Biology subjects

Sherman, J.

Publications and source records attributed to Sherman, J..

13 recordsLinked to original sources

bioRxiv2026

Environment and plant genetics shape barley rhizosphere microbiome structure across contrasting locations

AbstractSoil microorganisms are crucial for plant survival and productivity, but factors governing rhizosphere recruitment across diverse regions remain unclear. This study investigated the rhizosphere microbiome of barley, using elite cultivars across seven location-year trials to evaluate the effects of environmental factors and crop genotype on bacterial and fungal community composition. Three locations were in the US northern Great Plains, and Hawaii was used as a contrasting environment. A greenhouse reciprocal transplant study determined the relative contributions of soil physicochemical factors and soil inoculum to rhizosphere community structure. Using 16S and ITS2 amplicon sequencing, the study characterized bacterial and fungal microbiomes and assessed the contribution of environment, soil chemistry, and barley genetics to microbial community assembly. In locations within the adapted range of barley, Actinobacteriota was the dominant phylum, while Proteobacteria was dominant in Hawaii. Variance partitioning showed that 73% of bacterial and 80% of fungal genera were associated with location-year effects while 53% of bacterial and 36% of fungal genera were responsive to soil factors. Enrichment analysis found 21.6% of bacterial and 51.4% of fungal ASVs were unique to specific barley genetic subpopulations. Results from the reciprocal transplant study validated field observations by demonstrating that 20.7% of the variation in community structure was explained by soil while 18.2% was explained by inoculum source. These findings demonstrate that environmental variation is the dominant constraint on rhizosphere community composition but within these constraints, barley genotype drives recruitment of distinct bacterial and fungal taxa. ImportanceThese findings underscore the complex interplay between plant genotype, environment, and microbial community assembly, providing insights into how barley recruits distinct microbial communities in the rhizosphere across different environments. These insights have the potential to be leveraged for management and plant breeding strategies to optimize plant-microbe interactions for enhancing agricultural sustainability.

microbiology↗

bioRxiv2025

Transcranial ultrasound stimulation modulates neuronal membrane potentials across broad timescales in the awake mammalian brain

BackgroundTranscranial ultrasound stimulation (TUS) offers noninvasive neuromodulation with high spatial and temporal precision, but its cellular-level effects in the awake brain remain poorly understood. ObjectiveWe investigated how low-intensity TUS modulates membrane voltage dynamics in single cortical neurons in awake mice. MethodsUsing the genetically encoded voltage indicator SomArchon, we performed high-speed kilohertz voltage imaging in awake head-fixed mice. TUS was delivered with a 0.35 MHz transducer at 10 or 40 Hz pulse repetition frequency with a 20% duty cycle, at intensities below the estimated threshold for auditory brainstem activation. We analyzed changes in membrane potential (Vm), spiking, and coordination across simultaneously recorded neurons. ResultsTUS evoked rapid (<10 ms) Vm depolarizations in 42.8% of neurons, while only 20.5% showed increased spiking, highlighting a direct effect of TUS on modulating synaptic inputs. Many neurons were entrained at both PRFs (20.8% at 10 Hz; 12.7% at 40 Hz) with Vm exhibiting significant phase-locking to individual TUS pulses. Vm entrainment was accompanied by increased temporal coordination across neurons and reset network synchrony. Furthermore, TUS-evoked cellular responses adapted over time, often transitioning from membrane depolarization to hyperpolarization upon repeated exposures, demonstrating prominent response depression. ConclusionBy resolving single-neuron responses, our results demonstrate that TUS directly activates individual cortical neuron with a latency shorter than 10 ms. TUS pulsed at physiologically relevant frequencies of 10 and 40 Hz robustly entrains neural dynamics, alters network coordination and evokes neuronal plasticity. These results highlight the therapeutic potential of designing TUS pulsing patterns to target specific neural circuit dynamics.

neuroscience↗

bioRxiv2024

Postmortem findings of free-ranging North American beavers (Castor canadensis) reveal potential threats to California freshwater ecosystems

