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2.
Mol Cell ; 84(16): 3163-3164, 2024 Aug 22.
Article in English | MEDLINE | ID: mdl-39142277
3.
Blood ; 2024 Aug 08.
Article in English | MEDLINE | ID: mdl-39116296

ABSTRACT

With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate inter-study comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to i) account for gender-specific differences in determining hemoglobin levels for eligibility criteria, ii) revise definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices, and iii) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks prior to study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs. non-TDA) and graded (major vs. minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.

4.
Adv Ther ; 41(9): 3722-3735, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38990433

ABSTRACT

INTRODUCTION: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration. METHODS: SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n = 156). Patient subgroups (n = 105 each) were defined by either baseline (1) hemoglobin (Hb) of < 100 g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of < 80 g/L for the previous 12 weeks); outcomes have been summarized descriptively. RESULTS: In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of < 100 g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower. CONCLUSION: In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02101268.


Patients with the rare blood cancer myelofibrosis often experience symptoms such as tiredness, an increase in the size of their spleens (an organ involved in filtering the blood), and anemia (too few red blood cells). One type of treatment for myelofibrosis, called a Janus kinase (JAK) inhibitor, can help patients to feel better and reduce the size of their spleens, but some JAK inhibitors do not help with anemia and may make it worse. In those situations, patients may continue to take their JAK inhibitor but also receive another type of treatment, called an anemia supportive therapy, and may also receive red blood cell transfusions. This study compared 2 treatment approaches, continuing the JAK inhibitor ruxolitinib and adding an anemia supportive therapy and/or transfusions versus switching to another treatment called momelotinib, in 2 groups of patients from a clinical trial: (1) patients with levels of hemoglobin (a red blood cell protein) at the start of the trial that indicated that they had anemia, and (2) patients who were already receiving red blood cell transfusions at the start of the trial. In both groups, more patients did not need red blood cell transfusions anymore at week 24 with momelotinib, and their hemoglobin levels on average became higher over time. More patients also had improvements in spleen size and symptoms with momelotinib. Overall, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using supportive therapies and/or red blood cell transfusions to treat anemia.


Subject(s)
Anemia , Janus Kinase Inhibitors , Nitriles , Primary Myelofibrosis , Pyrazoles , Pyrimidines , Humans , Pyrimidines/therapeutic use , Nitriles/therapeutic use , Pyrazoles/therapeutic use , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/complications , Anemia/drug therapy , Anemia/etiology , Male , Female , Aged , Middle Aged , Janus Kinase Inhibitors/therapeutic use , Benzamides/therapeutic use , Janus Kinase 1/antagonists & inhibitors , Erythrocyte Transfusion/statistics & numerical data , Aged, 80 and over , Treatment Outcome , Janus Kinase 2/antagonists & inhibitors
5.
Funct Integr Genomics ; 24(4): 129, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39039331

ABSTRACT

Genetically modified (GM) crops, expressing Bacillus thuringiensis (Bt) insecticidal toxins, have substantially transformed agriculture. Despite rapid adoption, their environmental and economic benefits face scrutiny due to unsustainable agricultural practices and the emergence of resistant pests like Spodoptera frugiperda, known as the fall armyworm (FAW). FAW's adaptation to Bt technology in corn and cotton compromises the long-term efficacy of Bt crops. To advance the understanding of the genetic foundations of resistance mechanisms, we conducted an exploratory comparative transcriptomic analysis of two divergent FAW populations. One population exhibited practical resistance to the Bt insecticidal proteins Cry1A.105 and Cry2Ab2, expressed in the genetically engineered MON-89Ø34 - 3 maize, while the other population remained susceptible to these proteins. Differential expression analysis supported that Cry1A.105 and Cry2Ab2 significantly affect the FAW physiology. A total of 247 and 254 differentially expressed genes were identified in the Cry-resistant and susceptible populations, respectively. By integrating our findings with established literature and databases, we underscored 53 gene targets potentially involved in FAW's resistance to Cry1A.105 and Cry2Ab2. In particular, we considered and discussed the potential roles of the differentially expressed genes encoding ABC transporters, G protein-coupled receptors, the P450 enzymatic system, and other Bt-related detoxification genes. Based on these findings, we emphasize the importance of exploratory transcriptomic analyses to uncover potential gene targets involved with Bt insecticidal proteins resistance, and to support the advantages of GM crops in the face of emerging challenges.


