnight hydromineral balance. Furthermore, this effect relies specifically on the activity of SCN vasopressin (VP) neurons that project to thirst neurons in the OVLT (organum vasculosum lamina terminalis), where VP is released as a neurotransmitter. SCN VP neurons become electrically active during the anticipatory period (ZT21.5–23.5), and depolarize and excite OVLT neurons through the activation of postsynaptic VP V1a receptors and downstream non-selective cation channels. Optogenetic induction of VP release before the anticipatory period (basal period; ZT19.5–21.5) excited OVLT neurons and prompted a surge in water intake. Conversely, optogenetic inhibition of VP release during the anticipatory period inhibited the firing of OVLT neurons and prevented the corresponding increase in water intake. Our findings reveal the existence of anticipatory thirst, and demonstrate this behaviour to be driven by excitatory peptidergic neurotransmission mediated by VP release from central clock neurons.