The STARD9/Kif16a kinesin associates with mitotic microtubules and regulates spindle pole assembly.

During cell division, cells form the microtubule-based mitotic spindle, a highly specialized and dynamic structure that mediates proper chromosome transmission to daughter cells. Cancer cells can show perturbed mitotic spindles and an approach in cancer treatment has been to trigger cell killing by targeting microtubule dynamics or spindle assembly. To identify and characterize proteins necessary for spindle assembly, and potential antimitotic targets, we performed a proteomic and genetic analysis of 592 mitotic microtubule copurifying proteins (MMCPs). Screening for regulators that affect both mitosis and apoptosis, we report the identification and characterization of STARD9, a kinesin-3 family member, which localizes to centrosomes and stabilizes the pericentriolar material (PCM). STARD9-depleted cells have fragmented PCM, form multipolar spindles, activate the spindle assembly checkpoint (SAC), arrest in mitosis, and undergo apoptosis. Interestingly, STARD9-depletion synergizes with the chemotherapeutic agent taxol to increase mitotic death, demonstrating that STARD9 is a mitotic kinesin and a potential antimitotic target.

An Exploratory, Randomized, Double-Blind Clinical Trial of Dipraglurant for Blepharospasm.

BACKGROUND: Blepharospasm is treated with botulinum toxin, but obtaining satisfactory results is sometimes challenging. OBJECTIVE: The aim is to conduct an exploratory trial of oral dipraglurant for blepharospasm. METHODS: This study was an exploratory, phase 2a, randomized, double-blind, placebo-controlled trial of 15 participants who were assigned to receive a placebo or dipraglurant (50 or 100 mg) and assessed over 2 days, 1 and 2 hours following dosing. Outcome measures included multiple scales rated by clinicians or participants, digital video, and a wearable sensor. RESULTS: Dipraglurant was well tolerated, with no obvious impact on any of the measurement outcomes. Power analyses suggested fewer subjects would be required for studies using a within-subject versus independent group design, especially for certain measures. Some outcome measures appeared more suitable than others. CONCLUSION: Although dipraglurant appeared well tolerated, it did not produce a trend for clinical benefit. The results provide valuable information for planning further trials in blepharospasm. © 2024 International Parkinson and Movement Disorder Society.

Severe congenital neutropenia, SRP54 pathogenicity, and a framework for surveillance.

Severe congenital neutropenia (SCN) is a rare disorder, often due to pathogenic variants in genes such as ELANE, HAX1, and SBDS. SRP54 pathogenic variants are associated with SCN and Shwachman-Diamond-like syndrome. Thirty-eight patients with SRP54-related SCN are reported in the literature. We present an infant with SCN, without classic Shwachman-Diamond syndrome features, who presented with recurrent bacterial infections and an SRP54 (c.349_351del) pathogenic variant. Despite ongoing granulocyte colony-stimulating factor therapy, this patient has no evidence of malignant transformation. Here we establish a framework for the future development of universal guidelines to care for this patient population.

Interrater reliability of motor severity scales for hemifacial spasm.

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants' motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lee's scale), clinical grading of spasm intensity (Chen's scale), and a modified version of the Abnormal Involuntary Movement Scale (Tunc's scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from "poor" to "moderate"; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lee's, Chen's, and Tunc's scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tunc's scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tunc's scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training.

Structure-based optimization of hydroxylactam as potent, cell-active inhibitors of lactate dehydrogenase.

Structure-based design was utilized to optimize 6,6-diaryl substituted dihydropyrone and hydroxylactam to obtain inhibitors of lactate dehydrogenase (LDH) with low nanomolar biochemical and single-digit micromolar cellular potencies. Surprisingly the replacement of a phenyl with a pyridyl moiety in the chemical structure revealed a new binding mode for the inhibitors with subtle conformational change of the LDHA active site. This led to the identification of a potent, cell-active hydroxylactam inhibitor exhibiting an in vivo pharmacokinetic profile suitable for mouse tumor xenograft study.

E-learning/online education in transfusion medicine: A cross-sectional international survey.

