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Little is known about the winter distribution of the Critically Endangered eastern population of North Pacific right whale Eubalaena japonica (NPRW), but it has been proposed that the eastern Aleutian Islands, specifically Unimak Pass, constitute a plausible migratory route for individuals. This is a major point of concern given the high shipping traffic in this pass. Therefore, a long-term acoustic recorder was deployed in Unimak Pass (2009-2015), and NPRWs were identified using the ‘up’ and ‘gunshot’ call types during manual review of data (8188 recorded hours). Calls were grouped into periods of hypothesized migration (Dec-Feb and Mar-May) and other (Jun-Aug and Sep-Nov). Overall, NPRW calling was intermittent and clustered in time, suggestive of a few individuals transiting the area across seasons. Upcalls (n = 31) were detected on 7 d and occurred most often during Dec-Feb, whereas gunshots (n = 465) were detected on 32 d, occurring in all months except February and October. The majority of individual gunshot calls (n = 306) occurred over 3 d in Dec-Feb 2014-15. Because of this pattern, gunshot calling occurred on more days during Jun-Aug, while more individual calls occurred during Dec-Feb. Diel and seasonal trends in hourly call detection rates were absent. Together, these data confirm that NPRW use Unimak Pass both during and outside of the assumed migratory period. Pervasive vessel noise throughout the study highlights near constant potential for interaction with anthropogenic disturbance. Consistently higher vessel noise during Dec-Feb suggests that this species is most vulnerable during the assumed migratory period.

To protect themselves, their patients and their coworkers, radiologic technologists should regularly refresh and reinforce their understanding of key radiation biology and protection principles. This article reviews the concepts of radiation physics, human biology and radiation protection strategies, with emphasis on how historical events and developing research affect radiation protection understanding and practice. [ABSTRACT FROM AUTHOR]

Sarcoidosis is an enigmatic disease with high variability in its manifestation within the body. Associated granulomas can form in many different parts of the body and can affect multiple organs. Some patients affected by this multiorgan disease never require treatment, while others require comprehensive long-term care and follow-up. Familiarity with the clinical and radiologic features of sarcoidosis is key to understanding how physicians diagnose and manage the disease. Further research is needed to comprehend the relationship between sarcoidosis and malignant neoplasms. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between men's body mass index (BMI), early embryo quality, and clinical outcomes in couples undergoing in vitro fertilization (IVF).Design: Prospective cohort study.Setting: Fertility clinic in an academic medical center.Patient(s): 114 couples who underwent 172 assisted reproduction cycles.Intervention(s): None.Main Outcome Measure(s): Fertilization rate, embryo quality, implantation rate, clinical pregnancy rate, and live birth rate.Result(s): The fertilization rate was higher among obese men than among normal weight men in conventional IVF cycles. No statistically significant associations were found between men's BMI and the proportion of poor-quality embryos on day 3, slow embryo cleavage rate, or accelerated embryo cleavage rate. Men's BMI was unrelated to positive β-human chorionic gonadotropin rate, clinical pregnancy rate, or live-birth rate per embryo transfer. Among couples undergoing intracytoplasmic sperm injection, the odds of live birth in couples with obese male partners was 84% lower than the odds in couples with men with normal BMI.Conclusion(s): Our data suggest a possible deleterious effect of male obesity on the odds of having a live birth among couples undergoing intracytoplasmic sperm injection. [ABSTRACT FROM AUTHOR]