Subject(s)
Bacillus thuringiensis Toxins , Bacterial Proteins , Endotoxins , Hemolysin Proteins , Insecticide Resistance , Spodoptera , Transcriptome , Spodoptera/drug effects , Spodoptera/genetics , Animals , Endotoxins/genetics , Endotoxins/pharmacology , Hemolysin Proteins/genetics , Hemolysin Proteins/pharmacology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Insecticide Resistance/genetics , Plants, Genetically Modified/genetics , Plants, Genetically Modified/parasitology , Zea mays/genetics , Zea mays/parasitology , Gene Expression Profiling
6.
Mol Genet Genomics ; 299(1): 73, 2024 Jul 27.
Article in English | MEDLINE | ID: mdl-39066857

ABSTRACT

Exploring the intricate relationships between plants and their resident microorganisms is crucial not only for developing new methods to improve disease resistance and crop yields but also for understanding their co-evolutionary dynamics. Our research delves into the role of the phyllosphere-associated microbiome, especially Actinomycetota species, in enhancing pathogen resistance in Theobroma grandiflorum, or cupuassu, an agriculturally valuable Amazonian fruit tree vulnerable to witches' broom disease caused by Moniliophthora perniciosa. While breeding resistant cupuassu genotypes is a possible solution, the capacity of the Actinomycetota phylum to produce beneficial metabolites offers an alternative approach yet to be explored in this context. Utilizing advanced long-read sequencing and metagenomic analysis, we examined Actinomycetota from the phyllosphere of a disease-resistant cupuassu genotype, identifying 11 Metagenome-Assembled Genomes across eight genera. Our comparative genomic analysis uncovered 54 Biosynthetic Gene Clusters related to antitumor, antimicrobial, and plant growth-promoting activities, alongside cutinases and type VII secretion system-associated genes. These results indicate the potential of phyllosphere-associated Actinomycetota in cupuassu for inducing resistance or antagonism against pathogens. By integrating our genomic discoveries with the existing knowledge of cupuassu's defense mechanisms, we developed a model hypothesizing the synergistic or antagonistic interactions between plant and identified Actinomycetota during plant-pathogen interactions. This model offers a framework for understanding the intricate dynamics of microbial influence on plant health. In conclusion, this study underscores the significance of the phyllosphere microbiome, particularly Actinomycetota, in the broader context of harnessing microbial interactions for plant health. These findings offer valuable insights for enhancing agricultural productivity and sustainability.


Subject(s)
Plant Diseases , Plant Leaves , Plant Leaves/microbiology , Plant Leaves/genetics , Plant Diseases/microbiology , Plant Diseases/genetics , Disease Resistance/genetics , Microbiota/genetics , Ecosystem , Actinobacteria/genetics , Actinobacteria/isolation & purification , Metagenomics/methods , Metagenome/genetics , Phylogeny , Brassicaceae/microbiology , Brassicaceae/genetics
7.
Genet Mol Biol ; 47(2): e20230301, 2024.
Article in English | MEDLINE | ID: mdl-38985012

ABSTRACT

The sacred ayahuasca brew, utilized by indigenous communities in the Amazon and syncretic religious groups in Brazil, primarily consists of a decoction of two plants: (i) the Amazonian liana known as Mariri or Jagube (Banisteriopsis caapi), and (ii) the shrub referred as Chacrona or Rainha (Psychotria viridis). While Chacrona leaves are rich in N,N-Dimethyltryptamine (DMT), a potent psychedelic, the macerated vine of Mariri provides beta-carboline alkaloids acting as monoamine oxidase inhibitors, preventing DMT's degradation. This study sequenced, assembled, and analyzed the complete genome of B. caapi's mitochondrion, yielding a circular structure spanning 503,502 bp. Although the mtDNA encompasses most plant mitochondrial genes, it lacks some ribosomal genes, presents some atypical genes, and contains plastid pseudogenes, suggesting gene transfer between organelles. The presence of a 7-Kb repetitive segment containing copies of the rrnL and trnfM genes suggests mitogenome isomerization, supporting the hypothesis of dynamic mitogenome maintenance in plants. Phylogenetics and phylogenomics across 24 Malpighiales confirms the sample's placement in the "Tucunacá" ethnovariety, aligning with morphological identification. This study spearheads efforts to decode the genome of this esteemed Malpighiaceae.