OBJECTIVES: This survey aims to assess the scope of transfusion e-learning courses in blood establishments and transfusion services internationally. BACKGROUND: E-learning/online education is increasingly used in the education of medical professionals. There is limited published data on the use of e-learning for transfusion medicine. MATERIAL AND METHODS: An International survey was designed and distributed to all members of the International Society of Blood Transfusion to assess utilisation of e-learning in their institutions. Descriptive statistics were used to summarise the results. RESULTS: A total of 177 respondents participated, 68 of which had e-learning modules in their institutions. Approximately two-thirds of the courses were developed in-house (66%), and 63% are available to learners from outside the host institutions. In one-third of institutions, these courses were established during the COVID-19 pandemic, while 15% had used e-learning courses for more than 10 years. The courses target different audiences and topics ranging from blood donation to hemovigilance. The most common audiences were physicians (71%), laboratory scientists/technologists (69%) and transfusion practitioners (63%). Formal assessment of learning outcomes is used in 70% of the programs. CONCLUSIONS: The survey demonstrates the widespread use of e-learning courses in transfusion education, with a substantial proportion being developed during the COVID-19 pandemic.

Pivotal Study of Leadless Tibial Nerve Stimulation with eCoin® for Urgency Urinary Incontinence: An Open-Label, Single Arm Trial.

PURPOSE: A novel leadless tibial nerve stimulator provides a primary battery-powered, coin-sized, minimally invasive option to deliver automatic low-duty cycle stimulation for overactive bladder syndrome therapy. A pivotal trial was conducted to evaluate the safety and efficacy of this investigational device, eCoin®, for treating refractory urgency urinary incontinence. MATERIALS AND METHODS: This was a prospective, open-label, single arm trial carried out at 15 U.S. medical centers involving 137 subjects with refractory urgency urinary incontinence. After implantation in the lower leg above the fascia over the tibial nerve, eCoin delivered automated stimulation sessions for the duration of the study. The primary efficacy measure was the proportion of subjects who achieved a 50% or greater reduction from baseline in urgency urinary incontinence episodes after 48 weeks of therapy. The primary safety measure was device-related adverse events at the same time point. RESULTS: Of 137 subjects enrolled, 133 were implanted with eCoin, and 132 were included in the intention-to-treat population. Of those 132 subjects, 98% were female, mean±SD age was 63.9±10.9 years, and baseline daily urgency urinary incontinence episodes were 4.3±3.1. The primary efficacy analysis showed 68% (95% CI: 60%-76%) of subjects experienced at least a 50% reduction in urgency urinary incontinence episodes at 48 weeks post-activation; 16% of implanted subjects experienced device-related events through 52 weeks post-implantation. CONCLUSIONS: eCoin demonstrated clinical benefit for treating overactive bladder syndrome with automatic delivery of an intermittent low-duty cycle and implanted with a minimally invasive, brief procedure.

Abnormal Neural Responses During Reflexive Blinking in Blepharospasm: An Event-Related Functional MRI Study.

BACKGROUND: The neurophysiological disruptions underlying blepharospasm, a disabling movement disorder characterized by increased blinking and involuntary muscle spasms of the eyelid, remain poorly understood. OBJECTIVE: To investigate the neural substrates underlying reflexive blinking in blepharospasm patients compared to healthy controls using simultaneous functional MRI and surface electromyography. METHODS: Fifteen blepharospasm patients and 15 healthy controls were recruited. Randomly timed air puffs to the left eye were used to induce reflexive eye blinks during two 8-minute functional MRI scans. Continuous surface electromyography and video recordings were used to monitor blink responses. Imaging data were analyzed using an event-related design. RESULTS: Fourteen blepharospasm patients (10 female; 61.6 ± 8.0 years) and 15 controls (11 female; 60.9 ± 5.5 years) were included in the final analysis. Reflexive eye blinks in controls were associated with activation of the right hippocampus and in patients with activation of the left caudate nucleus. Reflexive blinks in blepharospasm patients showed increased activation in the right postcentral gyrus and precuneus, left precentral gyrus, and left occipital cortex compared to controls. Dystonia severity negatively correlated with activity in the left occipital cortex, and disease duration negatively correlated with reflexive-blink activity in the cerebellum. CONCLUSIONS: Reflexive blinking in blepharospasm is associated with increased activation in the caudate nucleus and sensorimotor cortices, suggesting a loss of inhibition within the sensorimotor corticobasal ganglia network. The association between decreasing neural response during reflexive blinking in the cerebellum with disease duration suggests an adaptive role. © 2020 International Parkinson and Movement Disorder Society.

Fuel treatment effectiveness in the context of landform, vegetation, and large, wind-driven wildfires.

