Biology subjects

Goldstein, L.

Publications and source records attributed to Goldstein, L..

4 recordsLinked to original sources

bioRxiv2025

Molecular insights into phycobilisome assembly pathway reveal crystalline bodies in cyanobacteria

In oxygenic photosynthetic organisms, light energy is converted to chemical energy to drive CO2 fixation reactions and sustain life on Earth. Cyanobacteria contain phycobilisome (PBS) complexes that play critical roles in light harvesting and directing light energy to the photosystem I and II reaction centers. The proper assembly of PBS components is an intricate process that is required for their activity and association with photosystem I and II. To understand the complex mechanisms regulating the PBS assembly, we knocked out the terminal emitter apcE, which forms the structural scaffold for the PBS core. ApcE knockout led to growth and pigment defects, including elevated levels of photosystem II and abnormal emission spectra. Light microscopy experiments revealed the accumulation of highly fluorescent puncta localized to the pole of apcE knockout cells. Further investigation using electron cryo-tomography identified highly repetitive crystalline arrays of densely packed PBS cylinders. Together, these data indicate that cyanobacteria may accumulate PBS components in the form of highly organized crystalline bodies as intermediates during PBS assembly.

microbiology↗

bioRxiv2025

Robust Production of Parvalbumin Cortical Interneurons and Fast-Spiking Neurons from Human Medial Ganglionic Eminence Organoids

The medial ganglionic eminence (MGE) gives rise to parvalbumin (PV)-and somatostatin (SST)-expressing cortical interneurons essential for regulating cortical excitability. Although PV interneurons are linked to various neurodevelopmental and neurodegenerative disorders, reliably generating them from human pluripotent stem cells (hPSCs) has been extremely challenging. We present a robust, reproducible protocol for generating single-rosette MGE organoids (MGEOs) from hPSCs. Transcriptomic analyses reveal that MGEOs exhibit MGE regional identity and faithfully model the developing human fetal MGE. As MGEOs mature, they generate abundant PV-expressing cortical interneurons, including putative basket and axoaxonic cells, at a scale not previously achieved in vitro. When fused with human cortical organoids (hCOs), these interneurons rapidly migrate into the hCOs, integrate into excitatory networks, and contribute to complex electrophysiological patterns and the emergence of large numbers of fast-spiking neurons. Using this model, we uncover a previously unreported migration deficit of MGE interneurons in a disease model of SLC6A1 developmental and epileptic encephalopathy, offering potential insights into the developmental contributions to epileptogenesis. MGEOs thus offer a powerful in vitro approach for probing human MGE-lineage cortical and subcortical GABAergic neuron development, modeling various neuropsychiatric disorders, and advancing cell-based therapies for neurodevelopmental and neurodegenerative disorders. HighlightsO_LIGeneration of subpallial organoids highly enriched for MGE lineages C_LIO_LIMGE organoids (MGEOs) robustly produce parvalbumin-expressing cortical interneurons C_LIO_LIComplex network activity and fast-spiking neurons are generated in assembloids C_LIO_LIImpaired interneuron migration in SLC6A1 knockout and patient-derived MGEOs C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/662594v2_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1fce574org.highwire.dtl.DTLVardef@3c28d2org.highwire.dtl.DTLVardef@19bf737org.highwire.dtl.DTLVardef@834f2b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

A selective inhibitor of oncogenic JNK signalling perturbs metastatic outgrowth of triple-negative breast cancer through metabolic blockade

Although c-Jun N-terminal Kinase (JNK) represents an attractive anti-cancer target, its pleiotropic functionality limits the use of direct JNK inhibitors. Here, we identify a distinct subcellular pattern of JNK activity as a therapeutic vulnerability in breast cancer, where cytoplasmic JNK activity predicts poor survival outcomes, is elevated in triple-negative breast cancers (TNBC) and is essential for metastatic outgrowth. Mechanistic analyses reveal cytoplasmic JNK acts through multiple mechanisms, with downstream targets involved in cellular metabolism and cytoskeletal regulation. On this basis, we leveraged actin-based phenotypic drug-screening and identified K12, an indirect but selective inhibitor of cytoplasmic JNK that blocks TNBC metastatic outgrowth in vivo. We reveal that K12 inhibits glutaminase-1 and the pyruvate dehydrogenase complex, and that this poly-pharmacology overcomes pyruvate anaplerosis, a known resistance mechanism of existing glutaminase inhibitors. These findings demonstrate the potential of selectively targeting the oncogenic function of JNK, offering new treatment options for early-stage metastatic TNBC.

cancer biology↗

bioRxiv2019

Massively parallel single-cell B-cell receptor sequencing enables rapid discovery of diverse antigen-reactive antibodies

Using high-throughput single-cell B-cell receptor sequencing (scBCR-seq) we obtained accurately paired full-length heavy- and light-chain variable domains from thousands of individual B cells in a massively parallel fashion. We sequenced more than 250,000 B cells from rat, mouse and human repertoires to characterize their lineages and expansion. In addition, we immunized rats with chicken ovalbumin and profiled antigen-reactive B cells from lymph nodes of immunized animals. The scBCR-seq data recovered 81% (n = 56/69) of B-cell lineages identified from hybridomas generated from the same set of B cells that were subjected to scBCR-seq. Importantly, scBCR-seq identified an additional 710 candidate lineages that were not recovered as hybridomas. We synthesized, expressed and tested 93 clones from the identified lineages and found that 99% (n = 92/93) of the clones were antigen-reactive. Our results establish scBCR-seq as a powerful tool for antibody discovery.

immunology↗