bluuebunny/crossref_metadata_2025 huggingface dataset:
105 Effects of Monensin on Intake, Growth Performance, and Health of Newly-Received Feedlot Calves
Authors: Foster Ryan C , Gouvêa Vinícius N , Proctor Jarret A , Smithyman Mackenzie M , Beck Matthew R , Long Nathan S , Smith Jason K , Duff Glenn C
Published: May 2023

Monensin is an ionophore commonly fed to feedlot cattle to increase feed efficiency (gain:feed ratio; G:F) typically by decreasing dry matter intake (DMI) when fed at the commonly adopted dose of 33 mg∙kg DM-1. During the receiving period when intake is often suppressed due to management stressors, feeding monensin to light-weight feedlot calves may be detrimental to DMI and consequently to growth performance. The objective of this experiment was to evaluate the effects of feeding sodium monensin to newly-received feedlot calves. A total of 380 crossbred beef steers [initial body weight (BW) = 231 ± 25 kg and approximately 8 months of age] were sourced from local auctions in Delhi, LA and transported approximately 16 h to Clayton, NM. Upon arrival, steers were processed, blocked by off-truck shrunk BW, randomly assigned to 20 pens (19 animal∙pen-1), and pens were then randomly assigned to one of two dietary treatments (n = 10 pens/treatment): control (CON; no feed additive) or sodium monensin at 170 mg∙animal-1∙day-1 (MON; Rumensin 90; Elanco Animal Health, Greenfield, IN). The basal diet consisted of a complete starter feed composed predominantly of wet corn gluten feed (RAMP; Cargill Sweet Bran, Dalhart, TX). The experiment was 56 days in length. The amount of feed offered to each pen was adjusted based on the DMI of the previous day and bunks were managed to contain trace amounts of feed at 0600 h. Body weight was recorded on days 0, 14, 28, and 56 for average daily gain (ADG) and G:F calculation. Dietary net energy for maintenance (NEm) and gain (NEg) were estimated based on observed growth performance. Daily animal health evaluations were performed using a 4-point scale method based on depression, appetite, respiration, and temperature throughout the experiment. All data were analyzed as a randomized complete block design using SAS with pen serving as the experimental unit. Feeding MON did not affect feed intake (P = 0.58) compared with CON, yet ADG was increased (P < 0.01) by 12.5% in steers fed MON compared with CON. Thus, there was a 10.7% increase (P < 0.01) in G:F for MON, which corresponds with a greater (P = 0.02) observed NEm and NEg for MON compared with CON. Feeding MON tended (P = 0.07) to elicit a 2.9% increase in final BW compared with CON. Additionally, there was no treatment effect (P ≥ 0.57) on morbidity based on the number of therapeutic treatments among calves which were treated for indications of bovine respiratory disease. Moreover, treatments did not affect mortality rate. In summary, feeding monensin at 170 mg∙animal-1∙d-1 (26 mg∙kg DM-1) increases growth performance of light-weight, newly-received feedlot cattle without influencing DMI or animal health.
151 Effect of Neogen Igenity Beef Index Scores on Performance of Steers During Finishing
Authors: De Vries Jacee k , Farran Garrett , Beck Paul A , Briggs Emma A , Moore Mikayla F , Major Mike , Lalman David
Published: May 2023

Genomic testing of feeder cattle is reported to be beneficial in selecting cattle for the feedlot, as well as making management and marketing decisions. The objective of this study was to determine differences in performance and efficiency of finishing steers with a range of Neogen Igenity Beef scores for average daily gain (ADG) and milk. Spring born steer calves from the Oklahoma State University Range Cow Research Center (n = 83, BW = 419 ± 31.9) of Angus ancestry were placed on feed at the Willard Sparks Beef Research Center on May 5, 2022, after grazing wheat pasture for 155 d. The steers were grouped based on Igenity ADG Score [low (1-4), medium (5-6), or high (7-10)] and Milk Score [low (1-5) or high (6-10)] based on the Igenity results. Steers were allocated into pens (n = 5 steers/pen) in heavy and light BW blocks. Steers were fed a step-up diet for 30 d before being switched to a finishing ration diet (8% prairie hay, 20% Sweet Bran and 62% dry-rolled corn). Cattle were fed ractopamine for 30 d before slaughter. The heavy block were on feed for 119 d, while the light block were on feed for 148 d. Data were analyzed as a randomized complete block design using the mixed procedure of SAS (SAS Inst. Inc., Cary NC) with pen as the experimental unit. Steers with high growth (HG) scores gained weight more rapidly during finishing and weighed more at slaughter than medium growth (MG) and low growth (LG; P < 0.01); while steers with high milk (HM) gained faster (P < 0.01) and tended (P = 0.06) to be heavier at slaughter than low milk (LM). Growth score was shown to have an effect on dry matter intake (P < 0.01) with HG consuming more feed than MG or LG. Cattle with HM scores were less efficient than LM scores (P = 0.01), but there was no difference (P = 0.37) in feed efficiency due to ADG score. Those with high growth and milk scores had a higher average daily gain (P < 0.01). These data indicate that Igenity ADG scores can be used to select cattle with higher performance and bodyweight at slaughter with no adverse effect on feed efficiency. Steers with higher Igenity Milk scores were less efficient than those with LM scores. Igenity Milk scores can be used to predict efficiency, according to these data.
162 The Effect of Innate Immune Receptor Activation on Differential Breed Responses toHaemonchus Contortus in Sheep
Authors: Johnson Samanthia R , Middleton Denzel D , Bowdridge Scott L , Greiner Scott P
Published: May 2023

