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Biology subjects

Ebrahimi, S.

Publications and source records attributed to Ebrahimi, S..

7 recordsLinked to original sources

A geometric and dynamical theory of latent computations in biological neural networks

Many neural recordings have revealed low-dimensional sets of behaviorally relevant variables encoded within large-scale neural activity patterns. However, dimensionality reduction analyses alone cannot yield causal explanations for how networks stably implement computations that are resilient to the substantial variability of single neuron dynamics. Further, existing methods for dimensionality reduction often rely on simplifying assumptions about network structure that limit their applicability and explanatory power. To provide a theoretical framework describing the dynamics of low-dimensional computation in high-dimensional neural networks, here we introduce the concept of latent processing units (LPUs), which are architecture-agnostic computational elements operating within biological neural circuitry. Six theorems governing coding and computation by LPUs collectively provide explanations for a range of common biological findings: low-dimensional sets of coding variables can generate high-dimensional neural dynamics; many neurons have activity patterns that represent behaviorally relevant variables but exert little influence on downstream circuits; linear readouts of neural population activity commonly permit near-optimal decoding; the drift of neural representations is often substantial even while network computations remain intact. Overall, our treatment of LPUs, as enacted in network dynamics, unifies the geometric and dynamical views of neural computation under a joint framework and provides systems neuroscience with a causal account of how the brain executes reliable computations.

neuroscience↗

Regulation of NFKBIZ by precise Regnase-1 endoribonuclease cleavage and subsequent uridylation

A conserved sequence in the 3'UTR of NFKBIZ mRNA has long been recognized as a regulator of cytokine production and interferon responses. We show that the endoribonuclease Regnase-1 controls NFKBIZ expression through a precise and modular RNA degradation mechanism. The structured core element undergoes specific endonucleolytic cleavage, while flanking upstream and downstream stem-loop modules, previously implicated in Regnase-1 recognition, act cooperatively to enhance cleavage efficiency by [~]25-fold. Following cleavage, the upstream fragment is rapidly uridylated, accelerating decay of the NFKBIZ open reading frame. This pathway explains how driver mutations - found in this RNA region - responsible for diffuse large B-cell lymphoma elevate NFKBIZ expression and how a segment of the SARS-CoV-2 genome - previously linked to NFKBIZ activation - suppresses Regnase-1 cleavage via hybridization to this regulatory RNA segment. Together, these findings define a mechanistic framework for Regnase-1-mediated control of NFKBIZ, linking its cleavage activity to both lymphomagenesis and viral pathogenesis.

biochemistry↗

ActSort: An active-learning accelerated cell sorting algorithm for large-scale calcium imaging datasets

Recent advances in calcium imaging enable simultaneous recordings of up to a million neurons in behaving animals, producing datasets of unprecedented scales. Although individual neurons and their activity traces can be extracted from these videos with automated algorithms, the results often require human curation to remove false positives, a laborious process called cell sorting. To address this challenge, we introduce ActSort, an active-learning algorithm for sorting large-scale datasets that integrates features engineered by domain experts together with data formats with minimal memory requirements. By strategically bringing outlier cell candidates near the decision boundary up for annotation, ActSort reduces human labor to about 1-3% of cell candidates and improves curation accuracy by mitigating annotator bias. To facilitate the algorithms widespread adoption among experimental neuroscientists, we created a user-friendly software and conducted a first-of-its-kind benchmarking study involving about 160,000 annotations. Our tests validated ActSorts performance across different experimental conditions and datasets from multiple animals. Overall, ActSort addresses a crucial bottleneck in processing large-scale calcium videos of neural activity and thereby facilitates systems neuroscience experiments at previously inaccessible scales.

neuroscience↗

Beet curly top Iran virus Rep and V2 gene work as silencing suppressors through separate mechanisms

Beet curly top Iran Virus (BCTIV) is a yield-limiting geminivirus belonging to the becurtovirus genus. The genome organization of BCTIV is unique such that the complementary strand of BCTIV resembles mastreviruses, whereas the virion strand organization is close to curtoviruses. Geminiviruses are known to avoid the plant defense system by suppressing the RNA interference mechanisms both at the transcriptional gene silencing (TGS) and post-transcriptional gene silencing (PTGS) level. Multiple geminivirus genes have been identified as viral suppressors of RNA silencing (VSR) but VSR activity remains elusive in becurtoviruses. By screening all verified open reading frames in the BCTIV genome, we found that only V2 and Rep were able to suppress specific PTGS mechanisms, triggered by the expression of a partial or full-length sense-strand transcript of the target gene (S-PTGS). BCTIV-V2 could suppress S-PTGS more efficiently than BCTIV-Rep when then the target GFP gene is transiently expressed. On the other hand, S-PTGS is suppressed by Rep but not V2 when target GFP is only stably expressed. Deletional mutagenesis of BCTIV-Rep implicated that multiple domains are required for its VSR activity. Furthermore, neither V2 nor Rep could fully suppress local PTGS induced by inverted repeat targeting GFP (GFP-IR). Also, in a closer look at the spread of local silencing by GFP-IR, we observed that V2 or Rep are not able to suppress the movement of sRNAs. Nevertheless, Rep suppressed the systemic silencing induced by GFP-IR in 16C plants. Northern blot analyses showed that BCTIV-Rep inhibits silencing by mitigating sRNA production, whereas BCTIV-V2 does not alter sRNA levels. In summary, both the silencing phenotype and the molecular signatures of silencing implicate distinct modes of VSR activity of BCTIV-Rep and -V2.

