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Found 37048 matches. Displaying 41-50
Alavi A, Prens EP, Kimball AB, Frew JW, Krueger JG, Mukhopadhyay S, Gao HL, Ranganathan U, Ivanoff NB, Daly ACH, Zouboulis CC
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Proof-of-concept study exploring the effect of spesolimab in patients with moderate-to-severe hidradenitis suppurativa: a randomized double-blind placebo-controlled clinical trial

Background Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective targeted therapies.Objectives To explore the effects of spesolimab treatment in patients with HS.Methods This randomized double-blind placebo-controlled proof-of-clinical-concept (PoCC) study was conducted at 25 centres across 12 countries from 3 May 2021 to 21 April 2022. Patients had moderate-to-severe HS for >= 1 year before enrolment. Patients were randomized (2 : 1) to receive a loading dose of 3600-mg intravenous spesolimab (1200 mg at weeks 0, 1 and 2) or matching placebo, followed by maintenance with either 1200-mg subcutaneous spesolimab every 2 weeks from weeks 4 to 10 or matching placebo. The primary endpoint was the percentage change from baseline in total abscess and inflammatory nodule (AN) count at week 12. Secondary endpoints were the absolute change from baseline in the International Hidradenitis Suppurativa Severity Score System (IHS4), percentage change from baseline in draining tunnel (dT) count, the proportion of patients achieving a dT count of 0, absolute change from baseline in the revised Hidradenitis Suppurativa Area and Severity Index (HASI-R), the proportion of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR50), the proportion of patients with >= 1 flare (all at week 12) and patient-reported outcomes.Results In this completed trial, randomized patients (n = 52) received spesolimab (n = 35) or placebo (n = 17). The difference vs. placebo in least squares mean is reported. At week 12, the percentage change in total AN count was similar between treatment arms: -4.1% [95% confidence interval (CI) -31.7 to 23.4]. There was greater numerical improvement in the spesolimab arm, as measured by IHS4 (13.9, 95% CI -25.6 to -2.3); percentage change from baseline in dT count (-96.6%, 95% CI -154.5 to -38.8); and the proportion of patients achieving a dT count of 0 (18.3%, 95% CI -7.9 to 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 vs. placebo. Spesolimab demonstrated a favourable safety profile, similar to that observed in trials in other diseases.Conclusions This exploratory PoCC study supports the development of spesolimab as a new therapeutic option in HS. Graphical Abstract Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that affects approximately 0.4% to 1% of people worldwide. HS mainly affects areas where skin touches skin and can result in painful lumps and abscesses. Tunnel-shaped structures often form below the skin and discharge pus and can greatly affect a person's quality of life.In this study, we tested a drug called 'spesolimab' as a treatment for people with moderate-to-severe HS. Spesolimab is a medicine in development that affects the immune system. This 12-week study included 52 adults who had moderate-to-severe HS for at least 1 year, from North America, Europe and Australia. People who took part were selected at random to receive either spesolimab or placebo. Thirty-five people received spesolimab and 17 received placebo into a vein once a week for 3 weeks, starting at week 0. They then received four injections of spesolimab or placebo under the skin once every 2 weeks until week 10. The number of lumps and abscesses, tunnels and a score based on their combination, called the International Hidradenitis Suppurativa Severity Score System (IHS4), were evaluated before spesolimab or placebo were given, and at week 12.We found that spesolimab and the placebo had a similar effect on the number of lumps and abscesses. However, more people treated with spesolimab showed improvements in tunnels and IHS4 score than those who received the placebo. The safety of spesolimab was favourable, similar to when spesolimab has been used in studies of other diseases. Our findings support further research into the use of spesolimab as a medicine for HS. This 12-week study explored the effects of spesolimab, which inhibits interleukin (IL)-36 signalling, in patients with moderate-to-severe hidradenitis suppurativa for at least 1 year. Patients received spesolimab (n = 35) or placebo (n = 17) intravenously once weekly for 3 weeks starting at week 0. Patients then received four subcutaneous injections of spesolimab or placebo once every 2 weeks until week 10. At week 12, the percentage change from baseline in total abscess and inflammatory nodule count was similar between the treatment arms. However, spesolimab did improve IHS4, percentage change from baseline in draining tunnel count, HASI-R and HiSCR50 vs. placebo. Furthermore, spesolimab demonstrated a favourable safety profile, similar to that observed in trials in other diseases
Veith J, Chaigne T, Svanidze A, Dressler LE, Hoffmann M, Gerhardt B, Judkewitz B
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The mechanism for directional hearing in fish