Cellular resistance can limit the effectiveness of antifolate drugs for the treatment of cancer and autoimmune diseases. We examined the biochemical and cellular effects of a propargyl linked, non-classical antifolate UCP1162 that shows exceptional potency and resilience in the background of methotrexate resistance. UCP1162 inhibited the human DHFR enzyme with affinity and kinetics comparable to methotrexate (MTX). UCP1162 also inhibited cancer cell proliferation and bound cellular DHFR at low nanomolar concentrations. Leucovorin suppressed the cellular effects of UCP1162, consistent with UCP1162 working as an antifolate. Like other antifolates, UCP1162 reduced acute inflammation in mice and inhibited FLS cell growth and motility. Single cell RNA-seq showed that MTX and UCP1162 generated overlapping gene expression changes after a 48-hour exposure. However, while leukemia cells (CCRF-CEM) resistant to MTX could be readily selected, UCP1162-resistant cells could not be obtained. Long-term exposure to UCP1162 resulted in static culture expressing stem cell genes (CD34, ABCG2, ABCB1), adaptive genes (TCN2, CDKN1A), and genes that might serve as therapeutic targets (TPBG/5T4, TNFRSF10A, ACE). These findings suggest that UCP1162 is a unique tool for studying cellular responses to long-term antifolate treatment and holds promise as a lead compound capable of overcoming some forms of antifolate resistance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DOT, SK, DS, JK, PM, IB, EN, WH, CEN, CG: no conflicts. AM, LW, DLW: Affiliated with Quercus Molecular Design, an early-stage biotechnology company developing antifolates., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Dilated cardiomyopathy (DCM) is often hereditary, with 20% to 40% of nonischemic cases showing familial linkage, yet genetic testing is underused. This report describes an unreported pathogenic nonsense variant in the Titin (TTN) gene (NM_001267550.2:c.92603G>A) in a 24-year-old man with severe DCM and acute fibrinoid organizing pneumonia, highlighting a unique cardiopulmonary pathology., Methods: We conducted detailed gross, histopathologic, immunophenotypic, and exome-based DNA sequencing analysis in the workup of this case. We also included the patient's clinical and radiologic findings in our study., Results: With rapid clinical deterioration and complex comorbidities, including substance abuse and psychiatric conditions, which precluded transplantation, the patient's cardiac function progressively worsened. Autopsy findings included extreme cardiomegaly, biventricular hypertrophy, and acute and chronic pericarditis. Significant pulmonary pathology consistent with acute fibrinoid organizing pneumonia was also noted. Molecular testing confirmed a deleterious maternally inherited TTN variant that was absent in the sibling of the proband and the extant medical literature, highlighting its rarity and significance., Conclusions: This case contributes to the ongoing body of work on the impact of TTN variants on DCM. It suggests a potential link between genetic variants and complex cardiac injury patterns, emphasizing the need for further investigation into the interplay between cardiomyopathy and pulmonary pathology., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Drugs that modulate N-methyl-D-aspartate (NMDA) or γ-Aminobutyric acid type A (GABA A ) receptors can shed light on their role in synaptic plasticity mechanisms underlying the effects of non-invasive brain stimulation. However, research on the combined effects of these drugs and exogenous stimulation on motor learning is limited. This study aimed to investigate the effects of pharmacological interventions combined with intermittent theta-burst stimulation (iTBS) on human motor learning. Nine right-handed healthy subjects (mean age ± SD: 31.56 ± 12.96 years; 6 females) participated in this double-blind crossover study. All participants were assigned to four drug conditions in a randomized order: (1) D-cycloserine (partial NMDA receptor agonist), (2) D-cycloserine + dextromethorphan (NMDA receptor agonist + antagonist), (3) lorazepam (GABA A receptor agonist), and (4) placebo (identical microcrystalline cellulose capsule). After drug intake, participants practiced the 12-item keyboard sequential task as a baseline measure. Two hours after drug intake, iTBS was administered at the primary motor cortex. Following iTBS, the retention test was performed in the same manner as the baseline measure. Our findings revealed that lorazepam combined with iTBS impaired motor learning during the retention test. Future studies are still needed for a better understanding of the mechanisms through which TMS may influence human motor learning.

Administering anodal transcranial direct current stimulation (tDCS) at the primary motor cortex (M1) at various temporal loci relative to motor training is reported to affect subsequent performance gains. Stimulation administered in conjunction with motor training appears to offer the most robust benefit that emerges during offline epochs. This conclusion is made, however, based on between-experiment comparisons that involved varied methodologies. The present experiment addressed this shortcoming by administering the same 15-minute dose of anodal tDCS at M1 before, during, or after practice of a serial reaction time task (SRTT). It was anticipated that exogenous stimulation during practice with a novel SRTT would facilitate offline gains. Ninety participants were randomly assigned to one of four groups: tDCS before practice, tDCS during practice, tDCS after practice, or no tDCS. Each participant was exposed to 15 min of 2 mA of tDCS and motor training of an eight-element SRTT. The anode was placed at the right M1 with the cathode at the left M1, and the left hand was used to execute the SRTT. Test blocks were administered 1 and 24 h after practice concluded. The results revealed significant offline gain for all conditions at the 1-hour and 24-hour test blocks. Importantly, exposure to anodal tDCS at M1 at any point before, during, or after motor training failed to change the trajectory of skill development as compared to the no-stimulation control condition. These data add to the growing body of evidence questioning the efficacy of a single bout of exogenous stimulation as an adjunct to motor training for fostering skill learning., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Motor learning involves acquiring new movement sequences and adapting motor commands to novel conditions. Labile motor memories, acquired through sequence learning and dynamic adaptation, undergo a consolidation process during wakefulness after initial training. This process stabilizes the new memories, leading to long-term memory formation. However, it remains unclear if the consolidation processes underlying sequence learning and dynamic adaptation are independent and if distinct neural regions underpin memory consolidation associated with sequence learning and dynamic adaptation. Here, we first demonstrated that the initially labile memories formed during sequence learning and dynamic adaptation were stabilized against interference through time-dependent consolidation processes occurring during wakefulness. Furthermore, we found that sequence learning memory was not disrupted when immediately followed by dynamic adaptation and vice versa, indicating distinct mechanisms for sequence learning and dynamic adaptation consolidation. Finally, by applying patterned transcranial magnetic stimulation to selectively disrupt the activity in the primary motor (M1) or sensory (S1) cortices immediately after sequence learning or dynamic adaptation, we found that sequence learning consolidation depended on M1 but not S1, while dynamic adaptation consolidation relied on S1 but not M1. For the first time in a single experimental framework, this study revealed distinct neural underpinnings for sequence learning and dynamic adaptation consolidation during wakefulness, with significant implications for motor skill enhancement and rehabilitation., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The eastern North Pacific right whale (NPRW) is the most endangered population of whale and has been observed north of its core feeding ground in recent years with low sea ice extent. Sea ice and water temperature are important drivers for zooplankton dynamics within the whale's core feeding ground in the southeastern Bering Sea, seasonally forming stable fronts along the shelf that give rise to distinct zooplankton communities. A northward shift in NPRW distribution driven by changing distribution of prey resources could put this species at increased risk of entanglement and vessel strikes. We modeled the abundance of NPRW prey, Calanus glacialis, Neocalanus, and Thysanoessa species, using a dynamic biophysical food web model of nine zooplankton guilds in the Bering shelf zooplankton community during a period of warming (2006-2016). This model is unique among prior zooplankton studies from the region in that it includes density dependence, thereby allowing us to ask whether species interactions influence zooplankton dynamics. Modeling confirmed the importance of sea ice and ocean temperature to zooplankton dynamics in the region. Density-independent growth drove community dynamics, while dependent factors were comparatively minimal. Overall, Calanus responded to environment terms, with the strength and direction of response driven by copepodite stage. Neocalanus and Thysanoessa responses were weaker, likely due to their primary occurrence on the outer shelf. We also modeled the steady-state (equilibrium) abundance of Calanus in conditions with and without wind gusts to test whether advection of outer shelf species might disrupt the steady-state dynamics of Calanus abundance; the results did not support disruption. Given the annual fall sampling design, we interpret our results as follows: low-ice-extent winters induced stronger spring winds and weakened fronts on the shelf, thereby advecting some outer shelf species into the study region; increased development rates in these warm conditions influenced the proportion of C. glacialis copepodite stages over the season. Residual correlation suggests missing drivers, possibly predators, and phytoplankton bloom composition. Given the continued loss of sea ice in the region and projected continued warming, our findings suggest that C. glacialis will move northward, and thus, whales may move northward to continue targeting them., (© 2023 The Ecological Society of America.)