8.
Mol Cell ; 84(15): 2807-2821, 2024 Aug 08.
Article in English | MEDLINE | ID: mdl-39025071

ABSTRACT

RAS proteins are conserved guanosine triphosphate (GTP) hydrolases (GTPases) that act as molecular binary switches and play vital roles in numerous cellular processes. Upon GTP binding, RAS GTPases adopt an active conformation and interact with specific proteins termed RAS effectors that contain a conserved ubiquitin-like domain, thereby facilitating downstream signaling. Over 50 effector proteins have been identified in the human proteome, and many have been studied as potential mediators of RAS-dependent signaling pathways. Biochemical and structural analyses have provided mechanistic insights into these effectors, and studies using model organisms have complemented our understanding of their role in physiology and disease. Yet, many critical aspects regarding the dynamics and biological function of RAS-effector complexes remain to be elucidated. In this review, we discuss the mechanisms and functions of known RAS effector proteins, provide structural perspectives on RAS-effector interactions, evaluate their significance in RAS-mediated signaling, and explore their potential as therapeutic targets.


Subject(s)
Signal Transduction , ras Proteins , Humans , ras Proteins/metabolism , ras Proteins/chemistry , Animals , Protein Binding , Models, Molecular , Structure-Activity Relationship , Protein Conformation , Guanosine Triphosphate/metabolism
9.
Leuk Lymphoma ; 65(9): 1314-1324, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38838026

ABSTRACT

The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 109/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5-43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs.


Subject(s)
Nitriles , Primary Myelofibrosis , Pyrazoles , Pyrimidines , Pyrrolidines , Humans , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/diagnosis , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Pyrazoles/administration & dosage , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/administration & dosage , Male , Female , Aged , Middle Aged , Pyrrolidines/therapeutic use , Treatment Outcome , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/administration & dosage , COVID-19/epidemiology , Aged, 80 and over , SARS-CoV-2 , Spleen/pathology , Spleen/drug effects , Adult , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/administration & dosage , Benzenesulfonamides
10.
Am J Hematol ; 99(8): 1462-1474, 2024 08.
Article in English | MEDLINE | ID: mdl-38877813

ABSTRACT

Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.


Subject(s)
Aspirin , Drug Administration Schedule , Hemorrhage , Platelet Aggregation Inhibitors , Thrombocythemia, Essential , Humans , Aspirin/administration & dosage , Aspirin/therapeutic use , Thrombocythemia, Essential/drug therapy , Thrombocythemia, Essential/blood , Male , Middle Aged , Female , Aged , Adult , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/adverse effects , Hemorrhage/chemically induced , Thromboxane B2/blood , Platelet Activation/drug effects , Aged, 80 and over , Treatment Outcome
11.
Am J Hematol ; 99(8): 1550-1559, 2024 08.
Article in English | MEDLINE | ID: mdl-38841874

ABSTRACT

The variant allele frequency (VAF) of driver mutations (JAK2, CALR) in myeloproliferative neoplasms is associated with features of advanced disease and complications. Ruxolitinib and interferon were reported to variably reduce the mutant VAF, but the long-term impact of molecular responses (MR) remains debated. We prospectively measured changes in JAK2 and CALR VAF in 77 patients with polycythemia vera and essential thrombocythemia, treated with ruxolitinib for a median of 8 years, and assessed correlation with complete clinical and hematological response (CCHR) and outcomes. At last observation time, JAK2 VAF reduced overall from a median of 68% (range, 20%-99%) to 3.5% (0%-98%). A profound and durable MR (DMR; defined as a VAF stably ≤2%), including complete MR in 8%, was achieved in 20% of the patients, a partial MR (PMR; VAF reduction >50% of the baseline level) in 25%, and 56% had no molecular response (NMR). A CCHR was reached by 69% overall, independently of any degree of MR achieved; conversely, a DMR correlated with longer duration of CCHR and, most importantly, with reduced rate of progression to myelofibrosis and with longer myelofibrosis-free, event-free and progression-free survival. Achievement of PMR also had some favorable impact on outcomes, compared to NMR. A baseline JAK2 VAF <50%, and a VAF reduction of ≥35% after 2 years of treatment, predicted for the achievement of DMR and reduced progression to myelofibrosis. Overall, these findings support the clinical value of achieving profound, durable MR and its consideration as surrogate endpoint in future clinical trials.