Large wildfires (>50,000 ha) are becoming increasingly common in semiarid landscapes of the western United States. Although fuel reduction treatments are used to mitigate potential wildfire effects, they can be overwhelmed in wind-driven wildfire events with extreme fire behavior. We evaluated drivers of fire severity and fuel treatment effectiveness in the 2014 Carlton Complex, a record-setting complex of wildfires in north-central Washington State. Across varied topography, vegetation, and distinct fire progressions, we used a combination of simultaneous autoregression (SAR) and random forest (RF) approaches to model drivers of fire severity and evaluated how fuel treatments mitigated fire severity. Predictor variables included fuel treatment type, time since treatment, topographic indices, vegetation and fuels, and weather summarized by progression interval. We found that the two spatial regression methods are generally complementary and are instructive as a combined approach for landscape analyses of fire severity. Simultaneous autoregression improves upon traditional linear models by incorporating information about neighboring pixel burn severity, which avoids type I errors in coefficient estimates and incorrect inferences. Random forest modeling provides a flexible modeling environment capable of capturing complex interactions and nonlinearities while still accounting for spatial autocorrelation through the use of spatially explicit predictor variables. All treatment areas burned with higher proportions of moderate and high-severity fire during early fire progressions, but thin and underburn, underburn only, and past wildfires were more effective than thin-only and thin and pile burn treatments. Treatment units had much greater percentages of unburned and low severity area in later progressions that burned under milder fire weather conditions, and differences between treatments were less pronounced. Our results provide evidence that strategic placement of fuels reduction treatments can effectively reduce localized fire spread and severity even under severe fire weather. During wind-driven fire spread progressions, fuel treatments that were located on leeward slopes tended to have lower fire severity than treatments located on windward slopes. As fire and fuels managers evaluate options for increasing landscape resilience to future climate change and wildfires, strategic placement of fuel treatments may be guided by retrospective studies of past large wildfire events.

Increased water deficit decreases Douglas fir growth throughout western US forests.

Changes in tree growth rates can affect tree mortality and forest feedbacks to the global carbon cycle. As air temperature increases, evaporative demand also increases, increasing effective drought in forest ecosystems. Using a spatially comprehensive network of Douglas fir (Pseudotsuga menziesii) chronologies from 122 locations that represent distinct climate environments in the western United States, we show that increased temperature decreases growth via vapor pressure deficit (VPD) across all latitudes. Using an ensemble of global circulation models, we project an increase in both the mean VPD associated with the lowest growth extremes and the probability of exceeding these VPD values. As temperature continues to increase in future decades, we can expect deficit-related stress to increase and consequently Douglas fir growth to decrease throughout its US range.

Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.

Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition.

Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors.

Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼ 200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors.

Anterior Cruciate Ligament Graft Removal Versus Retention in the Setting of Septic Arthritis After Reconstruction: A Systematic Review and Expected Value Decision Analysis.

PURPOSE: To provide further guidance on the optimal decision between anterior cruciate ligament (ACL) graft removal versus retention in the setting of septic arthritis following reconstruction using an expected value decision analysis. METHODS: A systematic review and expected value decision analysis and sensitivity analyses were performed to quantify the clinical decision. A decision tree was created with 5 outcomes of interest: nonoperative complications, revision surgery, early reoperation, late reoperation, and "well." Pooled probabilities of each outcome were generated through a systematic literature review. We included only peer-reviewed studies, published in English, with at least 6 months of follow-up. One hundred randomly selected volunteers were given descriptions of the clinical scenario, the 2 treatment options, and outcomes of interest. Patients younger than 18 and older than 50 years and those previously treated for either ACL injury or septic arthritis, or both, were excluded from the analysis to minimize bias. These hypothetical patients indicated preferences for each outcome on a visual analog scale and responses were averaged to generate overall "utility values." Fold-back analysis summed products of pooled outcomes probabilities with respective averaged utility values. The resulting overall expected values for graft removal and debridement were compared, with the highest expected value considered to be superior. We then performed 1-way sensitivity analyses to mitigate sample bias. RESULTS: Fold-back analysis revealed graft removal to be strongly favored over retention, with overall expected values of 17.2 and 8.64, respectively. The most important contributor to the difference in overall expected values was late reoperation (8.59 vs 2.50 for removal and retention, respectively). Despite adjustments made to the rates of revision and early reoperation during the 1-way sensitivity analyses, graft removal remained the optimal strategy. CONCLUSIONS: This expected value decision analysis revealed that ACL graft removal was strongly favored by patients over graft retention in the setting of postoperative septic arthritis when consideration was given to the probabilities of wellness, nonoperative complications, revision surgery, early reoperation, and late reoperation. Sensitivity analysis revealed that although variation in rates of other outcomes did not impact this preference, the rate of late reoperation had a substantial impact. Only a sizable increase in the probability of late reoperation (from 0% to 60%) after graft removal would cause potential patients to favor graft retention. LEVEL OF EVIDENCE: Level IV, systematic review and decision analysis.