Previous studies have indicated the importance of Nod-like receptor pyrin containing domain 3 (NLRP3) to early immune response in St. Croix (STC) sheep. NLRP3 is important to Th2 immune response, which is the classical response to Haemonchus contortus larval antigen (HcLA). Th2 response is driven by interleukin (IL) -4 and IL-13 cytokine production and early production prevents parasite establishment and further resistance as seen in STC response to LPS, classical NLRP3 activation. Distinct differences have been seen in the structure of NLRP3 between both STC and SUF. STC upregulates inflammatory genes NLRP3, TLR4 and TLR2 in response to LPS, while SUF showed delayed responses leading to their susceptibility. The objective of this study was to investigate the role of NLRP3 in differential breed response, in the context of Hc infection. P Peripheral blood mononuclear cells (PBMC) from both SUF and STC were isolated and stimulated with HcLA antigen only, HcLA antigen in combination with pharmacological inhibitor of NLRP3 (MCC950) and complete media for 6 hours. Gene expression revealed that treatment with MCC950 upregulated TLR2 (P < 0.001), TLR4 (P < 0.001), STAT6 (P < 0.001), IL-4 and IL-10 (P < 0.001) in SUF PBMC while STC showed an increase in IL-1β (P < 0.001). This indicates that inhibition of NLRP3 improves response of SUF to Hc antigen and confirms importance of NLRP3 to immune response in STC.
S1PR1-dependent migration of ILC3s from intestinal tissue to the heart in a mouse model of viral myocarditis
Authors: Tian Yu , Gong Xiangmei , Qin Demeng , Cao Yuwen , Zhang Shiqing , Xia Lin , Liu Fang , Su Zhaoliang
Published: May 2023

Type 3 innate lymphocytes have recently been reported as key factors in inflammatory diseases, but their role in viral myocarditis is unclear. By flow cytometry, coxsackievirus B3–induced myocarditis mice were detected to increase the number of type 3 innate lymphocytes, and their main type was NKp46+ type 3 innate lymphocytes. In contrast, application of CD90.2 neutralizing antibody in T-cell–deficient mice reduced the number of innate lymphocytes and improved myocarditis. Innate lymphocytes from CD45.1 mouse intestinal lamina propria lymphocytes were adoptively transferred into recipient mice, and a comparable proportion of CD45.1+ cells were observed in the hearts of coxsackievirus B3–infected recipient mice. The upregulation of S1PR1, KLF2, CXCR6, and CXCL16 in the hearts of coxsackievirus B3–infected mice, as well as the greatly reduced numbers of innate lymphocytes infiltrating the hearts after S1PR1 inhibition, suggests that intestinal innate lymphocytes may migrate to the hearts via the CXCL16/CXCR6 axis. Taken together, our results demonstrate that increased type 3 innate lymphocytes in the heart during viral myocarditis may contribute to inflammatory progression and that this increased population of type 3 innate lymphocytes likely originates from the intestine.
Red-flag signs and symptoms for earlier diagnosis of early-onset colorectal cancer
Authors: Fritz Cassandra D L , Otegbeye Ebunoluwa E , Zong Xiaoyu , Demb Joshua , Nickel Katelin B , Olsen Margaret A , Mutch Matthew , Davidson Nicholas O , Gupta Samir , Cao Yin
Published: May 2023

Background

Prompt detection of colorectal cancer (CRC) among individuals younger than age 50 years (early-onset CRC) is a clinical priority because of its alarming rise.

Methods

We conducted a matched case-control study of 5075 incident early-onset CRC among US commercial insurance beneficiaries (113 million adults aged 18-64 years) with 2 or more years of continuous enrollment (2006-2015) to identify red-flag signs and symptoms between 3 months to 2 years before the index date among 17 prespecified signs and symptoms. We assessed diagnostic intervals according to the presence of these signs and symptoms before and within 3 months of diagnosis.

Results

Between 3 months and 2 years before the index date, 4 red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia) were associated with an increased risk of early-onset CRC, with odds ratios (ORs) ranging from 1.34 to 5.13. Having 1, 2, or at least 3 of these signs and symptoms were associated with a 1.94-fold (95% confidence interval [CI] = 1.76 to 2.14), 3.59-fold (95% CI = 2.89 to 4.44), and 6.52-fold (95% CI = 3.78 to 11.23) risk (Ptrend < .001), respectively, with stronger associations for younger ages (Pinteraction < .001) and rectal cancer (Pheterogenity = .012). The number of different signs and symptoms was predictive of early-onset CRC beginning 18 months before diagnosis. Approximately 19.3% of patients had their first sign or symptom occur between 3 months and 2 years before diagnosis (median diagnostic interval = 8.7 months), and approximately 49.3% had the first sign or symptom within 3 months of diagnosis (median diagnostic interval = 0.53 month).