NATURE 2024 2024 JUN 19; ?(?):?
Locating sound sources such as prey or predators is critical for survival in many vertebrates. Terrestrial vertebrates locate sources by measuring the time delay and intensity difference of sound pressure at each ear 1-5 . Underwater, however, the physics of sound makes interaural cues very small, suggesting that directional hearing in fish should be nearly impossible 6 . Yet, directional hearing has been confirmed behaviourally, although the mechanisms have remained unknown for decades. Several hypotheses have been proposed to explain this remarkable ability, including the possibility that fish evolved an extreme sensitivity to minute interaural differences or that fish might compare sound pressure with particle motion signals 7,8 . However, experimental challenges have long hindered a definitive explanation. Here we empirically test these models in the transparent teleost Danionella cerebrum, one of the smallest vertebrates 9,10 . By selectively controlling pressure and particle motion, we dissect the sensory algorithm underlying directional acoustic startles. We find that both cues are indispensable for this behaviour and that their relative phase controls its direction. Using micro-computed tomography and optical vibrometry, we further show that D. cerebrum has the sensory structures to implement this mechanism. D. cerebrum shares these structures with more than 15% of living vertebrate species, suggesting a widespread mechanism for inferring sound direction. A study demonstrates that the fish Danionella cerebrum is able to discriminate the direction of sound by comparing the relative phase of pressure and particle motion.
Bellafard A, Namvar G, Kao JC, Vaziri A, Golshani P
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Volatile working memory representations crystallize with practice

NATURE 2024 2024 MAY 15; ?(?):?
Working memory, the process through which information is transiently maintained and manipulated over a brief period, is essential for most cognitive functions 1-4 . However, the mechanisms underlying the generation and evolution of working-memory neuronal representations at the population level over long timescales remain unclear. Here, to identify these mechanisms, we trained head-fixed mice to perform an olfactory delayed-association task in which the mice made decisions depending on the sequential identity of two odours separated by a 5 s delay. Optogenetic inhibition of secondary motor neurons during the late-delay and choice epochs strongly impaired the task performance of the mice. Mesoscopic calcium imaging of large neuronal populations of the secondary motor cortex (M2), retrosplenial cortex (RSA) and primary motor cortex (M1) showed that many late-delay-epoch-selective neurons emerged in M2 as the mice learned the task. Working-memory late-delay decoding accuracy substantially improved in the M2, but not in the M1 or RSA, as the mice became experts. During the early expert phase, working-memory representations during the late-delay epoch drifted across days, while the stimulus and choice representations stabilized. In contrast to single-plane layer 2/3 (L2/3) imaging, simultaneous volumetric calcium imaging of up to 73,307 M2 neurons, which included superficial L5 neurons, also revealed stabilization of late-delay working-memory representations with continued practice. Thus, delay- and choice-related activities that are essential for working-memory performance drift during learning and stabilize only after several days of expert performance. Delay- and choice-related activities that are essential for working-memory performance drift during learning and stabilize only after several days of expert performance.
Cohen JE
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Gaps Between Consecutive Primes and the Exponential Distribution

Based on the primes less than 4 x 10(18), Oliveira e Silva et al. (Math. Comp., 83(288):2033-2060, 2014) conjectured an asymptotic formula for the sum of the kth power of the gaps between consecutive primes less than a large number x. We show that the conjecture of Oliveira e Silva holds if and only if the kth moment of the first n gaps is asymptotic to the kth moment of an exponential distribution with mean log n, though the distribution of gaps is not exponential. Asymptotically exponential moments imply that the gaps asymptotically obey Taylor's law of fluctuation scaling: variance of the first n gaps similar to (mean of the first n gaps)(2). If the distribution of the first n gaps is asymptotically exponential with mean log n, then the expectation of the largest of the first n gaps is asymptotic to ( log n)(2). The largest of the first n gaps is asymptotic to ( log n)(2) if and only if the Cramer-Shanks conjecture holds. Numerical counts of gaps and the maximal gap Gn among the first n gaps test these results. While most values of Gn are better approximated by ( log n)2 than by other models, seven exceptional values of n with G(n)>2e(-gamma)( log n)(2) suggest that lim sup(n ->infinity)G(n)/[2e(-gamma)( log n)(2)] may exceed 1.
Abt I, Aggarwal R, Aushev V, Behnke O, Bertolin A, Bloch I, Brock I, Brook NH, Brugnera R, Bruni A, Bussey PJ, Caldwell A, Catterall CD, Chwastowski J, Ciborowski J, Ciesielski R, Cooper-Sarkar AM, Corradi M, Dementiev RK, Dusini S, Ferrando J, Foster B, Gallo E, Gangadharan D, Garfagnini A, Geiser A, Grzelak G, Gwenlan C, Hochman D, Jomhari NZ, Kadenko I, Karshon U, Kaur P, Klanner R, Klein U, Korzhavina IA, Kovalchuk N, Kuze M, Levchenko BB, Levy A, Löhr B, Lohrmann E, Longhin A, Lorkowski F, Lunghi E, Makarenko I, Malka J, Masciocchi S, Nagano K, Nam JD, Onishchuk Y, Paul E, Pidhurskyi I, Polini A, Przybycien M, Quintero A, Ruspa M, Schneekloth U, Schörner-Sadenius T, Selyuzhenkov I, Shchedrolosiev M, Shcheglova LM, Sherrill N, Skillicorn IO, Slominski W, Solano A, Stanco L, Stefaniuk N, Surrow B, Tokushuku K, Turkot O, Tymieniecka T, Verbytskyi A, Abdullah WATW, Wichmann K, Wing M, Yamada S, Yamazaki Y, Arnecki AFZ, Zenaiev O
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Measurement of jet production in deep inelastic scattering and NNLO determination of the strong coupling at ZEUS