Subject(s)
Janus Kinase 2 , Mutation , Polycythemia Vera , Pyrazoles , Thrombocythemia, Essential , Humans , Janus Kinase 2/genetics , Polycythemia Vera/genetics , Polycythemia Vera/drug therapy , Thrombocythemia, Essential/genetics , Thrombocythemia, Essential/drug therapy , Male , Female , Middle Aged , Aged , Adult , Pyrazoles/therapeutic use , Aged, 80 and over , Pyrimidines/therapeutic use , Nitriles/therapeutic use , Gene Frequency , Alleles , Calreticulin/genetics , Prospective Studies , Treatment Outcome
12.
Am J Physiol Regul Integr Comp Physiol ; 327(2): R164-R172, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38842514

ABSTRACT

This study investigated whether a heavy-intensity priming exercise precisely prescribed within the heavy-intensity domain would lead to a greater peak-power output (POpeak) and a longer maximal oxygen uptake (V̇o2max) plateau. Twelve recreationally active adults participated in this study. Two visits were required: 1) a step-ramp-step test [ramp-incremental (RI) control], and 2) an RI test preceded by a priming exercise within the heavy-intensity domain (RI primed). A piecewise equation was used to quantify the V̇o2 plateau duration (V̇o2plateau-time). The mean response time (MRT) was computed during the RI control condition. The delta (Δ) V̇o2 slope (S; mL·min-1·W-1) and V̇o2-Y intercept (Y; mL·min-1) within the moderate-intensity domain between conditions (RI primed minus RI control) were also assessed using a novel graphical analysis. V̇o2plateau-time (P = 0.001; d = 1.27) and POpeak (P = 0.003; d = 1.08) were all greater in the RI primed. MRT (P < 0.001; d = 2.45) was shorter in the RI primed compared with the RI control. A larger ΔV̇o2plateau-time was correlated with a larger ΔMRT between conditions (r = -0.79; P = 0.002). This study demonstrated that heavy-intensity priming exercise lengthened the V̇o2plateau-time and increased POpeak. The overall faster RI-V̇o2 responses seem to be responsible for the longer V̇o2plateau-time. Specifically, a shorter MRT, but not changes in RI-V̇o2-slopes, was associated with a longer V̇o2plateau-time following priming exercise.NEW & NOTEWORTHY It remains unclear whether priming exercise extends the maximal oxygen uptake (V̇o2max) plateau and increases peak-power output (POpeak) during ramp-incremental (RI) tests. This study demonstrates that a priming exercise, precisely prescribed within the heavy-intensity domain, extends the plateau at V̇o2max and leads to a greater POpeak. Specifically, the extended V̇o2max plateau was associated with accelerated RI-V̇o2 responses.


Subject(s)
Exercise , Oxygen Consumption , Humans , Male , Oxygen Consumption/physiology , Adult , Female , Young Adult , Exercise/physiology , Exercise Test , Time Factors , Muscle, Skeletal/physiology
13.
Gigascience ; 132024 01 02.
Article in English | MEDLINE | ID: mdl-38837946

ABSTRACT

BACKGROUND: Theobroma grandiflorum (Malvaceae), known as cupuassu, is a tree indigenous to the Amazon basin, valued for its large fruits and seed pulp, contributing notably to the Amazonian bioeconomy. The seed pulp is utilized in desserts and beverages, and its seed butter is used in cosmetics. Here, we present the sequenced telomere-to-telomere genome of cupuassu, disclosing its genomic structure, evolutionary features, and phylogenetic relationships within the Malvaceae family. FINDINGS: The cupuassu genome spans 423 Mb, encodes 31,381 genes distributed in 10 chromosomes, and exhibits approximately 65% gene synteny with the Theobroma cacao genome, reflecting a conserved evolutionary history, albeit punctuated with unique genomic variations. The main changes are pronounced by bursts of long-terminal repeat retrotransposons at postspecies divergence, retrocopied and singleton genes, and gene families displaying distinctive patterns of expansion and contraction. Furthermore, positively selected genes are evident, particularly among retained and dispersed tandem and proximal duplicated genes associated with general fruit and seed traits and defense mechanisms, supporting the hypothesis of potential episodes of subfunctionalization and neofunctionalization following duplication, as well as impact from distinct domestication process. These genomic variations may underpin the differences observed in fruit and seed morphology, ripening, and disease resistance between cupuassu and the other Malvaceae species. CONCLUSIONS: The cupuassu genome offers a foundational resource for both breeding improvement and conservation biology, yielding insights into the evolution and diversity within the genus Theobroma.