The primary motor cortex (M1) is broadly acknowledged for its crucial role in executing voluntary movements. Yet, its contributions to cognitive and sensory functions remain largely unexplored. Transcranial direct current stimulation (tDCS) is a noninvasive neurostimulation method that can modify brain activity, thereby enabling the establishment of a causal link between M1 activity and behavior. This study aimed to investigate the online effects of tDCS over M1 on cognitive-motor and sensory-motor functions. Sixty-four healthy participants underwent either anodal or sham tDCS while concurrently performing a set of standardized robotic tasks. These tasks provided sensitive and objective assessments of brain functions, including action selection, inhibitory control, cognitive control of visuomotor skills, proprioceptive sense, and bimanual coordination. Our results revealed that anodal tDCS applied to M1 enhances decision-making capacity in selecting appropriate motor actions and avoiding distractors compared to sham stimulation, suggesting improved action selection and inhibitory control capabilities. Furthermore, anodal tDCS reduces the movement time required to accomplish bimanual movements, suggesting enhanced bimanual performance. However, we found no impact of anodal tDCS on cognitive control of visuomotor skills and proprioceptive sense. This study suggests that augmenting M1 activity via anodal tDCS influences cognitive-motor and sensory-motor functions in a task-dependent manner., (© 2023. The Author(s).)

Integrated crop-livestock systems provide an array of benefits to agricultural systems, including a reduction in nitrogen (N) leaching. A farm approach to integrate crops and livestock is the adoption of grazed cover crops. Moreover, the addition of perennial grasses into crop rotations may improve soil organic matter and decrease N leaching. However, the effect of grazing intensity in such systems is not fully understood. This 3-year study investigated short-term effects of cover crop planting (cover and no cover), cropping system (no grazing, integrated crop-livestock [ICL], and sod-based rotation [SBR]), grazing intensity (heavy, moderate, and light grazing), and cool-season N fertilization (0, 34, and 90 kg N ha -1 ) on NO 3 -N and NH 4 -N concentration in leachate, and cumulative N leaching by using 1.5-m deep drain gauges. The ICL was a cool-season cover crop-cotton (Gossypium hirsutum L.) rotation, whereas SBR was a cool-season cover crop-bahiagrass (Paspalum notatum Flüggé) rotation. There was a treatment × year × season for cumulative N leaching (p = 0.035). Further contrast analysis indicated that cover crops decreased cumulative N leaching compared to no cover (18 vs. 32 kg N ha -1 season -1 ). Nitrogen leaching was lesser for grazed compared to nongrazed systems (14 vs. 30 kg N ha -1 season -1 ). Treatments containing bahiagrass had lesser NO 3 -N concentration in leachate (7 vs. 11 mg L -1 ) and cumulative N leaching (8 vs. 20 kg N ha -1 season -1 ) compared to ICL systems. Adding cover crops can reduce cumulative N leaching in crop-livestock systems; moreover, warm-season perennial forages can further enhance this benefit., (© 2023 The Authors. Journal of Environmental Quality published by Wiley Periodicals LLC on behalf of American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America.)