Conclusions

Early recognition of red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia) may improve early detection and timely diagnosis of early-onset CRC.
Local phytochrome signalling limits root growth in light by repressing auxin biosynthesis
Authors: Spaninks Kiki , Offringa Remko
Published: May 2023

In nature, plant shoots are exposed to light whereas the roots grow in relative darkness. Surprisingly, many root studies rely on in vitro systems that leave the roots exposed to light whilst ignoring the possible effects of this light on root development. Here, we investigated how direct root illumination affects root growth and development in Arabidopsis and tomato. Our results show that in light-grown Arabidopsis roots, activation of local phytochrome A and B by far-red or red light inhibits respectively PHYTOCHROME INTERACTING FACTORS 1 or 4, resulting in decreased YUCCA4 and YUCCA6 expression. As a result, auxin levels in the root apex become suboptimal, ultimately resulting in reduced growth of light-grown roots. These findings highlight once more the importance of using in vitro systems where roots are grown in darkness for studies that focus on root system architecture. Moreover, we show that the response and components of this mechanism are conserved in tomato roots, thus indicating its importance for horticulture as well. Our findings open up new research possibilities to investigate the importance of light-induced root growth inhibition for plant development, possibly by exploring putative correlations with responses to other abiotic signals, such as temperature, gravity, touch, or salt stress.
Redefining Possible: Combining Phylogenomic and Supersparse Data in Frogs
Authors: Portik Daniel M , Streicher Jeffrey W , Blackburn David C , Moen Daniel S , Hutter Carl R , Wiens John J
Published: May 2023

The data available for reconstructing molecular phylogenies have become wildly disparate. Phylogenomic studies can generate data for thousands of genetic markers for dozens of species, but for hundreds of other taxa, data may be available from only a few genes. Can these two types of data be integrated to combine the advantages of both, addressing the relationships of hundreds of species with thousands of genes? Here, we show that this is possible, using data from frogs. We generated a phylogenomic data set for 138 ingroup species and 3,784 nuclear markers (ultraconserved elements [UCEs]), including new UCE data from 70 species. We also assembled a supermatrix data set, including data from 97% of frog genera (441 total), with 1–307 genes per taxon. We then produced a combined phylogenomic–supermatrix data set (a “gigamatrix”) containing 441 ingroup taxa and 4,091 markers but with 86% missing data overall. Likelihood analysis of the gigamatrix yielded a generally well-supported tree among families, largely consistent with trees from the phylogenomic data alone. All terminal taxa were placed in the expected families, even though 42.5% of these taxa each had >99.5% missing data and 70.2% had >90% missing data. Our results show that missing data need not be an impediment to successfully combining very large phylogenomic and supermatrix data sets, and they open the door to new studies that simultaneously maximize sampling of genes and taxa.
Kinetic principles of ParA2-ATP cycling guide dynamic subcellular localizations inVibrio cholerae
Authors: Chodha Satpal S , Brooks Adam C , Davis Peter J , Ramachandran Revathy , Chattoraj Dhruba K , Hwang Ling Chin
Published: May 2023

Dynamic protein gradients are exploited for the spatial organization and segregation of replicated chromosomes. However, mechanisms of protein gradient formation and how that spatially organizes chromosomes remain poorly understood. Here, we have determined the kinetic principles of subcellular localizations of ParA2 ATPase, an essential spatial regulator of chromosome 2 segregation in the multichromosome bacterium, Vibrio cholerae. We found that ParA2 gradients self-organize in V. cholerae cells into dynamic pole-to-pole oscillations. We examined the ParA2 ATPase cycle and ParA2 interactions with ParB2 and DNA. In vitro, ParA2-ATP dimers undergo a rate-limiting conformational switch, catalysed by DNA to achieve DNA-binding competence. This active ParA2 state loads onto DNA cooperatively as higher order oligomers. Our results indicate that the midcell localization of ParB2-parS2 complexes stimulate ATP hydrolysis and ParA2 release from the nucleoid, generating an asymmetric ParA2 gradient with maximal concentration toward the poles. This rapid dissociation coupled with slow nucleotide exchange and conformational switch provides for a temporal lag that allows the redistribution of ParA2 to the opposite pole for nucleoid reattachment. Based on our data, we propose a ‘Tug-of-war’ model that uses dynamic oscillations of ParA2 to spatially regulate symmetric segregation and positioning of bacterial chromosomes.
Faster, broader, and deeper! Suggested directions for research on net-zero transitions
Authors: Andersen Allan Dahl , Geels Frank W , Coenen Lars , Hanson Jens , Korsnes Marius , Linnerud Kristin , Makitie Tuukka , Nordholm Amber , Ryghaug Marianne , Skjolsvold Tomas , Steen Markus , Wiebe Kirsten
Published: May 2023

The growing attention to the political goal of achieving net-zero emissions by mid-century reflects past failures to alter the trajectory of increasing greenhouse gas (GHG) emissions. As a consequence, the world now needs to decarbonize all systems and sectors at an unprecedented pace. This commentary discusses how the net-zero challenge presents transition scholarship with four enhanced research challenges that merit more attention: (1) the speed, (2) breadth and (3) depth of transitions as well as (4) tensions and interactions between these.
Petrology and Tectonic Significance of Epidote Blueschist-Facies Rocks from the Northern Margin of the Pelagonian Unit in the Republic of North Macedonia
Authors: Altherr Rainer , Hanel Michael , Soder Christian G , Peters Daniel , Bahl Chiara
Published: May 2023

