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Sample Size Impact (SaSii): An R script for estimating optimal sample sizes in population genetics and population genomics studies
Obtaining large sample sizes for genetic studies can be challenging, time-consuming, and expensive, and small sample sizes may generate biased or imprecise results. Many studies have suggested the minimum sample size necessary to obtain robust and reliable results, but it is not possible to define one ideal minimum sample size that fits all studies. Here, we present SaSii (Sample Size Impact), an R script to help researchers define the minimum sample size. Based on empirical and simulated data analysis using SaSii , we present patterns and suggest minimum sample sizes for experiment design. The patterns were obtained by analyzing previously published genotype datasets with SaSii and can be used as a starting point for the sample design of population genetics and genomic studies. Our results showed that it is possible to estimate an adequate sample size that accurately represents the real population without requiring the scientist to write any program code, extract and sequence samples, or use population genetics programs, thus simplifying the process. We also confirmed that the minimum sample sizes for SNP (single-nucleotide polymorphism) analysis are usually smaller than for SSR (simple sequence repeat) analysis and discussed other patterns observed from empirical plant and animal datasets.
Treatment of relapsed/refractory MCL
Abstract Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that is clinically characterized by its heterogeneous behavior, with courses ranging from indolent to highly aggressive cases with limited prognosis. Targeted treatment alternatives in first-line and relapse settings are more and more shaping the therapeutic landscape of MCL. The development and implementation of new targeted and immunotherapeutic approaches have already improved outcomes for patients with MCL with refractory or relapsed disease. However, long-term prognosis is still limited, and patients with relapsed/refractory (R/R) disease, especially those failing Bruton tyrosine kinase (BTK) inhibitor treatment, usually have a dismal outcome. This review summarizes the current and emerging treatment options for R/R MCL, focusing on the implementation of combined targeted treatment strategies such as BTK inhibitors and BCL2 inhibitors, as well as immune-therapeutic approaches including chimeric antigen receptor T cells and bispecific antibodies.
Stressosome-independent but RsbT-dependent environmental stress sensing in Bacillus subtilis
EEG theta and alpha oscillations during tactical decision-making: An examination of the neural efficiency hypothesis in volleyball
According to the neural efficiency hypothesis (NEH), individuals with higher expertise in a domain use their brain more efficiently when processing domain-specific tasks and show more efficient brain activity than individuals with lower expertise. In this study 64 participants with differing levels of volleyball expertise were recruited to investigate the NEH by means of a volleyball-specific tactical decision-making task. The participants, which were allocated to three different expertise groups (based on prior volleyball experience), saw videos of setting situations of real volleyball matches and were asked to predict the outcome of these situations. Behavioral performance and event-related de-/synchronization (ERD/S) in the EEG theta and alpha bands during the completion of the task, were examined. Our results show significantly higher prediction accuracy in relation to volleyball expertise. Significantly stronger theta synchronization, as well as alpha desynchronization were observed during the tactical prediction condition compared to a control condition. No significant group differences in theta or alpha ERD/S were observed. Descriptive examinations of theta and alpha ERD/S distributions, which revealed mixed results regarding support for the NEH, are discussed. Our findings provide new insights to the ongoing debate on how the NEH applies to the domain of sport.
Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 coactivation
Abstract Initial clinical trials with drugs targeting epigenetic modulators, such as bromodomain and extraterminal protein (BET) inhibitors, demonstrate modest results in acute myeloid leukemia (AML). A major reason for this involves an increased transcriptional plasticity within AML, which allows the cells to escape therapeutic pressure. In this study, we investigated the immediate epigenetic and transcriptional responses after BET inhibition and demonstrated that BET inhibitor–mediated release of bromodomain-containing protein 4 from chromatin is accompanied by acute compensatory feedback that attenuates downregulation or even increases the expression of specific transcriptional modules. This adaptation is marked at key AML maintenance genes and is mediated by p300, suggesting a rational therapeutic opportunity to improve outcomes by combining BET and p300 inhibition. p300 activity is required during all steps of resistance adaptation; however, the specific transcriptional programs that p300 regulates to induce resistance to BET inhibition differ, in part, between AML subtypes. As a consequence, in some AMLs, the requirement for p300 is highest during the earlier stages of resistance to BET inhibition, when p300 regulates transitional transcriptional patterns that allow leukemia-homeostatic adjustments. In other AMLs, p300 shapes a linear resistance to BET inhibition and remains critical throughout all stages of the evolution of resistance. Altogether, our study elucidates the mechanisms that underlie an “acute” state of resistance to BET inhibition, achieved through p300 activity, and how these mechanisms remodel to mediate “chronic” resistance. Importantly, our data also suggest that sequential treatment with BET and p300 inhibition may prevent resistance development, thereby improving outcomes.