The C3 region in the international 10-20 system for electroencephalography (EEG) recording is assumed to represent the right motor hand area. Therefore, in the absence of transcranial magnetic stimulation (TMS) or a neuronavigational system, neuromodulation methods, such as transcranial direct current stimulation, target C3 or C4, based on the international 10-20 system, to influence the cortical excitability of the right and left hand, respectively. The purpose of this study is to compare the peak-to-peak motor evoked potential (MEP) amplitudes of the right first dorsal interosseus (FDI) muscle after single-pulse TMS at C3 and C1 in the 10-20 system and at the region between C3 and C1 (i.e., C3h in the 10-5 system). Using an intensity of 110% of the resting motor threshold, 15 individual MEPs from each of C3, C3h, C1, and hotspots were randomly recorded from FDI for sixteen right-handed undergraduate students. Average MEPs were greatest at C3h and C1, with both being larger than those recorded at C3. These data are congruent with recent findings using topographic analysis of individual MRIs that revealed poor correspondence between C3/C4 and the respective hand knob. Implications for the use of scalp locations determined using the 10-20 system for localizing the hand area are highlighted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

53BP1 (also known as TP53BP1) is a key mediator of the non-homologous end joining (NHEJ) DNA repair pathway, which is the primary repair pathway in interphase cells. However, the mitotic functions of 53BP1 are less well understood. Here, we describe 53BP1 mitotic stress bodies (MSBs) formed in cancer cell lines in response to delayed mitosis. These bodies displayed liquid-liquid phase separation characteristics, were close to centromeres, and included lamin A/C and the DNA repair protein RIF1. After release from mitotic arrest, 53BP1 MSBs decreased in number and moved away from the chromatin. Using GFP fusion constructs, we found that the 53BP1 oligomerization domain region was required for MSB formation, and that inclusion of the 53BP1 N terminus increased MSB size. Exogenous expression of 53BP1 did not increase MSB size or number but did increase levels of MSB-free 53BP1. This was associated with slower mitotic progression, elevated levels of DNA damage and increased apoptosis, which is consistent with MSBs suppressing a mitotic surveillance by 53BP1 through sequestration. The 53BP1 MSBs, which were also found spontaneously in a subset of normally dividing cancer cells but not in non-transformed cells (ARPE-19), might facilitate the survival of cancer cells following aberrant mitoses. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Plant-parasitic and free-living nematodes - bacterivores, fungivores, omnivores, predators - comprise the nematode community. Nematicide application and crop rotation are important tools to manage plant-parasitic nematodes, but effects on free-living nematodes and nematode ecological indices need further study. The nematicide fluopyram was recently introduced in cotton ( Gossypium hirsutum ) production and its effects on the nematode community need assessment. This research was conducted in 2017 and 2018 at a long-term field site in Quincy, FL where perennial grass/sod-based (bahiagrass, Paspalum notatum ) and conventional cotton rotations were established in 2000. The objective of this research was to evaluate the effects of fluopyram nematicide, crop rotation phase, and irrigation on free-living nematodes and nematode ecological indices based on three soil sampling dates each season. We did not observe consistent effects of crop rotation phase on free-living nematodes or nematode ecological indices. Only omnivores were consistently negatively impacted by fluopyram. Nematode ecological indices reflected this negative effect by exhibiting a degraded/ stressed environmental condition relative to untreated plots. Free-living nematodes were not negatively impacted by nematicide when sod-based rotation was used., (© 2022 Schumacher et al., published by Sciendo.)

Key Message: Eight soybean genomic regions, including six never before reported, were found to be associated with resistance to soybean rust (Phakopsora pachyrhizi) in the southeastern USA. Soybean rust caused by Phakopsora pachyrhizi is one of the most important foliar diseases of soybean [Glycine max (L.) Merr.]. Although seven Rpp resistance gene loci have been reported, extensive pathotype variation in and among fungal populations increases the importance of identifying additional genes and loci associated with rust resistance. One hundred and ninety-one soybean plant introductions from Japan, Indonesia and Vietnam, and 65 plant introductions from other countries were screened for resistance to P. pachyrhizi under field conditions in the southeastern USA between 2008 and 2015. The results indicated that 84, 69, and 49% of the accessions from southern Japan, Vietnam or central Indonesia, respectively, had negative BLUP values, indicating less disease than the panel mean. A genome-wide association analysis using SoySNP50K Infinium BeadChip data identified eight genomic regions on seven chromosomes associated with SBR resistance, including previously unreported regions of Chromosomes 1, 4, 6, 9, 13, and 15, in addition to the locations of the Rpp3 and Rpp6 loci. The six unreported genomic regions might contain novel Rpp loci. The identification of additional sources of rust resistance and associated genomic regions will further efforts to develop soybean cultivars with broad and durable resistance to soybean rust in the southern USA., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In this review, we explore recombination in two very different virus families that have become major threats to human health. The Herpesviridae are a large family of pathogenic double-stranded DNA viruses involved in a range of diseases affecting both people and animals. Coronaviridae are positive-strand RNA viruses (CoVs) that have also become major threats to global health and economic stability, especially in the last two decades. Despite many differences, such as the make-up of their genetic material (DNA vs. RNA) and overall mechanisms of genome replication, both human herpes viruses (HHVs) and CoVs have evolved to rely heavily on recombination for viral genome replication, adaptation to new hosts and evasion of host immune regulation. In this review, we will focus on the roles of three viral exonucleases: two HHV exonucleases (alkaline nuclease and PolExo) and one CoV exonuclease (ExoN). We will review the roles of these three nucleases in their respective life cycles and discuss the state of drug discovery efforts against these targets.