In the Republic of North Macedonia, the northern marginal part of the Pelagonian Unit comprises several isolated slivers of low-grade blueschist-facies rocks. These rocks were metamorphosed at conditions of the epidote-blueschist facies with rare transitions to the lawsonite-epidote blueschist facies. If present, lawsonite occurs as relic inclusions in albite, suggesting a local metasomatic enrichment of Na. No aragonite or fibrous calcite was detected, suggesting that the rocks were equilibrated at pressures below the aragonite-calcite boundary. When present, calcite + quartz coexist with glaucophane, epidote, and titanite suggesting the presence of a metamorphic H2O-rich fluid phase with very low XCO2 values (< 0.002). Most samples contain chlorite and only some have garnet, which is nearly free of Mg, but contains an andradite component. Albite only occurs in garnet-free rocks. A core-to-rim decrease of Fe3+/(Fe3++Al3++Cr + Mn3+) in epidote, VIFe3+/VI(Fe3++Al) in blue Na-rich amphibole, and Fe3+/(Fe2++Fe3+) in garnet grains suggest a decrease of ƒO2 during metamorphism. The general absence of magnetite and the presence of very small amounts of hematite in some samples suggest that the hematite–magnetite buffer curve was probably not crossed. It is thought that the investigated blueschist-facies rocks were part of the once highly oxidized sedimentary cover of the subducting oceanic plate. The underlying basaltic crust and oceanic mantle, however, were probably relatively reduced. Aqueous fluids which left this part of the lithosphere during subduction (dehydration) partially reduced the overlying oxidized metasediments. Concerning metamorphic P–T conditions, a pressure range of 0.7–0.9 GPa is defined by the presence of glaucophane + epidote + quartz at the lower boundary and the absence of aragonite at the higher boundary. The temperature range of 320–420°C is defined by the absence of Fe-Mg-pumpellyite at the lower side and the presence of lawsonite + albite at the higher side. These conditions can be narrowed down by using calculated equilibrium mineral assemblage diagrams (pseudosections) for three different bulk-rock compositions, resulting in P = 0.74–0.85 GPa and T = 340–370°C. It must, however, be emphasized that many phases (garnet, glaucophane, epidote, and phengite) show significant chemical zonation, which makes the use of pseudosections problematic.
Suppression of the Arabidopsis cinnamoyl-CoA reductase 1-6 intronic T-DNA mutation by epigenetic modification
Authors: Wouters Marlies , Bastiaanse Héloïse , Rombauts Stephane , de Vries Lisanne , De Pooter Tim , Strazisar Mojca , Neutelings Godfrey , Vanholme Ruben , Boerjan Wout
Published: May 2023

Arabidopsis (Arabidopsis thaliana) transfer DNA (T-DNA) insertion collections are popular resources for fundamental plant research. Cinnamoyl-CoA reductase 1 (CCR1) catalyzes an essential step in the biosynthesis of the cell wall polymer lignin. Accordingly, the intronic T-DNA insertion mutant ccr1-6 has reduced lignin levels and shows a stunted growth phenotype. Here, we report restoration of the ccr1-6 mutant phenotype and CCR1 expression levels after a genetic cross with a UDP-glucosyltransferase 72e1 (ugt72e1),-e2,-e3 T-DNA mutant. We discovered that the phenotypic recovery was not dependent on the UGT72E family loss of function but due to an epigenetic phenomenon called trans T-DNA suppression. Via trans T-DNA suppression, the gene function of an intronic T-DNA mutant was restored after the introduction of an additional T-DNA sharing identical sequences, leading to heterochromatinization and splicing out of the T-DNA–containing intron. Consequently, the suppressed ccr1-6 allele was named epiccr1-6. Long-read sequencing revealed that epiccr1-6, not ccr1-6, carries dense cytosine methylation over the full length of the T-DNA. We showed that the SAIL T-DNA in the UGT72E3 locus could trigger the trans T-DNA suppression of the GABI-Kat T-DNA in the CCR1 locus. Furthermore, we scanned the literature for other potential cases of trans T-DNA suppression in Arabidopsis and found that 22% of the publications matching our query report on double or higher-order T-DNA mutants that meet the minimal requirements for trans T-DNA suppression. These combined observations indicate that intronic T-DNA mutants need to be used with caution since methylation of intronic T-DNA might derepress gene expression and can thereby confound results.
Financial Crises and the Transmission of Monetary Policy to Consumer Credit Markets
Authors: Indarte Sasha
Published: May 2023

How does creditor health affect the pass-through of monetary policy to households? Using data on the universe of U.S. credit unions, I document that creditor asset losses increase the sensitivity of consumer credit to monetary policy. Identification exploits plausibly exogenous variation in asset losses and high-frequency identification of monetary policy shocks. Weaker lenders can respond more if they face financial frictions that easing alleviates. The estimates imply constraints on monetary policy become more costly in financial crises featuring creditor asset losses and that an additional benefit of monetary easing is that it weakens the causal, contractionary effect of asset losses.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online
Ten-year safety and clinical benefit from open-label etanercept treatment in children and young adults with juvenile idiopathic arthritis
Authors: Vojinović Jelena , Foeldvari Ivan , Dehoorne Joke , Panaviene Violeta , Susic Gordana , Horneff Gerd , Stanevicha Valda , Kobusinska Katarzyna , Zuber Zbigniew , Dobrzyniecka Bogna , Akikusa Jonathan , Avcin Tadej , Borlenghi Cecilia , Arthur Edmund , Tatulych Svitlana Y , Zang Chuanbo , Tsekouras Vassilis , Vlahos Bonnie , Martini Alberto , Ruperto Nicolino
Published: May 2023

Objectives

CLIPPER2 was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study on the safety and efficacy of etanercept in patients with JIA, categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA) or PsA.

Methods

Participants with eoJIA (2–17 years old), ERA or PsA (each 12–17 years old) who received ≥1 etanercept dose (0.8 mg/kg weekly; maximum 50 mg) in CLIPPER could enter CLIPPER2. Primary end point was occurrence of malignancy. Efficacy assessments included proportions achieving JIA ACR 30/50/70/90/100 criteria and ACR inactive disease criteria, and clinical remission (ACR criteria) or Juvenile Arthritis DAS (JADAS) ≤1.