Coarse-graining network flow through statistical physics and machine learning
Genetic diversity and population structure analysis of Forsythia ovata, a Korean endemic, based on genotyping-by-sequencing
The perennial shrub Forsythia ovata Nakai, native to the Korean Peninsula, has a highly restricted natural habitat, occurring only in a small area within the Baekdudaegan Mountain Range located in Gangwon-do Province. These characteristics give this species high conservation value, but there is a significant lack of genetic concerning about its populations for conservation purposes. In this study, we utilized genotyping-by-sequencing (GBS) to examine the genetic diversity and population structure of F. ovata. Our analysis including 5,017 single nucleotide polymorphisms (SNPs) from 72 individuals, representing nine distinct populations. The results revealed a mean expected heterozygosity (He) of 0.212, indicating a moderate level of genetic diversity within the species. Additionally, a relatively low levels of genetic differentiation (FST) and high gene flow (Nm) between populations were detected. The analysis of molecular variance (AMOVA) results indicated that most genetic variation occurred within individuals, accounting for 86.66% of the total variance. In contrast, only 6.90% and 6.44% of the molecular variance was attributed to differences among individuals and between populations, respectively. Considering the results of Bayesian structure analysis on the basis of ∆ K, principal coordinate analysis and phylogenetic analysis, we propose two management units for conservation. In addition, given the current conditions faced by F. ovata, both in situ and ex situ conservation should be considered for some populations (SG and BD).
Long-term 3-year follow-up of mosunetuzumab in relapsed or refractory follicular lymphoma after ≥2 prior therapies
Abstract Mosunetuzumab, a CD20×CD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7 to not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of CR was not reached (NR; 95% CI, 33.0 to NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE to NE). Median progression-free survival was 24.0 months (95% CI, 12.0 to NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) after 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions, and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe, and effective treatment for patients with R/R FL, including those with high-risk disease. This trial was registered at www.clinicaltrials.gov as #NCT02500407.
Solvent-free fabrication of ultrathin two-dimensional metal oxides/sulfides in a fixed interlayer by geometric confinement
Current and emerging approaches to cochlear immunosuppression with translation to human inner ear stem cell therapy: A systematic review
Hearing loss is a significant health burden across all stages of life. One in 5 people suffer hearing loss, with 5% of the world’s population experiencing disabling hearing loss. A large proportion of this loss is the consequence of damage or loss of neurosensory structures, termed “sensorineural” hearing loss. A recent advance in the treatment of sensorineural hearing loss has occurred, with the advent of inner ear stem cell therapy. Focus has pivoted from augmenting existing neural structures to regenerating neural frameworks. To date, stem cell therapy is limited by the host immune system and rejection of donor cells. A better understanding of immunity in the inner is ear required to progress stem cell therapy for hearing loss. This review outlines a contemporary understanding of the inner ear immune system. We discuss concepts of immune dysregulation that may lead to common inner ear pathologies, and, in doing so, review the efficacy of current pharmacotherapies that mitigate end organ damage through a process of immunosuppression. Current literature is appraised through a systematic review exploring two areas of focus; immunosuppression therapies for the treatment of inner ear pathology associated immune dysregulation, and, subsequently, the efficacy of immunosuppressive agents in translational models of inner ear stem cell therapy. Through greater understanding of these concepts, and systematic appraisal of the literature, this review summarises the literature for contemporary immunosuppressive regimes that may facilitate stem cell accommodation in the cochlea and auditory nerve.
