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Le Pen J, Rice CM
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The antiviral state of the cell: lessons from SARS-CoV-2

CURRENT OPINION IN IMMUNOLOGY 2024 APR; 87(?):? Article 102426
In this review, we provide an overview of the intricate host-virus interactions that have emerged from the study of SARS-CoV-2 infection. We focus on the antiviral mechanisms of interferonstimulated genes (ISGs) and their modulation of viral entry, replication, and release. We explore the role of a selection ISGs, restricting SARS-CoV-2 infection and discuss the virus's countermeasures. By synthesizing the latest research on SARSCoV-2 and host antiviral responses, this review aims to provide a deeper understanding of the antiviral state of the cell under SARS-CoV-2 and other viral infections, offering insights for the development of novel antiviral strategies and therapeutics.
Chen JX, Hou DF, Ren HC
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Drag force and heavy quark potential in a rotating background

JOURNAL OF HIGH ENERGY PHYSICS 2024 MAR 29; ?(3):? Article 171
We explored the gravity dual of a rotating quark-gluon plasma by transforming the boundary coordinates of the large black hole limit of Schwarchild-AdS5 metric. The Euler-Lagrange equation of the Nambu-Goto action and its solution become more complex than those without rotation. For small angular velocity, we obtained an analytical form of the drag force acting on a quark moving in the direction of the rotation axis and found it stronger than that without rotation. We also calculated the heavy quark potential under the same approximation. For the quarkonium symmetric with respect to the rotation axis, the depth of the potential is reduced by the rotation. For the quarkonium oriented in parallel to the rotation axis, the binding force is weakened and the force range becomes longer. We also compared our holographic formulation with others in the literature.
Rossi M, Hausmann AE, Alcami P, Moest M, Roussou R, Van Belleghem SM, Wright DS, Kuo CY, Lozano-Urrego D, Maulana A, Melo-Florez L, Rueda-Munoz G, Mcmahon S, Linares M, Osman C, Mcmillan WO, Pardo-Diaz C, Salazar C, Merrill RM
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Adaptive introgression of a visual preference gene

SCIENCE 2024 MAR 22; 383(6689):1368-1373
Visual preferences are important drivers of mate choice and sexual selection, but little is known of how they evolve at the genetic level. In this study, we took advantage of the diversity of bright warning patterns displayed by Heliconius butterflies, which are also used during mate choice. Combining behavioral, population genomic, and expression analyses, we show that two Heliconius species have evolved the same preferences for red patterns by exchanging genetic material through hybridization. Neural expression of regucalcin1 correlates with visual preference across populations, and disruption of regucalcin1 with CRISPR-Cas9 impairs courtship toward conspecific females, providing a direct link between gene and behavior. Our results support a role for hybridization during behavioral evolution and show how visually guided behaviors contributing to adaptation and speciation are encoded within the genome.
Zheng FW, Yao NY, Georgescu RE, Li HL, O'Donnell ME
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Structure of the PCNA unloader Elg1-RFC

SCIENCE ADVANCES 2024 MAR 1; 10(9):? Article eadl1739
During DNA replication, the proliferating cell nuclear antigen (PCNA) clamps are loaded onto primed sites for each Okazaki fragment synthesis by the AAA+ heteropentamer replication factor C (RFC). PCNA encircling duplex DNA is quite stable and is removed from DNA by the dedicated clamp unloader Elg1-RFC. Here, we show the cryo-EM structure of Elg1-RFC in various states with PCNA. The structures reveal essential features of Elg1-RFC that explain how it is dedicated to PCNA unloading. Specifically, Elg1 contains two external loops that block opening of the Elg1-RFC complex for DNA binding, and an "Elg1 plug" domain that fills the central DNA binding chamber, thereby reinforcing the exclusive PCNA unloading activity of Elg1-RFC. Elg1-RFC was capable of unloading PCNA using non-hydrolyzable AMP-PNP. Both RFC and Elg1-RFC could remove PCNA from covalently closed circular DNA, indicating that PCNA unloading occurs by a mechanism that is distinct from PCNA loading. Implications for the PCNA unloading mechanism are discussed.
Materna M, Delmonte OM, Bosticardo M, Momenilandi M, Conrey PE, Charmeteau-De Muylder B, Bravetti C, Bellworthy R, Cederholm A, Staels F, Ganoza CA, Darko S, Sayed S, Le Floc'h C, Ogishi M, Rinchai D, Guenoun A, Bolze A, Khan T, Gervais A, Krüger R, Völler M, Palterer B, Sadeghi-Shabestari M, de Septenville AL, Schramm CA, Shah S, Tello-Cajiao JJ, Pala F, Amini K, Campos JS, Lima NS, Eriksson D, Lévy R, Seeleuthner Y, Jyonouchi S, Ata M, Al Ali F, Deswarte C, Pereira A, Mégret J, Le Voyer T, Bastard P, Berteloot L, Dussiot M, Vladikine N, Cardenas PP, Jouanguy E, Alqahtani M, Hasan A, Thanaraj TA, Rosain J, Al Qureshah F, Sabato V, Alyanakian MA, Leruez-Ville M, Rozenberg F, Haddad E, Regueiro JR, Toribio ML, Kelsen JR, Salehi M, Nasiri S, Torabizadeh M, Rokni-Zadeh H, Changi-Ashtiani M, Vatandoost N, Moravej H, Akrami SM, Mazloomrezaei M, Cobat A, Meyts I, Toyofuku E, Nishimura M, Moriya K, Mizukami T, Imai K, Abel L, Malissen B, Al-Mulla F, Alkuraya FS, Parvaneh N, von Bernuth H, Beetz C, Davi F, Douek DC, Cheynier R, Langlais D, Landegren N, Marr N, Morio T, Shahrooei M, Schrijvers R, Henrickson SE, Luche H, Notarangelo LD, Casanova JL, Béziat V
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The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants

SCIENCE 2024 MAR 1; 383(6686):? Article eadh4059
We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-alpha T cell receptor (pre-TCR alpha) expression. Low circulating naive alpha beta T cell counts at birth persisted over time, with normal memory alpha beta and high gamma delta T cell counts. Their TCR alpha repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue alpha beta T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive alpha beta T cell counts but high gamma delta T cell counts. Although residual pre-TCR alpha expression drove the differentiation of more alpha beta T cells, autoimmune conditions were more frequent in these patients compared with the general population.
Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, Chirino A, Jahn J, Sondhi AK, Gajewski S, Tan YS, Yung S, Urban A, Wang E, Han CJ, Mi XL, Kim WJ, Sievers Q, Auger P, Bousquet H, Brathaban N, Bravo B, Gessner M, Guiducci C, Iuliano JN, Kane T, Mukerji R, Reddy PJ, Powers J, de los Rios MSG, Ye J, Risso CB, Tsai D, Pardo G, Notti RQ, Pardo A, Affer M, Nawaratne V, Totiger TM, Pena-Velasquez C, Rhodes JM, Zelenetz AD, Alencar A, Roeker LE, Mehta S, Garippa R, Linley A, Soni RK, Skånland SS, Brown RJ, Mato AR, Hansen GM, Abdel-Wahab O, Taylor J
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Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127

SCIENCE 2024 FEB 2; 383(6682):496-+ Article eadi5798
Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.
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.
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
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.