Results

Overall, 109/127 (86%) CLIPPER participants entered CLIPPER2 [n = 55 eoJIA, n = 31 ERA, n = 23 PsA; 99 (78%) on active treatment]; 84 (66%) completed 120 months’ follow-up [32 (25%) on active treatment]. One malignancy (Hodgkin’s disease in 18-year-old patient with eoJIA treated with methotrexate for 8 years) was reported; there were no cases of active tuberculosis or deaths. Numbers and incidence rates (events per 100 patient-years) of TEAEs (excluding infections/ISRs) decreased from 193 (173.81) in Year 1 to 9 (27.15) in Year 10; TE infections and serious infections also decreased. Over 45% of participants (n = 127) achieved JIA ACR50 responses from Month 2 onwards; 42 (33%) and 34 (27%) participants achieved JADAS and ACR clinical remission, respectively.

Conclusions

Etanercept treatment up to 10 years was well tolerated, consistent with the known safety profile, with durable response in the participants still on active treatment. The benefit–risk assessment of etanercept in these JIA categories remains favourable.

Trial registration

ClinicalTrials.gov IDs: CLIPPER (NCT00962741); CLIPPER2 (NCT01421069)
A uniquein vivopharmacokinetic profile,in vitrometabolic stability and hepatic first-pass metabolism of garcinol, a promising novel anticancer phytoconstituent, by liquid chromatography–mass spectrometry
Authors: Rao Gajula Siva Nageswara , Talari Sasikala , Chilvery Shrilekha , Godugu Chandraiah , Sonti Rajesh
Published: May 2023

Objectives

Garcinol exhibits promising potential anticancer activity in cancer cells by inhibiting several critical regulatory pathways. Despite its pharmacological activity, information regarding its pharmacokinetics and metabolism is unavailable. Hence, we aimed to systematically determine the in vivo pharmacokinetic parameters, in vitro metabolic stability and hepatic first-pass metabolism of garcinol.

Methods

We developed and validated a sensitive bioanalytical method for the quantitative determination of garcinol in rat plasma and human liver microsomes using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The developed method was applied to assess the pharmacokinetic parameters, bioavailability and metabolic stability associated with metabolic half-life and intrinsic hepatic clearance. Further, we calculated the hepatic first-pass metabolism of garcinol from the metabolic stability data.

Key findings

The metabolic stability of garcinol in human liver microsomes demonstrated it as a medium clearance drug with a CLint value of 33.94 µL/min/mg microsomal protein and 94% of garcinol would escape the hepatic first-pass metabolism. Furthermore, a pharmacokinetics study of garcinol in Sprague Dawley rats showed 26.64 ± 0.23% and 35.72 ± 0.97% oral bioavailability at two doses, that is 22.5 and 45 mg/kg, respectively. The Cmax values at these two oral doses were 2317.69 ± 180.44 and 3446.14 ± 190.12 ng/mL.

Conclusions

Metabolic stability data showed that garcinol is a medium clearance drug and less fraction of the drug undergoes hepatic first-pass metabolism. The determined pharmacokinetic parameters and metabolic stability data help to understand and optimise the dose and route of administration for designing clinical trials to further develop garcinol as an anticancer drug.
Mindfulness Combined With Exercise Online (MOVE) Compared With a Self-management Guide for Adults With Chronic Pain
Authors: Deegan Orla , Fullen Brona M. , Casey Maire-Brid , Segurado Ricardo , Hearty Conor , Doody Catherine
Published: May 2023

Objective:

Limited studies exist combining mindfulness-based stress reduction (MBSR) and exercise in a pain management programme (PMP), with none thus far delivering a combined intervention as an online PMP. This study aimed to explore the acceptability and feasibility of a combined MBSR and exercise online PMP for adults with chronic pain and to examine the feasibility of conducting a randomized controlled trial (RCT) comparing MBSR and exercise delivered online with an online self-management guide.

Materials and Methods:

A feasibility RCT was conducted with participants randomized into the MOVE group (8-wk MBSR and exercise live online) or the self-management (SM) group (8-wk online self-management guide). Primary outcomes included recruitment, attrition, intervention adherence, and satisfaction. Participants wore a Fitbit watch during the study and completed patient-reported outcome measures at baseline, postintervention, and 12-week follow-up.

Results:

Ninety-six participants were randomized and 80 (83.3%) completed the interventions. Higher mean satisfaction (Client Satisfaction Questionnaire-8) was reported in the MOVE group 26.2 (±5.5) than the SM group 19.4 (±5.6). The Patient Global Impression of Change scale showed favourable changes in both groups; 65.1% of the MOVE group, 42.3% of the SM group reporting improvement. Seventy-three participants (76.3%) adhered to wearing the Fitbit for 8 weeks. Comparable improvements postintervention and at a 12-week follow-up were noted within both groups for Brief Pain Inventory, Pain Self-Efficacy Questionnaire, Pain Disability Index, Pain Catastrophising Scale, Fear Avoidance Belief Questionnaire and Short Form-36 Health Survey.

Discussion:

The findings suggest both interventions explored are acceptable and feasible. A fully powered RCT examining the effectiveness of MBSR combined with exercise, delivered live online is warranted.
Spatial and temporal epidemiological analysis on the mortality rate of female breast cancer in Suzhou, China: 2006–2020
Authors: Wang Linchi , Lu Yan , Huang Chunyan , Tang Jing
Published: May 2023

Objective:

The epidemiological trend and spatial distribution of female breast cancer mortality in Suzhou were analyzed, so as to provide a scientific basis for the prevention and treatment of breast cancer.

