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These results show that transcription stress is an important contributor to SETX mutation-associated chromosome fragility and AOA2.Srs2 is a superfamily 1 (SF1) helicase that participates in several pathways necessary for the repair of damaged DNA. Srs2 regulates formation of early homologous recombination (HR) intermediates by actively removing the recombinase Rad51 from single-stranded DNA (ssDNA). It is not known whether and how Srs2 itself is down-regulated to allow for timely HR progression. Rad54 and Rdh54 are two closely related superfamily 2 (SF2) motor proteins that promote the formation of Rad51-dependent recombination intermediates. Rad54 and Rdh54 bind tightly to Rad51-ssDNA and act downstream of Srs2, suggesting that they may affect the ability of Srs2 to dismantle Rad51 filaments. Here, we used DNA curtains to determine whether Rad54 and Rdh54 alter the ability of Srs2 to disrupt Rad51 filaments. We show that Rad54 and Rdh54 act synergistically to greatly restrict the antirecombinase activity of Srs2. Our findings suggest that Srs2 may be accorded only a limited time window to act and that Rad54 and Rdh54 fulfill a role of prorecombinogenic licensing factors.Quantitative understanding of factors driving yield increases of major food crops is essential for effective prioritization of research and development. Yet previous estimates had limitations in distinguishing among contributing factors such as changing climate and new agronomic and genetic technologies. Here, we distinguished the separate contribution of these factors to yield advance using an extensive database collected from the largest irrigated maize-production domain in the world located in Nebraska (United States) during the 2005-to-2018 period. We found that 48% of the yield gain was associated with a decadal climate trend, 39% with agronomic improvements, and, by difference, only 13% with improvement in genetic yield potential. The fact that these findings were so different from most previous studies, which gave much-greater weight to genetic yield potential improvement, gives urgency to the need to reevaluate contributions to yield advances for all major food crops to help guide future investments in research and development to achieve sustainable global food security. If genetic progress in yield potential is also slowing in other environments and crops, future crop-yield gains will increasingly rely on improved agronomic practices.To further advance functional MRI (fMRI)-based brain science, it is critical to dissect fMRI activity at the circuit level. To achieve this goal, we combined brain-wide fMRI with neuronal silencing in well-defined regions. Since focal inactivation suppresses excitatory output to downstream pathways, intact input and suppressed output circuits can be separated. Highly specific cerebral blood volume-weighted fMRI was performed with optogenetic stimulation of local GABAergic neurons in mouse somatosensory regions. Brain-wide spontaneous somatosensory networks were found mostly in ipsilateral cortical and subcortical areas, which differed from the bilateral homotopic connections commonly observed in resting-state fMRI data. The evoked fMRI responses to somatosensory stimulation in regions of the somatosensory network were successfully dissected, allowing the relative contributions of spinothalamic (ST), thalamocortical (TC), corticothalamic (CT), corticocortical (CC) inputs, and local intracortical circuits to be determined. The ventral posterior thalamic nucleus receives ST inputs, while the posterior medial thalamic nucleus receives CT inputs from the primary somatosensory cortex (S1) with TC inputs. The secondary somatosensory cortex (S2) receives mostly direct CC inputs from S1 and a few TC inputs from the ventral posterolateral nucleus. The TC and CC input layers in cortical regions were identified by laminar-specific fMRI responses with a full width at half maximum of less then 150 µm. Long-range synaptic inputs in cortical areas were amplified approximately twofold by local intracortical circuits, which is consistent with electrophysiological recordings. Overall, whole-brain fMRI with optogenetic inactivation revealed brain-wide, population-based, long-range circuits, which could complement data typically collected in conventional microscopic functional circuit studies.What was the nature of the Late Hesperian climate, warm and wet or cold and dry? Formulated this way the question leads to an apparent paradox since both options seem implausible. A warm and wet climate would have produced extensive fluvial erosion but few valley networks have been observed at the age of the Late Hesperian. A too cold climate would have kept any northern ocean frozen most of the time. A moderate cold climate would have transferred the water from the ocean to the land in the form of snow and ice. But this would prevent tsunami formation, for which there is some evidence. Here, we provide insights from numerical climate simulations in agreement with surface geological features to demonstrate that the Martian climate could have been both cold and wet. Using an advanced general circulation model (GCM), we demonstrate that an ocean can be stable, even if the Martian mean surface temperature is lower than 0 °C. Rainfall is moderate near the shorelines and in the ocean. The southern plateau is mostly covered by ice with a mean temperature below 0 °C and a glacier return flow back to the ocean. This climate is achieved with a 1-bar CO2-dominated atmosphere with 10% H2 Under this scenario of 3 Ga, the geologic evidence of a shoreline and tsunami deposits along the ocean/land dichotomy are compatible with ice sheets and glacial valleys in the southern highlands.Sheep and goats (caprines) were domesticated in