Introduction: Distinct cortical activities contribute to unilateral and bilateral motor control. However, it remains largely unknown whether the behavior of motor neurons differs between unilateral and bilateral isometric force generation. Here, we first investigated motor units (MUs) recruitment patterns during unilateral and bilateral force generation. Considering that the force control is primarily regulated by low-frequency synaptic inputs to motor neurons, we also examined the relation between MU discharge rate and force output during unilateral and bilateral muscle contractions., Methods: Using advanced electromyography (EMG) sensor arrays and spike-triggered averaging techniques, we examined a large population of MUs in the right first dorsal interosseous (FDI) muscle during unilateral and bilateral force tracking tasks. Using the principal component analysis, we analyzed the first common component (FCC) of MU discharge rate to describe the force fluctuations during unilateral and bilateral contractions., Results: We found that MU discharge rate decreased during bilateral compared with unilateral contractions. MU recruitment threshold increased, while the amplitude and duration of MU action potential (MUAP) remained unchanged during bilateral compared with unilateral contractions. We found that the coefficients of variation (CV) for the force and FCC signal increased during bilateral compared with unilateral contractions. Notably, the FCC signal captured a great amount of MU discharge variability, and its CV correlated with the CV of the force signal., Conclusion: Our findings suggest that MU recruitment patterns are altered during bilateral compared with unilateral isometric force generation, likely related to changes at the low-frequency portion of the synaptic drive., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The present study investigated the long-term benefit of Random-Practice (RP) over Blocked-Practice (BP) within the contextual interference (CI) effect for motor learning. We addressed the extent to which motor sequence length and practice amount factors moderate the CI effect given that previous reports, often in applied research, have reported no long-term advantage from RP. Based on predictions arising from the Cognitive framework of Sequential Motor Behavior (C-SMB) and using the Discrete Sequence Production (DSP) task, two experiments were conducted to compare limited and extended practice amounts of 4- and 7-key sequences under RP and BP schedules. Twenty-four-hour delayed retention performance confirmed the C-SMB prediction that the CI-effect occurs only with short sequences that receive little practice. The benefit of RP with limited practice was associated with overnight motor memory consolidation. Further testing with single-stimulus as well as novel and unstructured (i.e., random) sequences indicated that limited practice under RP schedules enhances both reaction and chunking modes of sequence execution with the latter mode benefitting from the development of implicit and explicit forms of sequence representation. In the case of 7-key sequences, extended practice with RP and BP schedules provided for equivalent development of sequence representations. Higher explicit awareness of sequence structures was associated with faster completion of practiced but also of novel and unstructured sequences., (© 2021. The Author(s).)

Two plasmid-encoded dihydrofolate reductase (DHFR) isoforms, DfrA1 and DfrA5, that give rise to high levels of resistance in Gram-negative bacteria were structurally and biochemically characterized to reveal the mechanism of TMP resistance and to support phylogenic groupings for drug development against antibiotic resistant pathogens. Preliminary screening of novel antifolates revealed related chemotypes that showed high levels of inhibitory potency against Escherichia coli chromosomal DHFR (EcDHFR), DfrA1, and DfrA5. Kinetics and biophysical analysis, coupled with crystal structures of trimethoprim bound to EcDHFR, DfrA1 and DfrA5, and two propargyl-linked antifolates (PLA) complexed with EcDHFR, DfrA1 and DfrA5, were determined to define structural features of the substrate binding pocket and guide synthesis of pan-DHFR inhibitors., (© 2022. The Author(s).)