North American beavers (Castor canadensis) are semi-aquatic rodents recognized as keystone species that increase the diversity of freshwater ecosystems. This study aimed to characterize the mortality and pathological findings of free-ranging beavers in California and, based on these results, establish the potential threats to freshwater ecosystems. This study included eighteen beavers submitted for postmortem examination between 2008 and 2024 at the California Animal Health and Food Safety Laboratory, UC Davis. Gross and microscopic examination, bacteriological, parasitological, immunohistochemical, and molecular techniques were used as tools to diagnose the cause of death/reason for euthanasia and comorbidities in the beavers. Encephalitis caused by the larva migrans of Baylisascaris spp. was the most prevalent (9/18) cause of mortality/reason for euthanasia followed by bacterial infections in 6 individuals. In these 6 animals, bacterial bronchopneumonia was diagnosed in two (Staphylococcus aureus and a mix of gram-negative and -positive bacterial infection) and Listeria monocytogenes encephalitis, bacterial myofascitis (Aeromonas bestiarum and Pasteurella multocida), bacterial encephalitis (Acinetobacter towneri), and tularemia (Francisella tularensis) were diagnosed in one beaver each. Three animals died or were euthanized due to non-infectious causes including motor vehicle trauma, squamous cell carcinoma, and capture cardiomyopathy. Endoparasitism was the main comorbidity including granulomatous hepatitis by a suspected capillarid species, cerebral toxoplasmosis, Giardia infection, gastric nematodiasis, and cecal trematodiasis. In California, beavers are exposed to various pathogens that represent threats to humans, domestic animals, and wildlife. Since the interspecies transmission of these pathogens occurs in rivers, streams, lakes, and ponds, we suggest that studying beaver health can reflect freshwater ecosystem health. This study also indicates that the translocation of beavers into new areas without consideration and/or mitigation represents a potential risk for pathogen introduction.

pathology↗

bioRxiv2024

Ultrasound pulse repetition frequency preferentially activates different neuron populations independent of cell type

Transcranial ultrasound activates mechanosensitive cellular signaling and modulates neural dynamics. Given that intrinsic neuronal activity is limited to a couple hundred hertz and often exhibits frequency preference, we examined whether pulsing ultrasound at physiologic pulse repetition frequencies (PRFs) could selectively influence neuronal activity in the mammalian brain. We performed calcium imaging of individual motor cortex neurons, while delivering 0.35 MHz ultrasound at PRFs of 10, 40, and 140 Hz in awake mice. We found that most neurons were preferentially activated by only one of the three PRFs, highlighting unique cellular effects of physiologic PRFs. Further, ultrasound evoked responses were similar between excitatory neurons and parvalbumin positive interneurons regardless of PRFs, indicating that individual cell sensitivity dominates ultrasound-evoked effects, consistent with the heterogeneous mechanosensitive channel expression we found across single neurons in mice and humans. These results highlight the feasibility of tuning ultrasound neuromodulation effects through varying PRFs.

neuroscience↗

bioRxiv2022

In silico, biochemical, and in vitro analysis of silvestrol binding to the DEAD box RNA helicase eIF4A reveals broad anti-pathogen potential of rocaglates across the eukaryotic tree of life