Novel CAR T cells to combat antigen escape in AML
Author Correction: A multi-model study to inform the United States’ 2035 NDC
On people’s perceptions of climate change and its impacts in a hotspot of global warming
The Hindu Kush Himalayan region is a global hotspot for climate change and highly vulnerable to its direct and indirect impacts. Understanding people’s perception of climate change is crucial for effective adaptation strategies. We conducted a study by using quantitative (Household survey, n = 660) and qualitative data collection tools (Focus group discussion, n = 12; In-depth interviews, n = 27) in central Nepal encompassing three altitudinal regions: Lowland (<1000 m amsl; Terai region), Midland (1000–1500 m amsl; hilly region) and Highland (1500–2100 m amsl; mountainous region). We analyzed 37 years (1981–2017) of climatic data from respective districts (Lowland: Chitwan, Dhading; Midland: Kathmandu, Lalitpur; Highland: Nuwakot, Rasuwa). People’s perception was compared with climate extreme indices measured along these regions and evaluated if they accurately recognized the impacts on the environment and human health. Our findings show significant climate changes, including rising summer temperature, region-specific winter temperatures and extended monsoon seasons in Nepal. Participants in our study accurately perceived these trends but misperceived heavy precipitation patterns. Reported impacts are rise in crop diseases, human diseases, vector expansion and climate induced disasters like floods, landslides, and water resource depletion, with perception accuracy varying by region. These insights highlight the importance of understanding regional and cross-regional perceptions in relation to climate data in order to develop tailored climate adaptation strategies. Policymakers can use this information to establish region-specific educational and communication initiatives, addressing communities’ distinctive vulnerabilities and needs across diverse landscapes. Such approaches can enhance equitable and effective climate resilience in subtropical to alpine regions.
CD70 CAR T cells secreting an anti-CD33/anti-CD3 dual-targeting antibody overcome antigen heterogeneity in AML
Abstract CD70 has emerged as a promising target in acute myeloid leukemia (AML), and we have previously demonstrated the potency of an optimized CD70-targeted ligand-based chimeric antigen receptor (CAR). However, here, we identify in vivo CD70 antigen escape as a limitation of single-antigen targeting. Combination targeting of CD70 and CD33 may overcome AML antigen heterogeneity. We hypothesized that modifying our CD70 CAR platform to secrete a bispecific T-cell engaging antibody molecule (TEAM) targeting CD33 (7033) would create a therapeutic window whereby AML heterogeneity could be addressed without increasing tissue toxicity. We found that CD33 TEAMs mediated specific cytotoxicity across AML cell lines, including CD33 or CD70 single-antigen knockout tumors. 7033 CAR T cells eradicated tumor in an in vivo mixed tumor model of CD70 antigen escape and outperformed the previously optimized CD70 CAR in a patient-derived xenograft. In vivo gene expression profiling of CAR T cells revealed enhanced 7033 CAR T-cell pathway scoring for persistence, activation, and T-cell receptor signaling. Additionally, CD33 TEAMs successfully redirected T cells isolated from patients with AML to activate, secrete cytokines, and kill tumor targets despite exposure to substantial prior cytotoxic therapies. In summary, our findings demonstrate the feasibility of our 7033 CAR to overcome AML heterogeneity and leverage the bystander T cells of patients; this approach warrants further study in patients with this dire clinical need.