Materials and Methods:

The annual trend of female breast cancer mortality data from 2006 to 2020 years was analyzed. The spatial autocorrelation analysis was carried out by Moran’s I method of GeoDa software to explore its regional aggregation.

Results:

The average annual crude mortality rate (CR) of breast cancer in Suzhou was 8.54 per 100 000 from 2006 to 2020, while the age-standardized mortality rate (ASMR) was 7.38 per100 000. The annual change percentage (APC) of CR in the recent 15 years was 1.98% (1.30–2.66%), which was statistically significant (P<0.001). The annual change trend of ASMR was decreased slightly (APC=−0.95%, P=0.04). Spatial analysis indicated that there was a certain clustering of breast cancer in Suzhou. The CR of female breast cancer in Suzhou showed an upward trend, but ASMR decreased slightly.

Conclusion:

Health promotion and education should be strengthened in the areas with a high incidence of female breast cancer death in Suzhou, and the participation rate of breast cancer screening should be further improved.
Virus taxonomy and the role of the International Committee on Taxonomy of Viruses (ICTV)
Authors: Siddell Stuart G. , Smith Donald B. , Adriaenssens Evelien , Alfenas-Zerbini Poliane , Dutilh Bas E. , Garcia Maria Laura , Junglen Sandra , Krupovic Mart , Kuhn Jens H. , Lambert Amy J. , Lefkowitz Elliot J. , Łobocka Małgorzata , Mushegian Arcady R. , Oksanen Hanna M. , Robertson David L. , Rubino Luisa , Sabanadzovic Sead , Simmonds Peter , Suzuki Nobuhiro , Van Doorslaer Koenraad , Vandamme Anne-Mieke , Varsani Arvind , Zerbini F. Murilo
Published: May 2023

The taxonomy of viruses is developed and overseen by the International Committee on Taxonomy of Viruses (ICTV), which scrutinizes, approves and ratifies taxonomic proposals, and maintains a list of virus taxa with approved names (https://ictv.global). The ICTV has approximately 180 members who vote by simple majority. Taxon-specific Study Groups established by the ICTV have a combined membership of over 600 scientists from the wider virology community; they provide comprehensive expertise across the range of known viruses and are major contributors to the creation and evaluation of taxonomic proposals. Proposals can be submitted by anyone and will be considered by the ICTV irrespective of Study Group support. Thus, virus taxonomy is developed from within the virology community and realized by a democratic decision-making process. The ICTV upholds the distinction between a virus or replicating genetic element as a physical entity and the taxon category to which it is assigned. This is reflected by the nomenclature of the virus species taxon, which is now mandated by the ICTV to be in a binomial format (genus + species epithet) and is typographically distinct from the names of viruses. Classification of viruses below the rank of species (such as, genotypes or strains) is not within the remit of the ICTV. This article, authored by the ICTV Executive Committee, explains the principles of virus taxonomy and the organization, function, processes and resources of the ICTV, with the aim of encouraging greater understanding and interaction among the wider virology community.
A panel of diverse Klebsiella pneumoniae clinical isolates for research and development
Authors: Martin Melissa J. , Stribling William , Ong Ana C. , Maybank Rosslyn , Kwak Yoon I. , Rosado-Mendez Joshua A. , Preston Lan N. , Lane Katharine F. , Julius Michael , Jones Anthony R. , Hinkle Mary , Waterman Paige E. , Lesho Emil P. , Lebreton Francois , Bennett Jason W. , Mc Gann Patrick T.
Published: May 2023

Klebsiella pneumoniae

are a leading cause of healthcare-associated infections worldwide. In particular, strains expressing extended-spectrum β-lactamases (ESBLs) and carbapenemases pose serious treatment challenges, leading the World Health Organization (WHO) to designate ESBL and carbapenem-resistant Enterobacteriaceae as ‘critical’ threats to human health. Research efforts to combat these pathogens can be supported by accessibility to diverse and clinically relevant isolates for testing novel therapeutics. Here, we describe a panel of 100 diverse

K. pneumoniae

isolates that are publicly available to assist the research community in this endeavour. Whole-genome sequencing (WGS) was performed on 3878

K

.

pneumoniae

clinical isolates housed at the Multidrug-Resistant Organism Repository and Surveillance Network. The isolates were cultured from 63 facilities in 19 countries between 2001 and 2020. Core-genome multilocus sequence typing and high-resolution single-nucleotide polymorphism-based phylogenetic analyses captured the genetic diversity of the collection and were used to select the final panel of 100 isolates. In addition to known multidrug-resistant (MDR) pandemic lineages, the final panel includes hypervirulent lineages and isolates with specific and diverse resistance genes and virulence biomarkers. A broad range of antibiotic susceptibilities, ranging from pan-sensitive to extensively drug-resistant isolates, are described. The panel collection, and all associated metadata and genome sequences, are available at no additional cost and will be an important resource for the research community and for the design and development of novel antimicrobial agents and diagnostics against this important pathogen.
Role of SARS-CoV-2 mutations in the evolution of the COVID-19 pandemic
Authors: Colson Philippe , Chaudet Hervé , Delerce Jérémy , Pontarotti Pierre , Levasseur Anthony , Fantini Jacques , Scola Bernard LA , Devaux Christian , Raoult Didier
Published: May 2023

RNA viruses, including SARS-CoV-2, evolve by mutation acquisition, or by hybridization between viral genomes. The SARS-CoV-2 pandemic provided an exceptional opportunity to analyze the mutations that appeared over a three-year period.