Selective inhibition of eukaryotic initiation factor 4A (eIF4A), an RNA helicase, has been proposed as a strategy to fight pathogens. Plant-derived rocaglates exhibit some of the highest specificities among eIF4A inhibitors. Sensitivity to rocaglates is determined by key amino acid (aa) residues mediating reversible clamping of the eIF4A:RNA complex. To date, no comprehensive assessment of eIF4A sensitivity to rocaglates across the eukaryotic tree of life has been performed to determine their anti-pathogenic potential. We performed an in silico analysis of the substitution patterns of six aa residues in eIF4A1 critical to rocaglate binding (human positions 158, 159, 163, 192, 195, 199), uncovering 35 pattern variants among 365 eIF4As sequenced to date. In silico molecular docking analysis of the eIF4A:RNA:rocaglate complexes of the 35 variants, modeled in a human eIF4A environment, and in vitro thermal shift assays with recombinantly expressed human eIF4A mutants, representing select natural and artificial variants, revealed that sensitivity to a natural or one of two synthetic rocaglates--silvestrol, CR-1-31-B, or zotatifin--was associated with lower inferred binding energies and higher melting temperature shifts. Helicase activities were comparable across variants and independent of sensitivity to rocaglates. In vitro testing with silvestrol validated predicted resistance based on position 163 substitutions in Caenorhabditis elegans and Leishmania amazonensis and predicted sensitivity in Aedes sp., Schistosoma mansoni, Trypanosoma brucei, Plasmodium falciparum, and Toxoplasma gondii. Our analysis shows resistance to rocaglates emerging in disparate eukaryotic clades pointing to resistance being a selective neutral trait except in rocaglate-producing Aglaia plants and their fungal parasite Ophiocordyceps. The analysis further revealed the possibility of targeting important insect, plant, animal, and human pathogens including Galleria mellonella, Ustilago maydis, Babesia ovata, and Cryptosporidium sp., with rocaglates. Finally, combined docking and thermal shift analyses might help design novel synthetic rocaglate derivatives or alternative eIF4A inhibitors to fight pathogens. Author SummaryIn the ongoing search for novel ways to fight non-viral and non-bacterial pathogens, targeting translation--the universal process of protein synthesis--to inhibit growth and cell proliferation has emerged as an attractive strategy. Here, we focused on the potential of rocaglates, a group of plant-derived compounds, to inhibit an early step in translation mediated by a RNA helicase called eIF4A. We performed a comprehensive analysis of eIF4A sequence variants to determine their potential sensitivities to rocaglates, especially in pathogens of prokaryotic, fungal, or animal origin. We complemented this in silico analysis with enzyme-based in vitro and whole pathogen in vivo experiments to confirm the sensitivity or resistance to rocaglates of specific variants of eIF4A. Our analysis provides the first comprehensive picture of rocaglate sensitivity among pathogens and establishes targeting important insect, plant, animal, and human pathogens such as wax moth larvae, a major parasite of honey bees, corn smut, a widely distributed fungal disease, Babesia, a livestock parasite that causes anemia and babesiois, and Cryptosporidium, the causative organism of cryptosporidiosis in humans, with rocaglates as a viable anti-pathogen strategy.

molecular biology↗

bioRxiv2021

Mitochondrial Dysfunction is a Driver for SP-2509 Drug Resistance in Ewing Sarcoma

Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine specific demethylase-1 (LSD1) inhibitors, which are currently in early phase clinical trials. Single agent targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP- 2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509. These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents which prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.

cancer biology↗

bioRxiv2021

Deforestation projections imply range-wide population decline for critically endangered Bornean orangutan

Assessing where wildlife populations are at risk from future habitat loss is particularly important for land-use planning and avoiding biodiversity declines. Combining projections of future deforestation with species density information provides an improved way to anticipate such declines. Using the endemic and critically endangered Bornean orangutan (Pongo pygmaeus) as a case study we applied a spatio-temporally explicit deforestation model to forest loss data from 2001-2017 and projected future impacts on orangutans to the 2030s. Our projections point to continued deforestation across the island, amounting to a loss of forest habitat for 26,200 (CI: 19,500-34,000) orangutans. Populations currently persisting in forests gazetted for industrial timber and oil palm concessions, or unprotected forests outside of concessions, were projected to experience the worst losses within the next 15 years, amounting to 15,400 (CI: 12,000-20,500) individuals. Lowland forests with high orangutan densities in West and Central Kalimantan were also projected to be at high risk from deforestation, irrespective of land-use. In contrast, most protected areas and logging concessions currently harboring orangutans will continue to face low levels of deforestation. Our business-as-usual projections indicate the importance of protected areas, efforts to prevent the conversion of logged forests for the survival of highly vulnerable wildlife, and protecting orangutan habitat in plantation landscapes. The modeling framework could be expanded to other species with available density or occurrence data. Our findings highlight that species conservation should not only attempt to act on the current situation, but also be adapt to changes in drivers to be effective.

ecology↗

bioRxiv2021

Mapping Protein Numbers in Living Cells

We introduce a new, robust method to map the numbers of proteins in living cells. The method can be applied to laser scanning, spinning disk, and lattice light-sheet microscopes in a robust, reproducible, and scalable fashion. The method uses calibrated EGFP solutions that are imaged with the appropriate microscope modality to create a calibration curve that is then applied to convert the fluorescence intensities from 3D microscope images into molecule numbers. We applied this method to human induced pluripotent stem cells in which proteins representing key cellular structures were endogenously tagged with mEGFP. We used the ratio of mEGFP-tagged proteins to total proteins to create 3D maps of live cells showing the density of total proteins measured in molecules per {micro}m3. The method opens the door to new quantitative single cell analyses of cellular protein numbers in the context of single cell gene expression, associations with cellular complexes, and changes in cellular behaviors. The method is capable of quantifying protein numbers, over three orders of magnitude, in the cytoplasm or within various cellular structures while offering the unique advantages of each microscopy modality.