RNA Polymerase II Trigger Loop Mobility: INDIRECT EFFECTS OF Rpb9.

Rpb9 is a conserved RNA polymerase II (pol II) subunit, the absence of which confers alterations to pol II enzymatic properties and transcription fidelity. It has been suggested previously that Rpb9 affects mobility of the trigger loop (TL), a structural element of Rpb1 that moves in and out of the active site with each elongation cycle. However, a biochemical mechanism for this effect has not been defined. We find that the mushroom toxin α-amanitin, which inhibits TL mobility, suppresses the effect of Rpb9 on NTP misincorporation, consistent with a role for Rpb9 in this process. Furthermore, we have identified missense alleles of RPB9 in yeast that suppress the severe growth defect caused by rpb1-G730D, a substitution within Rpb1 α-helix 21 (α21). These alleles suggest a model in which Rpb9 indirectly affects TL mobility by anchoring the position of α21, with which the TL directly interacts during opening and closing. Amino acid substitutions in Rpb9 or Rpb1 that disrupt proposed anchoring interactions resulted in phenotypes shared by rpb9Δ strains, including increased elongation rate in vitro Combinations of rpb9Δ with the fast rpb1 alleles that we identified did not result in significantly faster in vitro misincorporation rates than those resulting from rpb9Δ alone, and this epistasis is consistent with the idea that defects caused by the rpb1 alleles are related mechanistically to the defects caused by rpb9Δ. We conclude that Rpb9 supports intra-pol II interactions that modulate TL function and thus pol II enzymatic properties.

The depth of fields: Managing focus in the epistemic subcultures of mind and brain science.

The 'psy' sciences emerged from the tangled roots of philosophy, physiology, biology and medicine, and these origins have produced heterogeneous fields. Scientists in these areas work in a complex, overlapping ecology of fields that results in the constant co-presence of dissonant theories, methods and research objects. This raises questions regarding how conceptual clarity is maintained. Using the optical metaphor 'depth of field', I show how researchers in all fields marginalize potential threats to routine scientific work by framing them as either too broad and imprecise or too narrow and technical. The appearance of this defocusing and devaluing across sites suggests a general aspect of scientific cognition, rather than a by-product of any specific scientific dispute.

All The Catalytic Active Sites of MoS2 for Hydrogen Evolution.

MoS2 presents a promising low-cost catalyst for the hydrogen evolution reaction (HER), but the understanding about its active sites has remained limited. Here we present an unambiguous study of the catalytic activities of all possible reaction sites of MoS2, including edge sites, sulfur vacancies, and grain boundaries. We demonstrate that, in addition to the well-known catalytically active edge sites, sulfur vacancies provide another major active site for the HER, while the catalytic activity of grain boundaries is much weaker. The intrinsic turnover frequencies (Tafel slopes) of the edge sites, sulfur vacancies, and grain boundaries are estimated to be 7.5 s-1 (65-75 mV/dec), 3.2 s-1 (65-85 mV/dec), and 0.1 s-1 (120-160 mV/dec), respectively. We also demonstrate that the catalytic activity of sulfur vacancies strongly depends on the density of the vacancies and the local crystalline structure in proximity to the vacancies. Unlike edge sites, whose catalytic activity linearly depends on the length, sulfur vacancies show optimal catalytic activities when the vacancy density is in the range of 7-10%, and the number of sulfur vacancies in high crystalline quality MoS2 is higher than that in low crystalline quality MoS2, which may be related with the proximity of different local crystalline structures to the vacancies.

A review of the relationships between drought and forest fire in the United States.

The historical and presettlement relationships between drought and wildfire are well documented in North America, with forest fire occurrence and area clearly increasing in response to drought. There is also evidence that drought interacts with other controls (forest productivity, topography, fire weather, management activities) to affect fire intensity, severity, extent, and frequency. Fire regime characteristics arise across many individual fires at a variety of spatial and temporal scales, so both weather and climate - including short- and long-term droughts - are important and influence several, but not all, aspects of fire regimes. We review relationships between drought and fire regimes in United States forests, fire-related drought metrics and expected changes in fire risk, and implications for fire management under climate change. Collectively, this points to a conceptual model of fire on real landscapes: fire regimes, and how they change through time, are products of fuels and how other factors affect their availability (abundance, arrangement, continuity) and flammability (moisture, chemical composition). Climate, management, and land use all affect availability, flammability, and probability of ignition differently in different parts of North America. From a fire ecology perspective, the concept of drought varies with scale, application, scientific or management objective, and ecosystem.