Afferent inputs to the primary somatosensory cortex (S1) are differentially processed during precision and power grip in humans. However, it remains unclear how S1 interacts with the primary motor cortex (M1) during these two grasping behaviors. To address this question, we measured short-latency afferent inhibition (SAI), reflecting S1-M1 interactions via thalamo-cortical pathways, using paired-pulse transcranial magnetic stimulation (TMS) during precision and power grip. The TMS coil over the hand representation of M1 was oriented in the posterior-anterior (PA) and anterior-posterior (AP) direction to activate distinct sets of corticospinal neurons. We found that SAI increased during precision compared with power grip when AP, but not PA, currents were applied. Notably, SAI tested in the AP direction were similar during two-digit than five-digit precision grip. The M1 receives movement information from S1 through direct cortico-cortical pathways, so intra-hemispheric S1-M1 interactions using dual-site TMS were also evaluated. Stimulation of S1 attenuated M1 excitability (S1-M1 inhibition) during precision and power grip, while the S1-M1 inhibition ratio remained similar across tasks. Taken together,our findings suggest that distinct neural mechanisms for S1-M1 interactions mediate precision and power grip, presumably by modulating neural activity along thalamo-cortical pathways., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Learning a motor adaptation task produces intrinsically unstable or transient motor memories. Despite the presence of effector-independent motor memories following the learning of novel environmental dynamics, it remains largely unknown how those memory traces decay in different contexts and whether an "offline" consolidation period protects memories against decay. Here, we exploit inter-effector transfer to address these questions. We found that newly acquired motor memories formed with one effector could be partially retrieved by the untrained effector to enhance its performance when the decay occurred with the passage of time or "washout" trials on which error feedback was provided. The decay of motor memories was slower following "error-free" trials, on which errors were artificially clamped to zero or removed, compared with "washout" trials. However, effector-independent memory components were abolished following movements made in the absence of task errors, resulting in no transfer gains. The brain can stabilize motor memories during daytime wakefulness. We found that 6 h of wakeful resting increased the resistance of effector-independent memories to decay. Collectively, our results suggest that the decay of effector-independent motor memories is context-dependent, and offline processing preserves those memories against decay, leading to improvements of the subsequent inter-effector transfer., (© 2022. The Author(s).)

The majority of drug discovery efforts against herpesviruses have focused on nucleoside analogs that target viral DNA polymerases, agents that are associated with dose-limiting toxicity and/or a narrow spectrum of activity. We are pursuing a strategy based on targeting two-metal ion-dependent (TMID) viral enzymes. This family of enzymes consists of structurally related proteins that share common active sites containing conserved carboxylates predicted to coordinate divalent cations essential for catalysis. Compounds that target TMID enzymes, such as HIV integrase and influenza endoribonuclease, have been successfully developed for clinical use. HIV integrase inhibitors have been reported to inhibit replication of herpes simplex virus (HSV) and other herpesviruses; however, the molecular targets of their antiviral activities have not been identified. We employed a candidate-based approach utilizing several two-metal-directed chemotypes and the potential viral TMID enzymatic targets in an effort to correlate target-based activity with antiviral potency. The panel of compounds tested included integrase inhibitors, the anti-influenza agent baloxavir, three natural products previously shown to exhibit anti-HSV activity, and two 8-hydroxyquinolines (8-HQs), AK-157 and AK-166, from our in-house program. The integrase inhibitors exhibited weak overall anti-HSV-1 activity, while the 8-HQs were shown to inhibit both HSV-1 and cytomegalovirus (CMV). Target-based analysis demonstrated that none of the antiviral compounds acted by inhibiting ICP8, contradicting previous reports. On the other hand, baloxavir inhibited the proofreading exonuclease of HSV polymerase, while AK-157 and AK-166 inhibited the alkaline exonuclease UL12. In addition, AK-157 also inhibited the catalytic activity of the HSV polymerase, which provides an opportunity to potentially develop dual-targeting agents against herpesviruses. IMPORTANCE Human herpesviruses (HHVs) establish lifelong latent infections, which undergo periodic reactivation and remain a major cause of morbidity and mortality, especially in immunocompromised individuals. Currently, HHV infections are treated primarily with agents that target viral DNA polymerase, including nucleoside analogs; however, long-term treatment can be complicated by the development of drug resistance. New therapies with novel modes of action would be important not only for the treatment of resistant viruses but also for use in combination therapy to reduce dose-limiting toxicities and potentially eliminate infection. Since many essential HHV proteins are well conserved, inhibitors of novel targets would ideally exhibit broad-spectrum activity against multiple HHVs.

Antimicrobial resistance presents a significant health care crisis. The mutation F98Y in Staphylococcus aureus dihydrofolate reductase (SaDHFR) confers resistance to the clinically important antifolate trimethoprim (TMP). Propargyl-linked antifolates (PLAs), next generation DHFR inhibitors, are much more resilient than TMP against this F98Y variant, yet this F98Y substitution still reduces efficacy of these agents. Surprisingly, differences in the enantiomeric configuration at the stereogenic center of PLAs influence the isomeric state of the NADPH cofactor. To understand the molecular basis of F98Y-mediated resistance and how PLAs' inhibition drives NADPH isomeric states, we used protein design algorithms in the osprey protein design software suite to analyze a comprehensive suite of structural, biophysical, biochemical, and computational data. Here, we present a model showing how F98Y SaDHFR exploits a different anomeric configuration of NADPH to evade certain PLAs' inhibition, while other PLAs remain unaffected by this resistance mechanism., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: B.R.D. and M.S.F. are founders of Ten63 Therapeutics. V.G.F. reports personal fees (consultancy) from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J. V.G.F. has grants received or pending to his institution from following entities: NIH, MedImmune, Cerexa, Forest, Actavis, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, Janssen. V.G.F. received educational fees from Green Cross, Cubist, Cerexa, Durata, Theravance, Debiopharm. V.G.F. received royalties from UpToDate. V.G.F. has a pending patent on host gene expression signature diagnostic for sepsis. B.R.D. was previously a guest editor for PLoS Comp. Biol.