EUROPEAN PHYSICAL JOURNAL C 2023 NOV 27; 83(11):? Article 1082
A new measurement of inclusive-jet cross sections in the Breit frame in neutral current deep inelastic scattering using the ZEUS detector at the HERA collider is presented. The data were taken in the years 2004-2007 at a centre-of-mass energy of 318 GeV and correspond to an integrated luminosity of 347 pb(-1). The jets were reconstructed using the k(t)-algorithm in the Breit reference frame. They have been measured as a function of the squared momentum transfer, Q(2), and the transverse momentum of the jets in the Breit frame, p(perpendicular to,Breit). The measured jet cross sections are compared to previous measurements and to perturbative QCD predictions. The measurement has been used in a next-to-next-to-leading-order QCD analysis to perform a simultaneous determination of parton distribution functions of the proton and the strong coupling, resulting in a value of alpha(s) (M-Z(2)) = 0.1142 +/- 0.0017 (experimental/fit)(-0.0007)(+0.0006) (model/parameterisation)(-0.0004)(+0.0006) (scale), whose accuracy is improved compared to similarmeasurements. In addition, the running of the strong coupling is demonstrated using data obtained at different scales.
Woods C, Contoreggi NH, Johnson MA, Milner TA, Wang G, Glass MJ
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Estrogen receptor beta activity contributes to both tumor necrosis factor alpha expression in the hypothalamic paraventricular nucleus and the resistance to hypertension following angiotensin II in female mice

NEUROCHEMISTRY INTERNATIONAL 2022 DEC; 161(?):? Article 105420
Sex differences in the sensitivity to hypertension and inflammatory processes are well characterized but insufficiently understood. In male mice, tumor necrosis factor alpha (TNF alpha) in the hypothalamic paraventricular nucleus (PVN) contributes to hypertension following slow-pressor angiotensin II (AngII) infusion. However, the role of PVN TNF alpha in the response to AngII in female mice is unknown. Using a combination of in situ hybridization, high-resolution electron microscopic immunohistochemistry, spatial-temporal gene silencing, and dihydroethidium microfluorography we investigated the influence of AngII on both blood pressure and PVN TNF alpha signaling in female mice. We found that chronic (14-day) infusion of AngII in female mice did not impact blood pressure, TNF alpha levels, the expression of the TNF alpha type 1 receptor (TNFR1), or the subcellular distribution of TNFR1 in the PVN. However, it was shown that blockade of estrogen receptor beta (ER beta), a major hypothalamic estrogen receptor, was accompanied by both elevated PVN TNF alpha and hypertension following AngII. Further, AngII hypertension following ER beta blockade was attenuated by inhibiting PVN TNF alpha signaling by local TNFR1 silencing. It was also shown that ER beta blockade in isolated PVN-spinal cord projection neurons (i.e. sympathoexcitatory) heightened TNF alpha-induced production of NADPH oxidase (NOX2)-mediated reactive oxygen species, molecules that may play a key role in mediating the effect of TNF alpha in hypertension. These results indicate that ER beta contributes to the reduced sensitivity of female mice to hypothalamic inflammatory cytokine signaling and hypertension in response to AngII.
Dhaouadi S, Bouchami O, Soufi L, Dhaouadi F, Chaari S, Bouglita W, Cherif A, de Lencastre H, Elandoulsi RB, Miragaia M
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Frequent dissemination and carriage of an SCC mec-mecC hybrid in methicillin-resistant Mammaliicoccus sciuri in farm animals from Tunisia