Editorial Expression of Concern: Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing
Molecular elucidation of cement hydration inhibition by silane coupling agents
Abstract Silane coupling agents are widely recognized to retard early hydration when incorporated into fresh cement paste, yet the atomic-level mechanisms underlying their effects on clinker dissolution, such as adsorption of silane monomer onto reactive surface sites and modification of ion detachment pathways, remain unexplored. Here we show dissolution behavior of tricalcium silicate (Ca3SiO5) under 3-aminopropyl triethoxysilane impact using ab initio metadynamics, with experimental validation of the retardation effects in silane-treated pastes. The shielding effect of silane induces shifts in free energy changes of stepwise calcium dissolution from negative to positive and alters the most stable Ca coordination state during dissolution, resulting in the transition of dissolution from spontaneous to non-spontaneous. Specifically, hydrolyzed silane adsorbs dissociatively onto the Ca3SiO5 surface by forming ionic Ca-O bonds, thereby occupying reactive sites and introducing steric hindrance. This, in turn, impedes coordination interactions between calcium ions and water molecules. Experimental results further corroborate these interactions, as evidenced by reduced calcium concentrations in silane-treated pastes, which in turn slowed the hydration process. These findings offer nanoscale insights into the role of SCAs in cement hydration and provide a foundation for future research into the complex interactions within organic/cement systems.
Zika virus modulates arthropod histone methylation for its survival in mosquito cells
Zika virus (ZIKV) is a mosquito-borne human pathogen that causes mild febrile illness in adults and severe neurological complications and microcephaly in newborns. Studies have reported that ZIKV modulates methylation of human and viral RNA critical for its replication in vertebrate cells. In this study, we show that ZIKV modulates mosquito S-adenosyl methionine (SAMe)-synthase, an enzyme involved in the production of SAMe (methyl donor), and histone methylation for its survival in mosquito cells. Reverse transcription quantitative PCR followed by immunoblotting analysis showed increased amounts of SAMe synthase at both RNA and protein levels, respectively, in C6/36 mosquito cells infected with ZIKV at day 1 post infection (p.i.). Increased levels of SAMe was noted upon ZIKV infection at day 1 p.i in mosquito cells. In addition, increased EZH2 histone methyl transferase-like gene transcripts and methylated histone (H3K27me3) levels were evident in mosquito cells upon ZIKV infection. Exogenous addition of SAMe to mosquito cells showed increased ZIKV loads and EZH2 histone methyl transferase-like gene transcript levels. Furthermore, treatment of mosquito cells with EZH2 inhibitor resulted in reduced histone methylation and ZIKV loads. Collectively, our study provides novel information in understanding the importance of SAMe and histone methylation in the survival of ZIKV in its arthropod vector.
Pesticides have negative effects on non-target organisms
The effect of acupuncture on quality of life in patients with irritable bowel syndrome: A systematic review and meta-analysis
Background Acupuncture has been used to improve the quality of life (QoL) of patients in clinical settings. However, the effect of acupuncture on QoL in patients with irritable bowel syndrome (IBS) remains unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of acupuncture on the QoL of patients with IBS. Method PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science were screened from inception to September 2023. RCTs published in English comparing acupuncture with sham acupuncture, usual care, pharmacological interventions, or other therapies were analyzed for QoL in patients with IBS. The primary outcome was QoL and secondary outcomes were the IBS-symptom severity scale (IBS-SSS) and abdominal pain. The Cochrane Collaboration recommendations were used to assess the risk of bias. Findings Fourteen articles with 2,038 participants were included. The pooled result showed acupuncture can significantly improve the QoL of patients with IBS compared to the conventional treatment (MD = 6.62, 95% CI, 2.30 to 10.94, P<0.001, I2 = 72.45%). Additionally, acupuncture was superior to other interventions in relieving the symptoms’ severity of IBS (MD = -46.58, 95% CI, -91.49 to -1.68, P<0.001, I2 = 90.76%). Nevertheless, acupuncture was not associated with abdominal pain reduction (MD = -0.35, 95% CI, -0.91 to 0.20, P = 0.21, I2 = 0.00%). Lower adverse events were observed in the acupuncture group. Thus, the quality of this study was relatively high. Conclusion The meta-analysis showed that acupuncture improves QoL and symptom severity in patients with IBS and that the optimal parameters for acupuncture to improve QoL in patients with IBS are 30 minutes of acupuncture per session, less than or equal to five sessions per week, and a 4-week course of treatment. However, more high-quality clinical trials are needed to provide stronger evidence.