plant biology↗

SARS-CoV-2 spike protein arrested in the closed state induces potent neutralizing responses

The majority of SARS-CoV-2 vaccines in use or in advanced clinical development are based on the viral spike protein (S) as their immunogen. S is present on virions as pre-fusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described that act against both open and closed conformations. The long-term success of vaccination strategies will depend upon inducing antibodies that provide long-lasting broad immunity against evolving, circulating SARS-CoV-2 strains, while avoiding the risk of antibody dependent enhancement as observed with other Coronavirus vaccines. Here we have assessed the results of immunization in a mouse model using an S protein trimer that is arrested in the closed state to prevent exposure of the receptor binding site and therefore interaction with the receptor. We compared this with a range of other modified S protein constructs, including representatives used in current vaccines. We found that all trimeric S proteins induce a long-lived, strongly neutralizing antibody response as well as T-cell responses. Notably, the protein binding properties of sera induced by the closed spike differed from those induced by standard S protein constructs. Closed S proteins induced more potent neutralising responses than expected based on the degree to which they inhibit interactions between the RBD and ACE2. These observations suggest that closed spikes recruit different, but equally potent, virus-inhibiting immune responses than open spikes, and that this is likely to include neutralizing antibodies against conformational epitopes present in the closed conformation. Together with their improved stability and storage properties we suggest that closed spikes may be a valuable component of refined, next-generation vaccines.

immunology↗

A thermostable, closed, SARS-CoV-2 spike protein trimer.

The spike (S) protein of SARS-CoV-2 mediates receptor binding and cell entry and is the dominant target of the immune system. S exhibits substantial conformational flexibility. It transitions from closed to open conformations to expose its receptor binding site, and subsequently from prefusion to postfusion conformations to mediate fusion of viral and cellular membranes. S protein derivatives are components of vaccine candidates and diagnostic assays, as well as tools for research into the biology and immunology of SARS-CoV-2. Here we have designed mutations in S which allow production of thermostable, crosslinked, S protein trimers that are trapped in the closed, pre-fusion, state. We have determined the structures of crosslinked and non-crosslinked proteins, identifying two distinct closed conformations of the S trimer. We demonstrate that the designed, thermostable, closed S trimer can be used in serological assays. This protein has potential applications as a reagent for serology, virology and as an immunogen.

biochemistry↗

Enriching and aggregating purple non-sulfur bacteria in an anaerobic sequencing-batch photobioreactor for nutrient capture from wastewater

Purple non-sulfur bacteria (PNSB), a guild of anoxygenic photomixotrophic organisms, rise interest to capture nutrients from wastewater in mixed-culture bioprocesses. One challenge targets the aggregation of PNSB biomass through gravitational separation from the treated water to facilitate its retention and accumulation, while avoiding the need for membranes. We aimed to produce an enriched, concentrated, well-settling, nutrient-removing PNSB biomass using sequencing batch regimes (SBR) in an anaerobic photobioreactor. The stirred tank was fed with a synthetic influent mimicking loaded municipal wastewater (430-860 mg CODAc LInf-1, COD:N:P ratio of 100:36:4-100:11:2 m/m/m), operated at 30{degrees}C and pH 7, and continuously irradiated with infrared (IR) light (>700 nm) at 375 W m-2. After inoculation with activated sludge at 0.1 g VSS L-1, PNSB were rapidly enriched in a first batch of 24 h: the genus Rhodobacter reached 54% of amplicon sequencing read counts. SBR operations at volume exchange ratio of 50% with decreasing hydraulic retention times (48 to 16 h; 1 to 3 cycles d-1) and increasing volumetric organic loading rates (0.2 to 1.3 kg COD m-3 d-1) stimulated the aggregation (compact granules of 50-150 m), settling (sedimentation G-flux of 4.7 kg h-1 m-2), and accumulation (as high as 3.8 g VSS L-1) of biomass. The sludge retention time (SRT) increased freely from 2.5 to 11 d without controlled sludge wasting. Acetate, ammonium, and orthophosphate were removed simultaneously (up to 96% at a rate of 1.1 kg COD m-3 d-1, 77% at 113 g N m-3 d-1, and 73% at 15 g P m-3 d-1) with a COD:N:P assimilation ratio of 100:6.7:0.9 (m/m/m). Competition for substrate and photons occurred in the PNSB guild. SBR regime shifts sequentially selected for Rhodobacter (90%) under shorter SRT and non-limiting acetate concentrations during reaction phases, Rhodopseudomonas (70%) under longer SRT and acetate limitation, and Blastochloris (10%) under higher biomass concentrations. We highlighted the benefits of a PNSB-based SBR process for biomass accumulation and simultaneous nutrient capture at substantial rates, and its underlying microbial ecology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/899062v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1f167bdorg.highwire.dtl.DTLVardef@1d1c1e2org.highwire.dtl.DTLVardef@fe591org.highwire.dtl.DTLVardef@1a8c4e3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPNSB were highly enriched (90%) in an anaerobic stirred-tank photobioreactor. C_LIO_LIThe mixed-culture SBR process fostered PNSB biomass aggregation and accumulation. C_LIO_LIPNSB sludge reached 3.8 g VSS L-1 and a sedimentation G-flux of 4.7 kg h-1 m-2. C_LIO_LIPNSB enabled a high simultaneous removal of COD (96%), N (77%), and P (73%). C_LIO_LIRhodobacter, Rhodopseudomonas, and Blastochloris competed for acetate and photons. C_LI

bioengineering↗