In this study, we analysed the type of mutations and their epidemic consequences on the thousands of genomes produced in our laboratory. These were obtained by next-generation sequencing from respiratory samples performed for genomic surveillance. The frequencies of mutations were calculated using Nextclade, Microsoft Excel, and an in-house Python script. In total, 61,397 genomes matching 483 Pangolin lineages were analyzed; 22,225 nucleotide mutations were identified, and of them 220 (1.0%) were each at the root of at least 836 genomes, a frequency threshold classifying mutations as “hyperfertile”. Two of these seeded the pandemic in Europe, namely a mutation in the RNA-dependent RNA polymerase associated with an increased mutation rate (P323L) and one in the spike protein (D614G), which plays a particular role in virus fitness. Most of these 220 “hyperfertile” mutations occurred in areas not predicted to be associated with increased virulence. Their number was 8±6 (0-22) per 1,000 nucleotides on average per gene. They were 3.7 times more frequent in accessory than informational genes (14 versus 4; p= 0.0037). Particularly, they were 4.1 times more frequent in ORF8 than in the gene encoding RNA polymerase. Interestingly, stop codons were present in 97 positions, almost only in six accessory genes including ORF7a (25 per 100 codons) and ORF8 (21). Furthermore, 1,661 mutations (16.3%) were associated with a lower number of “offspring” (50-835) and classified as “fertile”.

In conclusion, except for two initial mutations that could predict a change in the dynamics of the epidemic (mutation rate and change in the virus attachment site), most of the “hyperfertile” mutations did not predict the emergence of a new epidemic form. Significantly, some mutations were in non-coding areas and some consisted of stop codons, indicating that some genes (particularly ORF7a and ORF8) were rather “non-virulence genes” at a given stage of the epidemic, which is an unusual concept for viruses.
Analysis of tandem mass spectrometry data with CONGA: Combining Open and Narrow searches with Group-wise Analysis
Authors: Freestone Jack , Noble William S. , Keich Uri
Published: May 2023

Searching tandem mass spectrometry proteomics data against a database is a well-established method for assigning peptide sequences to observed spectra but typically cannot identify peptides harboring unexpected post-translational modifications (PTMs). Open modification searching aims to address this problem by allowing a spectrum to match a peptide even if the spectrum’s precursor mass differs from the peptide mass. However, expanding the search space in this way can lead to a loss in statistical power to detect peptides. We therefore developed a method, called CONGA, that takes into account results from both types of searches—a traditional “narrow window” search and an open modification search—while carrying out rigorous false discovery rate (FDR) control. The result is an algorithm that provides the best of both worlds: the ability to detect unexpected PTMs without a concomitant loss of power to detect unmodified peptides.
Climatic niches provide insights into the evolutionary origins and ecological significance of the succulent CAM syndrome around the world
Authors: Hernández-Hernández Tania , Vásquez-Cruz Marilyn , Loera Israel , DelAngel Melina , Nakamura Miguel
Published: May 2023

Although distributed globally, plants possessing the succulent syndrome are thought to have evolved to adapt to arid climates, because they possess modifications that increase their water use efficiency. Here we study the evolution and the ecological nature of the succulent CAM syndrome at a global scale by analyzing the climatic niches of succulents within the Caryophyllales, testing the hypothesis of a climatic niche specialization by comparing them with their non-succulent, non-arid adapted relatives. We assembled and carefully curated a worldwide dataset of 5447 species in 28 families, and analyzed the current and evolutionary trajectories of climatic niches with an array of statistical methods including ecological niche modeling, phylogenetic regression and divergence dates estimation. Our results confirm the Core Caryophyllales tend to inhabit drylands probably since their origin in the Early Cretaceous. However, the succulent syndrome appeared later with some lineages diversifying profusely afterwards. The climatic niche of succulents is not differentiated from their non-succulent relatives, but narrower, and contained within the non-succulents’, showing no relationship with extreme conditions such as high aridity or temperatures. Our results support alternative interpretations of the origin of the CAM syndrome and the ecological significance of succulence, as well as the prolific radiation of richest lineages.

Highlights

The climatic niche occupied by succulent CAM plants is not different from their non-succulent relatives. Estimated dates and character reconstruction suggest CO2 scarcity as the evolutionary pressure under these plants originated.
The soluble guanylyl cyclase pathway is inhibited to evade androgen deprivation-induced senescence and enable progression to castration resistance
Authors: Zhang Ling , Troccoli Clara I. , Mateo-Victoriano Beatriz , Lincheta Laura Misiara , Jackson Erin , Shu Ping , Plastini Trisha , Tao Wensi , Kwon Deukwoo , Chen Xi , Sharma Janaki , Jorda Merce , Gulley James L. , Bilusic Marijo , Lockhart Albert Craig , Beuve Annie , Rai Priyamvada
Published: May 2023

Castration-resistant prostate cancer (CRPC) is fatal and therapeutically under-served. We describe a novel CRPC-restraining role for the vasodilatory soluble guanylyl cyclase (sGC) pathway. We discovered that sGC subunits are dysregulated during CRPC progression and its catalytic product, cyclic GMP (cGMP), is lowered in CRPC patients. Abrogating sGC heterodimer formation in castration-sensitive prostate cancer (CSPC) cells inhibited androgen deprivation (AD)-induced senescence, and promoted castration-resistant tumor growth. We found sGC is oxidatively inactivated in CRPC. Paradoxically, AD restored sGC activity in CRPC cells through redox-protective responses evoked to protect against AD-induced oxidative stress. sGC stimulation via its FDA-approved agonist, riociguat, inhibited castration-resistant growth, and the anti-tumor response correlated with elevated cGMP, indicating on-target sGC activity. Consistent with known sGC function, riociguat improved tumor oxygenation, decreasing the PC stem cell marker, CD44, and enhancing radiation-induced tumor suppression. Our studies thus provide the first evidence for therapeutically targeting sGC via riociguat to treat CRPC.