Subject(s)
Evolution, Molecular , Genome, Plant , Phylogeny , Chromosomes, Plant , Genomics/methods , Malvaceae/genetics
14.
Materials (Basel) ; 17(11)2024 May 28.
Article in English | MEDLINE | ID: mdl-38893868

ABSTRACT

In this work, a self-lubricating composite was manufactured using a novel hybrid 3D printing/in situ spraying process that involved the printing of an acrylonitrile butadiene styrene (ABS) matrix using fused deposition modeling (FDM), along with the in situ spraying of alumina (Al2O3) and hexagonal boron nitride (hBN) reinforcements during 3D printing. The results revealed that the addition of the reinforcement induced an extensive formation of micropores throughout the ABS structure. Under tensile-loading conditions, the mechanical strength and cohesive interlayer bonding of the composites were diminished due to the presence of these micropores. However, under tribological conditions, the presence of the Al2O3 and hBN reinforcement improved the frictional resistance of ABS in extreme loading conditions. This improvement in frictional resistance was attributed to the ability of the Al2O3 reinforcement to support the external tribo-load and the shearing-like ability of hBN reinforcement during sliding. Collectively, this work provides novel insights into the possibility of designing tribologically robust ABS components through the addition of in situ-sprayed ceramic and solid-lubricant reinforcements.

15.
Int J Exerc Sci ; 17(2): 648-659, 2024.
Article in English | MEDLINE | ID: mdl-38864027

ABSTRACT

This study aimed to investigate the effects of chronic ß-alanine (ßA) plus acute sodium bicarbonate (SB) co-supplementation on neuromuscular fatigue during high-intensity intermittent efforts in swimming. Eleven regional and national competitive-level young swimmers performed a neuromuscular fatigue assessment before and immediately after two 20 × 25-m front crawl maximal efforts every 90 s, performed at pre- and post-4-week co-supplementation. Neuromuscular fatigue was evaluated by percutaneous electrical stimuli through the twitch interpolation technique on the triceps brachii and quadriceps femoris. Performance was defined by the mean time of the 20 efforts and blood samples to lactate concentrations were collected every four efforts. Participants supplemented 3.2-6.4 g·day-1 of chronic ßA or placebo (PL) during four weeks, and acute 0.3 g·kg-1 of SB or PL 60 min before the second assessment (allowing ßA+SB and PL+PL groups). No statistical changes were found in neuromuscular fatigue of triceps brachii. In the quadriceps femoris, a main effect of time was found in potentiated twitch delta values in pooled groups, showing a statistical increase of 19.01% after four weeks (Δ = 13.05 [0.35-25.75] N; p = 0.044), without time × group interactions. No statistical difference was found in the swimming performance. Blood lactate increased by 25.06% only in the ßA+SB group (Δ = 6.40 [4.62-8.18] mM; p Bonf < 0.001) after the supplementation period. In conclusion, 4-week ßA and SB co-supplementation were not able to reduce neuromuscular fatigue levels and improve performance in highintensity intermittent efforts, but statistically increased blood lactate levels.

16.
Blood Adv ; 8(17): 4511-4522, 2024 Sep 10.
Article in English | MEDLINE | ID: mdl-38820422

ABSTRACT

ABSTRACT: The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); and patients in cohort 3A/3B had stable ruxolitinib treatment before and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary end point was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary end point. In cohorts 1 and 3A (NTD), 27% and 50% of patients, respectively, had mean hemoglobin increase of ≥1.5 g/dL from baseline. Among TD patients, ∼50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. This trial was registered at www.ClinicalTrials.gov as #NCT03194542.