We examine the novel hypothesis that physical exercise and sleep have synergistic effects on memory. Exercise can trigger mechanisms that can create an optimal brain state during sleep to facilitate memory processing. The possibility that exercise could counteract the deleterious effects of sleep deprivation on memory by protecting neuroplasticity also is discussed., (Copyright © 2021 by the American College of Sports Medicine.)

Administering anodal transcranial direct current stimulation at the left dorsal premotor cortex (PMd) but not right PMd throughout the repetitive practice of three novel motor sequences resulted in improved offline performance usually only observed after interleaved practice. This gain only emerged following overnight sleep. These data are consistent with the proposed proprietary role of left PMd for motor sequence learning and the more recent claim that PMd is central to sleep-related consolidation of novel skill memory., (© 2021. The Author(s).)

When discussing procedural learning, it is now routine to consider both online and offline influences for skill acquisition. This is because it is commonly assumed that the evolution of a novel skill memory continues well after practice is over. Indeed, factors impacting offline contributions to skill memory development such as sleep and exercise have garnered considerable research interest in recent years. This is partly because of their capacity to foster postpractice consolidation, a process that has been identified as critical to moving a skill memory from a labile to more stable or elaborate form. While uncovering the potency of non-practice factors to facilitate consolidation is undoubtedly important, the present opinion is designed to remind the reader that a practice schedule, organized to challenge the learner, can, in and of itself, be effective in supporting consolidation resulting in significant gains in long-term skill retention., (Copyright © 2021 Kim and Wright.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Research has supported two distinct forms of motor skill consolidation that can occur between practice sessions: (1) off-line learning, and (2) memory stabilization. Off-line learning describes performance improvement between practice sessions that is above the gain observed at the end of practice, while memory stabilization describes a gain in performance that is maintained between practice sessions. This study used a Lissajous plot to provide concurrent feedback to train participants to produce a 90° relative phase between the index fingers (flexion/extension motion). Significant improvements in performance emerged after ten trials (5 min) of practice. At the end of training, participants were divided into two delay interval groups before retesting, 2-h and 6-h. The retesting session started with participants performing an interference task (10 trials, 5 min) that required training on a 45° relative phase between the fingers with concurrent feedback from the Lissajous plot. When training with the interference task was completed participants were retested with the 90° relative phase without the Lissajous plot feedback. In the retest of the 90° pattern, a performance loss was found in the 2-h delay group, whereas the 6-h delay group maintained the end of practice performance level. Maintenance of the same level of performance without the Lissajous plot represents memory stabilization of the initially trained 90° pattern. The findings are discussed within the context of current positions regarding procedural consolidation and the coordination dynamics framework wherein action and perception are linked through the informational nature of relative phase.

Training under high interference conditions through interleaved practice (IP) results in performance suppression during training but enhances long-term performance relative to repetitive practice (RP) involving low interference. Previous neuroimaging work addressing this contextual interference effect of motor learning has relied heavily on the blood-oxygen-level-dependent (BOLD) response using functional magnetic resonance imaging (fMRI) methodology resulting in mixed reports of prefrontal cortex (PFC) recruitment under IP and RP conditions. We sought to clarify these equivocal findings by imaging bilateral PFC recruitment using functional near-infrared spectroscopy (fNIRS) while discrete key pressing sequences were trained under IP and RP schedules and subsequently tested following a 24-h delay. An advantage of fNIRS over the fMRI BOLD response is that the former measures oxygenated and deoxygenated hemoglobin changes independently allowing for assessment of cortical hemodynamics even when there is neurovascular decoupling. Despite slower sequence performance durations under IP, bilateral PFC oxygenated and deoxygenated hemoglobin values did not differ between practice conditions. During test, however, slower performance from those previously trained under RP coincided with hemispheric asymmetry in PFC recruitment. Specifically, following RP, test deoxygenated hemoglobin values were significantly lower in the right PFC. The present findings contrast with previous behavioral demonstrations of increased cognitive demand under IP to illustrate a more complex involvement of the PFC in the contextual interference effect. IP and RP incur similar levels of bilateral PFC recruitment, but the processes underlying the recruitment are dissimilar. PFC recruitment during IP supports action reconstruction and memory elaboration while RP relies on PFC recruitment to maintain task variation information in working memory from trial to trial. While PFC recruitment under RP serves to enhance immediate performance, it does not support long-term performance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Immink, Pointon, Wright and Marino.)