Objectives: In this study, we aimed to assess the extent of dissemination of methicillin-resistant Mammaliicoccus sciuri in animal farms in Tunisia and evaluate the distribution of virulence and methicillin resistance genes in the M. sciuri population.Methods: Staphylococci and mammaliicocci isolated from unhealthy animals and healthy humans from adjacent farms in Tunisia were characterized for antimicrobial susceptibility, biofilm formation, agglutination, and hemolysis abilities. Mammaliicoccus sciuri relatedness and content in antibiotic resistance and virulence genes were analyzed by whole-genome sequencing (WGS).Results: Mammaliicoccus sciuri was the most prevalent species (46.2%), showing the highest resistance rates to fusidic acid (94.6%), oxacillin (73%), penicillin (40.5%), clindamycin (37%), ciprofloxacin (27%), and cefoxitin (24.3%). Some isolates carried genes encoding resistance to nine different antibiotic classes. mecA was found in 35% of M. sciuri and mecC in 16.2%. All isolates carrying mecC were of S. sciuri subspecies carnaticus and carried the hybrid element SCC mec-mecC. Mammaliicoccus sciuri were able to produce strong biofilm (27%) and have clumping ability (16%). Additionally, they carried genes for capsule production ( cap8 , 100%), iron-regulated surface determinants ( isdE , 24%; isdG , 3%), and virulence regulation ( clpC and clpP , 100%). Single nucleotide polymorphisms (SNPs) analysis showed that 17 M. sciuri cross-transmission events probably occurred between different animal species and farms. Moreover, SCC mec was estimated to have been acquired five times by S. sciuri subsp. carnaticus.Conclusion: Multidrug resistant and pathogenic M. sciuri were frequently disseminated between different animal species within the farm environment. mecA and mecC can be disseminated by both frequent acquisition of the SCC mec element and clonal dissemination.(c) 2022 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( )
Brown JA, Sanidad KZ, Lucotti S, Lieber CM, Cox RM, Ananthanarayanan A, Basu S, Chen J, Shan MR, Amir M, Schmidt F, Weisblum Y, Cioffi M, Li TT, Rowdo FM, Martin ML, Guo CJ, Lyssiotis C, Layden BT, Dannenberg AJ, Bieniasz PD, Lee B, Inohara N, Matei I, Plemper RK, Zeng MY
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Gut microbiota-derived metabolites confer protection against SARS-CoV-2 infection

GUT MICROBES 2022 DEC 31; 14(1):? Article 2105609
The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.
Mansisidor AR, Risca VI
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Chromatin accessibility: methods, mechanisms, and biological insights

NUCLEUS 2022 DEC 31; 13(1):236-276
Access to DNA is a prerequisite to the execution of essential cellular processes that include transcription, replication, chromosomal segregation, and DNA repair. How the proteins that regulate these processes function in the context of chromatin and its dynamic architectures is an intensive field of study. Over the past decade, genome-wide assays and new imaging approaches have enabled a greater understanding of how access to the genome is regulated by nucleosomes and associated proteins. Additional mechanisms that may control DNA accessibility in vivo include chromatin compaction and phase separation - processes that are beginning to be understood. Here, we review the ongoing development of accessibility measurements, we summarize the different molecular and structural mechanisms that shape the accessibility landscape, and we detail the many important biological functions that are linked to chromatin accessibility.
Lee UJ, Mortola EN, Kim EJ, Long MY
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Evolution and maintenance of phenotypic plasticity

BIOSYSTEMS 2022 DEC; 222(?):? Article 104791
We introduce a novel framework for exploring the evolutionary consequences of phenotypic plasticity (adaptive and non-adaptive) integrating both genic and epigenetic effects on phenotype via stochastic differential equations and in-silico selection. In accordance with the most significant results derived from prior models, we demonstrate how plasticity is differentially favored when subjected to small vs large environmental shifts, how plasticity is transiently favorable while accommodating a new environment, and how plasticity decreases during epochs where the environment remains stable (canalization). In contrast to these models, however, by allowing the same phenotypic value to be produced via two different paths, i.e. deterministic, genic, vs stochastic, epigenetic mechanisms, we demonstrate when genic contributions alone cannot produce an optimal phenotype, plastic, epigenetic contributions will instead fully accommodate new environments, allowing for both adaptive and non-adaptive plasticity to evolve. Furthermore, we show that while rates of phenotypic accommodation are relatively constant under a wide range of selective conditions, selection will favor the most efficient route to adaptation: deterministic, genic response, or stochastic, plastic response. As a result, plasticity may evolve or canalization may occur within a given epoch depending on the relative mutation rate of genic and epigenetic contributions to phenotype, highlighting the importance of genetic conflict on the evolution of plasticity.