Subject(s)
Anemia , Immunoglobulin Fc Fragments , Primary Myelofibrosis , Recombinant Fusion Proteins , Humans , Anemia/drug therapy , Anemia/etiology , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/complications , Female , Male , Aged , Middle Aged , Recombinant Fusion Proteins/therapeutic use , Recombinant Fusion Proteins/adverse effects , Immunoglobulin Fc Fragments/therapeutic use , Immunoglobulin Fc Fragments/adverse effects , Treatment Outcome , Activin Receptors, Type II/therapeutic use , Aged, 80 and over , Pyrazoles/therapeutic use , Pyrazoles/adverse effects
17.
Methods Mol Biol ; 2802: 189-213, 2024.
Article in English | MEDLINE | ID: mdl-38819561

ABSTRACT

The data generated in nearly 30 years of bacterial genome sequencing has revealed the abundance of transposable elements (TE) and their importance in genome and transcript remodeling through the mediation of DNA insertions and deletions, structural rearrangements, and regulation of gene expression. Furthermore, what we have learned from studying transposition mechanisms and their regulation in bacterial TE is fundamental to our current understanding of TE in other organisms because much of what has been observed in bacteria is conserved in all domains of life. However, unlike eukaryotic TE, prokaryotic TE sequester and transmit important classes of genes that impact host fitness, such as resistance to antibiotics and heavy metals and virulence factors affecting animals and plants, among other acquired traits. This provides dynamism and plasticity to bacteria, which would otherwise be propagated clonally. The insertion sequences (IS), the simplest form of prokaryotic TE, are autonomous and compact mobile genetic elements. These can be organized into compound transposons, in which two similar IS can flank any DNA segment and render it transposable. Other more complex structures, called unit transposons, can be grouped into four major families (Tn3, Tn7, Tn402, Tn554) with specific genetic characteristics. This chapter will revisit the prominent structural features of these elements, focusing on a genomic annotation framework and comparative analysis. Relevant aspects of TE will also be presented, stressing their key position in genome impact and evolution, especially in the emergence of antimicrobial resistance and other adaptive traits.


Subject(s)
DNA Transposable Elements , Genome, Bacterial , Genomics , Molecular Sequence Annotation , DNA Transposable Elements/genetics , Genomics/methods , Bacteria/genetics , Evolution, Molecular , Prokaryotic Cells/metabolism
20.
Mar Environ Res ; 198: 106520, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38685145

ABSTRACT

Altered ocean chemistry caused by ocean acidification (OA) is expected to have negative repercussions at different levels of the ecological hierarchy, starting from the individual and scaling up to the community and ultimately to the ecosystem level. Understanding the effects of OA on benthic organisms is of primary importance given their relevant ecological role in maintaining marine ecosystem functioning. The use of functional traits represents an effective technique to investigate how species adapt to altered environmental conditions and can be used to predict changes in the resilience of communities faced with stresses associated with climate change. Artificial supports were deployed for 1-y along a natural pH gradient in the shallow hydrothermal systems of the Bottaro crater near Panarea (Aeolian Archipelago, southern Tyrrhenian Sea), to explore changes in functional traits and metabolic rates of benthic communities and the repercussions in terms of functional diversity. Changes in community composition due to OA were accompanied by modifications in functional diversity. Altered conditions led to higher oxygen consumption in the acidified site and the selection of species with the functional traits needed to withstand OA. Calcification rate and reproduction were found to be the traits most affected by pH variations. A reduction in a community's functional evenness could potentially reduce its resilience to further environmental or anthropogenic stressors. These findings highlight the ability of the ecosystem to respond to climate change and provide insights into the modifications that can be expected given the predicted future pCO2 scenarios. Understanding the impact of climate change on functional diversity and thus on community functioning and stability is crucial if we are to predict changes in ecosystem vulnerability, especially in a context where OA occurs in combination with other environmental changes and anthropogenic stressors.


Subject(s)
Biodiversity , Climate Change , Ecosystem , Oceans and Seas , Seawater , Hydrogen-Ion Concentration , Seawater/chemistry , Animals , Aquatic Organisms/drug effects , Aquatic Organisms/physiology , Carbon Dioxide , Environmental Monitoring , Ocean Acidification
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