Southwest Asia in the early Holocene, but how and in how many places remain open questions. This study investigates the initial conditions and trajectory of caprine domestication at Aşıklı Höyük, which preserves an unusually high-resolution record of the first 1,000 y of Neolithic existence in Central Anatolia. Our comparative analysis of caprine age and sex structures and related evidence reveals a local domestication process that began around 8400 cal BC. Caprine management at Aşıklı segued through three viable systems. The earliest mode was embedded within a broad-spectrum foraging economy and directed to live meat storage on a small scale. This was essentially a "catch-and-grow" strategy that involved seasonal capture of wild lambs and kids from the surrounding highlands and raising them several months prior to slaughter within the settlement. The second mode paired modest levels of caprine reproduction on site with continued recruitment of wild infants. The third mode shows the hallmarks of a large-scale herding economy based on a large, reproductively viable captive population but oddly directed to harvesting adult animals, contra to most later Neolithic practices. Wild infant capture likely continued at a low level. The transitions were gradual but, with time, gave rise to early domesticated forms and monumental differences in human labor organization, settlement layout, and waste accumulation. Aşıklı was an independent center of caprine domestication and thus supports the multiple origins evolutionary model.To rapidly process temporal information at a low metabolic cost, biological neurons integrate inputs as an analog sum, but communicate with spikes, binary events in time. Analog neuromorphic hardware uses the same principles to emulate spiking neural networks with exceptional energy efficiency. However, instantiating high-performing spiking networks on such hardware remains a significant challenge due to device mismatch and the lack of efficient training algorithms. Surrogate gradient learning has emerged as a promising training strategy for spiking networks, but its applicability for analog neuromorphic systems has not been demonstrated. Here, we demonstrate surrogate gradient learning on the BrainScaleS-2 analog neuromorphic system using an in-the-loop approach. We show that learning self-corrects for device mismatch, resulting in competitive spiking network performance on both vision and speech benchmarks. Our networks display sparse spiking activity with, on average, less than one spike per hidden neuron and input, perform inference at rates of up to 85,000 frames per second, and consume less than 200 mW. In summary, our work sets several benchmarks for low-energy spiking network processing on analog neuromorphic hardware and paves the way for future on-chip learning algorithms.Climate change threatens the social, ecological, and economic benefits enjoyed by forest-dependent communities worldwide. Climate-adaptive forest management strategies such as genomics-based assisted migration (AM) may help protect many of these threatened benefits. However, such novel technological interventions in complex social-ecological systems will generate new risks, benefits, and uncertainties that interact with diverse forest values and preexisting risks. Using data from 16 focus groups in British Columbia, Canada, we show that different stakeholders (forestry professionals, environmental nongovernmental organizations, local government officials, and members of local business communities) emphasize different kinds of risks and uncertainties in judging the appropriateness of AM. We show the difficulty of climate-adaptive decisions in complex social-ecological systems in which both climate change and adaptation will have widespread and cascading impacts on diverse nonclimate values. Overarching judgments about AM as an adaptation strategy, which may appear simple when elicited in surveys or questionnaires, require that participants make complex trade-offs among multiple domains of uncertain and unknown risks. Overall, the highest-priority forest management objective for most stakeholders is the health and integrity of the forest ecosystem from which all other important forest values derive. The factor perceived as riskiest is our lack of knowledge of how forest ecosystems work, which hinders stakeholders in their assessment of AM's acceptability. These results are further evidence of the inherent risk in privileging natural science above other forms of knowledge at the science-policy interface. When decisions are framed as technical, the normative and ethical considerations that define our fundamental goals are made invisible.Rapid diversification is often observed when founding species invade isolated or newly formed habitats that provide ecological opportunity for adaptive radiation. However, most of the Earth's diversity arose in diverse environments where ecological opportunities appear to be more constrained. Here, we present a striking example of a rapid radiation in a highly diverse marine habitat. The hamlets, a group of reef fishes from the wider Caribbean, have radiated into a stunning diversity of color patterns but show low divergence across other ecological axes. Although the hamlet lineage is ∼26 My old, the radiation appears to have occurred within the last 10,000 generations in a burst of diversification that ranks among the fastest in fishes. As such, the hamlets provide a compelling backdrop to uncover the genomic elements associated with phenotypic diversification and an excellent opportunity to build a broader comparative framework for understanding the drivers of adaptive radiation. The analysis of 170 genomes suggests that color pattern diversity is generated by different combinations of alleles at a few large-effect loci.