cell biology↗

bioRxiv2021

Artemisinin-based hybrids produce intracellular proteasome inhibitors that overcome resistance in Plasmodium falciparum

Artemisinin resistant Plasmodium falciparum (Pf) is spreading despite combination chemotherapy (ACT). Here we report the design of artezomibs, single-molecule hybrids of an artemisinin and a Pf-selective proteasome inhibitor. Artezomibs exert a novel mode of action inside the malaria parasites. The artemisinin component covalently modifies parasite proteins, which become substrates of the Pf proteasome. The proteasomal degradation products that bear the proteasome inhibitor component of the hybrid then inhibit Pf proteasomes, including those with mutations that reduce binding affinity of the proteasome inhibitor component on its own. We demonstrated that artezomibs circumvent both artemisinin resistance conferred by Kelch13 polymorphism and resistance to the proteasome inhibitor associated with mutations in Pf proteasomes. This mode of action may enable the use of a single molecule with one pharmacokinetic profile to prevent the emergence of resistance.

microbiology↗

bioRxiv2021

Radio-pathomic maps of cell density identify glioma invasion beyond traditional MR imaging defined margins

Current MRI signatures of brain cancer often fail to identify regions of hypercellularity beyond the contrast enhancing region. Therefore, this study used autopsy tissue samples aligned to clinical MRIs in order to quantify the relationship between intensity values and cellularity, as well as to develop a radio-pathomic model to predict cellularity using MRI data. This study used 93 samples collected at autopsy from 44 brain cancer patients. Tissue samples were processed, stained for hematoxylin and eosin (HE) and digitized for nuclei segmentation and cell density calculation. Pre- and post-gadolinium contrast T1-weighted images (T1, T1C), T2 fluid-attenuated inversion recovery (FLAIR) images, and apparent diffusion coefficient (ADC) images calculated from diffusion imaging were collected from each patients final acquisition prior to death. In-house software was used to align tissue samples to the FLAIR image via manually defined control points. Mixed effect models were used to assess the relationship between single image intensity and cellularity for each image. An ensemble learner was trained to predict cellularity using 5 by 5 voxel tiles from each image, employing a 2/3-1/3 train-test split for validation. Single image analyses found subtle associations between image intensity and cellularity, with a less pronounced relationship within GBM patients. The radio-pathomic model was able to accurately predict cellularity in the test set (RMSE = 1015 cells/mm2) and identified regions of hypercellularity beyond the contrast enhancing region. We concluded that a radio-pathomic model for cellularity is able to identify regions of hypercellular tumor beyond traditional imaging signatures.

neuroscience↗

bioRxiv2021

Large-scale voltage imaging in the brain using targeted illumination

Recent improvements in genetically encoded voltage indicators enabled optical imaging of action potentials and subthreshold membrane voltage dynamics from single neurons in the mammalian brain. To perform high speed voltage imaging, widefield microscopy remains an essential tool for recording activity from many neurons simultaneously over a large anatomical area. However, the lack of optical sectioning makes widefield microscopy more prone to background signal contamination, and thus far voltage imaging using fully genetically encoded voltage indicators remains limited to simultaneous sampling of a few cells over a restricted field-of-view. We here demonstrate a strategy for large scale voltage imaging using the fully genetically encoded voltage indicator SomArchon and targeted illumination. We implemented a simple, low-cost digital micromirror device based targeted illumination strategy to restrict illumination to the cells of interest, and systematically quantified the improvement of this microscopy design theoretically and experimentally with SomArchon expressing neurons in single layer cell cultures and in the brains of awake mice. We found that targeted illumination, in comparison to widefield illumination, increased SomArchon signal contrast and reduced background cross-contamination in the brain. Such improvement permitted the reduction of illumination intensity, and thus reduced fluorescence photobleaching and prolonged imaging duration. When coupled with a high-speed, large area sCMOS camera, we routinely imaged tens of spiking neurons simultaneously over minutes in the brain. Thus, the widefield microscopy design with an integrated targeted illumination system described here offers a simple solution for voltage imaging analysis of large neuron populations in behaving animals.

neuroscience↗

bioRxiv2020

How widespread was the Tapanuli orangutan and what led to its decline?