Diverse field characteristics, weather patterns, and management practices can result in variable microclimates. The objective was to relate in-field microclimate conditions with peanut diseases and yield and determine the effect of irrigation and fungicides within these environments. Irrigation did not have a major impact on disease and yield. Stem rot ( Athelia rolfsii ) and early ( Passalora arachidicola ) and late ( Nothopassalora personata ) leaf spot were most affected by changes in environmental patterns across seasons. Average non-treated stem rot was 12.9% in 2017 which dropped considerably in 2018 to 0.2% but emerged again in 2019 to 3.2%. Stem rot incidence varied across the field, and the response to fungicides depended on management zone. Leaf spot defoliation in non-treated plots was severe in 2019 reaching an average of 73% at 126 days after planting but only reached 15% in 2017 and 35% in 2019 at the same stage. A low-input fungicide schedule was able to reduce foliar disease in all zones and seasons, but the microclimatic conditions in the low-lying area favored leaf spot in 2017 and 2018 although not in the dryer 2019 season. Seasonal differences in disease and plant growth affected the level of protection against average yield loss using a standard low-input program which in 2017 (527 kg/ha) was not as great as 2018 (2,235 kg/ha) or 2019 (1,763 kg/ha). Disease prediction models built on dynamic environmental factors in the context of multiple pathogens and natural field conditions could be developed to improve within-season management decisions for more efficient fungicide inputs.

Oligodendrocyte precursor cells (OPCs), also known as NG2 cells or polydendrocytes, are distributed widely throughout the developing and mature central nervous system. They remain proliferative throughout life and are an important source of myelinating cells in normal and demyelinating brain as well as a source of glioma, the most common type of primary brain tumor with a poor prognosis. OPC proliferation is dependent on signaling mediated by platelet-derived growth factor (PDGF) AA binding to its alpha receptor (PDGFRα). Here, we describe a group of structurally related compounds characterized by the presence of a basic guanidine group appended to an aromatic core that is effective in specifically repressing the transcription of Pdgfra but not the related beta receptor (Pdgfrb) in OPCs. These compounds specifically and dramatically reduced proliferation of OPCs but not that of astrocytes and did not affect signal transduction by PDGFRα. These findings suggest that the compounds could be further developed for potential use in combinatorial treatment strategies for neoplasms with dysregulated PDGFRα function., (© 2020 Wiley Periodicals LLC.)

Engagement of primary motor cortex (M1) is important for successful consolidation of motor skills. Recruitment of M1 has been reported to be more extensive during interleaved compared to repetitive practice and this differential recruitment has been proposed to contribute to the long-term retention benefit associated with interleaved practice. The present study administered anodal direct current stimulation (tDCS) during repetitive practice in an attempt to increase M1 activity throughout repetitive practice with the goal to improve the retention performance of individuals exposed to this training format. Fifty-four participants were assigned to one of three experimental groups that included: interleaved-sham, repetitive-sham, and repetitive-anodal tDCS. Real or sham stimulation at M1 was administered during practice of three motor sequences for approximately 20-min. Performance in the absence of any stimulation was evaluated prior to practice, immediately after practice as well as at 6-hr, and 24-h after practice was complete. As expected, for the sham conditions, interleaved as opposed repetitive practice resulted in superior offline gain. This was manifest as more rapid stabilization of performance after 6-h as well as an enhancement in performance with a period of overnight sleep. Administration of anodal stimulation at M1 during repetitive practice improved offline gains assessed at both 6-h and 24-h tests compared to the repetitive practice sham group. These data are consistent with the claims that reduced activation at M1 during repetitive practice impedes offline gain relative to interleaved practice and that M1 plays an important role in early consolidation of novel motor skills even in the context of the simultaneous acquisition of multiple new skills. Moreover, these findings highlight a possible role for M1 during sleep-related consolidation, possibly as part of a network including the dorsal premotor region, which supports delayed performance enhancement., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Reactive balance training (RBT) is an emerging fall prevention exercise intervention for older adults. To better understand factors that influence improvements after RBT, the goal of this study was to identify key factors that strongly associate with training-induced improvements in reactive balance. This study is a secondary analysis of data from a prior study. Twenty-eight residents of senior housing facilities participated, including 14 RBT participants and 14 Tai Chi participants (controls). Before and one week after training, participants completed balance and mobility tests and a reactive balance test. Reactive balance was operationalized as the maximum trunk angle in response to standardized trip-like perturbations on a treadmill. Bivariate (Pearson) correlation was used to identify participant characteristics before RBT and measures of performance during RBT that associated with training-induced changes in maximum trunk angle. Maximum trunk angle before reactive balance training exhibited the strongest association with training-induced changes in maximum trunk angle among RBT participants (r 2  = 0.84; p < .001), but not among Tai Chi participants (r 2  = 0.17; p = .138). Measures of performance during RBT, based upon perturbation speed, also associated with RBT-induced improvements in maximum trunk angle. These results help clarify the characteristics of individuals who can benefit from RBT, and support the use of treadmill perturbation speed as a surrogate measure of training-induced improvements in trunk kinematics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)