Statement of significance

Prostate cancer is the second highest cancer-related cause of death for American men. Once patients progress to castration-resistant prostate cancer, the incurable and fatal stage, there are few viable treatment options available. Here we identify and characterize a new and clinically actionable target, the soluble guanylyl cyclase complex, in castration-resistant prostate cancer. Notably we find that repurposing the FDA-approved and safely tolerated sGC agonist, riociguat, decreases castration-resistant tumor growth and re-sensitizes these tumors to radiation therapy. Thus our study provides both new biology regarding the origins of castration resistance as well as a new and viable treatment option.
Beyond Blast: Enabling Microbiologists to Better Extract Literature, Taxonomic Distributions and Gene Neighborhood Information for Protein Families
Authors: Reed Colbie J. , Denise Rémi , Hourihan Jacob , Babor Jill , Jaroch Marshall , Martinelli Maria , Hutinet Geoffrey , de Crécy-Lagard Valérie
Published: May 2023

Capturing the published corpus of information on all members of a given protein family should be an essential step in any study focusing on specific members of that said family. Using a previously gathered dataset of more than 280 references mentioning a member of the DUF34 (NIF3/Ngg1-interacting Factor 3), we evaluated the efficiency of different databases and search tools, and devised a workflow that experimentalists can use to capture the most published information on members of a protein family in the least amount of time. To complement this workflow, web-based platforms allowing for the exploration of protein family members across sequenced genomes or for the analysis of gene neighborhood information were reviewed for their versatility and ease of use. Recommendations that can be used for experimentalist users, as well as educators, are provided and integrated within a customized, publicly accessible Wiki.

Data summary

The authors confirm all supporting data, code, and protocols have been provided within the article or through supplementary data files. Complete set of supplementary data sheets may be accessed via FigShare.
An elastic proteinaceous envelope encapsulates the earlyArabidopsisembryo
Authors: Harnvanichvech Yosapol , Borassi Cecilia , Daghma Diaa Eldin S. , van der Kooij Hanne M. , Sprakel Joris , Weijers Dolf
Published: May 2023

Plant external surfaces are often covered by barriers that control the exchange of molecules, protect from pathogens, and offer mechanical integrity. A key question is when and how such surface barriers are generated. Post-embryonic surfaces have well-studied barriers, including the cuticle, and late Arabidopsis embryo was shown to be protected by an endosperm-derived sheath deposited onto a primordial cuticle. Here we show that both cuticle and sheath are preceded by another structure during the earliest stages of embryogenesis. This structure, which we named the embryonic envelope, is tightly wrapped around the embryonic surface but can be physically detached by cell wall digestion. We show that this structure is composed primarily of Extensin and ArabinogalactanO-glycoproteins and lipids, which appear to form a dense and elastic crosslinked embryonic envelope. The envelope forms in cuticle-deficient mutants and in a mutant that lacks endosperm. This embryo-derived envelope is therefore distinct from previously described cuticle and sheath structures. We propose that it acts as an expandable diffusion barrier, as well as a means to mechanically confine the embryo to maintain its tensegrity during early embryogenesis.

Summary statement

The early Arabidopsis embryo is surrounded by a proteinaceous envelope that is distinct from the cuticle or embryo sheath
Structural basis of the T4 bacteriophage primosome assembly and primer synthesis
Authors: Feng Xiang , Spiering Michelle M. , de Luna Almeida Santos Ruda , Benkovic Stephen J. , Li Huilin
Published: May 2023

The T4 bacteriophage gp41 helicase and gp61 primase assemble into a primosome complex to couple DNA unwinding with RNA primer synthesis for DNA replication. How a primosome is assembled and how the length of the RNA primer is defined in the T4 bacteriophage, or in any model system, are unclear. Here we report a series of cryo-EM structures of T4 primosome assembly intermediates at resolutions up to 2.7 Å. We show that the gp41 helicase is an open spiral in the absence of ssDNA, and ssDNA binding triggers a large-scale scissor-like conformational change that drives the open spiral to a closed ring that activates the helicase. We found that the activation of the gp41 helicase exposes a cryptic hydrophobic primase-binding surface allowing for the recruitment of the gp61 primase. The primase binds the gp41 helicase in a bipartite mode in which the N-terminal Zn-binding domain (ZBD) and the C-terminal RNA polymerase domain (RPD) each contain a helicase-interacting motif (HIM1 and HIM2, respectively) that bind to separate gp41 N-terminal hairpin dimers, leading to the assembly of one primase on the helicase hexamer. Based on two observed primosome conformations – one in a DNA-scanning mode and the other in a post RNA primer-synthesis mode – we suggest that the linker loop between the gp61 ZBD and RPD contributes to the T4 pentaribonucleotide primer. Our study reveals T4 primosome assembly process and sheds light on RNA primer synthesis mechanism.