The Tapanuli Orangutan (Pongo tapanuliensis) is the most threatened great ape species in the world. It is restricted to an area of about 1,000 km2 of upland forest where fewer than 800 animals survive in three declining subpopulations. Through a historical ecology approach involving analysis of newspaper, journals, books and museum records from the early 1800s to 2009, we demonstrate that historically Pongo tapanuliensis inhabited a much larger area, and across a much wider range of habitat types than now. Its current Extent of Occurrence is between 2.5% and 5.0% of the historical range in the 1890s and 1940s respectively. A combination of historical fragmentation of forest habitats, mostly for small-scale agriculture, and unsustainable hunting likely drove various populations to the south, east and west of the current population to extinction. This happened prior to the industrial-scale forest conversion that started in the 1970s. Our findings indicate how sensitive P. tapanuliensis is to the combined effects of habitat fragmentation and unsustainable take-off rates. Saving this species will require prevention of any further fragmentation and killings or other removal of animals from the remaining population. Without concerted action to achieve this, the remaining populations of P. tapanuliensis are doomed to become extinct within several orangutan generations.

zoology↗

bioRxiv2020

The importance of orangutans in small fragments for maintaining metapopulation dynamics

Orangutans (Pongo spp.) occur at low densities and therefore large areas are necessary to sustain viable metapopulations, defined here as sets of conspecific units of individuals linked by dispersal. Historically, orangutans lived in large contiguous areas of intact rainforest, but are now increasingly found in agricultural and other landscapes modified by people. Here we collate evidence of orangutans utilizing isolated forest fragments (< 500 ha) within multiple-use landscapes dominated by oil palm monoculture across Borneo. Orangutan signs (i.e. nests) were evident in 76 fragments surveyed by helicopter, and in 50 of 70 additional fragments surveyed on the ground; on average 63 ha in size. This includes presence of adult resident females with dependent young confirmed in 40% of the fragments assessed by ground survey. Our study revealed some resident females are raising offspring in isolated forest patches within mature oil palm stands. This not only confirms that some forest patches can sustain orangutans, but indicates migratory males are capable of reaching these fragments scattered throughout the multiple-use landscape. Therefore, orangutans that use or live in even small isolated forest patches are an essential part of the overall metapopulation by maintaining gene flow between, and genetic connectivity within, populations distributed across larger multiple-use landscapes. Orangutan survival is commonly thought to be low in small, isolated forest patches, and the customary management strategy is to remove (translocate) these individuals and release them in larger forests. In some cases, translocations may be necessary, i.e. in case of fire or when the animals are in eminent danger of being killed and have no other refuge. However, the small amount of data available indicates that mortality rates during and after translocations are high, while the impacts of removing animals from spatially dispersed metapopulations are unknown. Therefore, we argue the current policy of routine translocation rather than conserving the species within human-modified landscapes could inadvertently decrease critical metapopulation functionality necessary for long-term viability. It is clear that orangutans need natural forest to survive, but our findings show that fragmented agricultural landscapes can also serve as complementary conservation areas in addition to fully protected areas if they are well designed with ecological connections, and if orangutan killing can be prevented. To achieve this, we call for a paradigm shift from the traditional large single forest model to one that emphasizes metapopulation functionality in the fragmented forest - human use matrix characteristic of the Anthropocene. Version 2 (20 May 2020): this manuscript is a non-peer reviewed preprint shared via the BiorXiv server while being considered for publication in a peer-reviewed academic journal. Please refer to the permanent digital object identifier (https://doi.org/10.1101/2020.05.17.100842). Under the Creative Commons license (CC-BY Attribution-Non Commercial-No Derivatives 4.0 International) you are free to share the material as long as the authors are credited, you link to the license, and indicate if any changes have been made. You may not share the work in any way that suggests the licensor endorses you or your use. You cannot change the work in any way or use it commercially.

ecology↗