Sea ice fluctuations in the Baffin Bay and the Labrador Sea during glacial abrupt climate changes.

Sea ice decline in the North Atlantic and Nordic Seas has been proposed to contribute to the repeated abrupt atmospheric warmings recorded in Greenland ice cores during the last glacial period, known as Dansgaard-Oeschger (D-O) events. However, the understanding of how sea ice changes were coupled with abrupt climate changes during D-O events has remained incomplete due to a lack of suitable high-resolution sea ice proxy records from northwestern North Atlantic regions. Here, we present a subdecadal-scale bromine enrichment (Brenr) record from the NEEM ice core (Northwest Greenland) and sediment core biomarker records to reconstruct the variability of seasonal sea ice in the Baffin Bay and Labrador Sea over a suite of D-O events between 34 and 42 ka. Our results reveal repeated shifts between stable, multiyear sea ice (MYSI) conditions during cold stadials and unstable, seasonal sea ice conditions during warmer interstadials. The shift from stadial to interstadial sea ice conditions occurred rapidly and synchronously with the atmospheric warming over Greenland, while the amplitude of high-frequency sea ice fluctuations increased through interstadials. Our findings suggest that the rapid replacement of widespread MYSI with seasonal sea ice amplified the abrupt climate warming over the course of D-O events and highlight the role of feedbacks associated with late-interstadial seasonal sea ice expansion in driving the North Atlantic ocean-climate system back to stadial conditions.

Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis.

TDP-43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects. TDP-43 gain-of-function effects in these mice reveal a novel category of splicing events controlled by TDP-43, referred to as "skiptic" exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain-of-function mutation in endogenous Tardbp causes an adult-onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain-of-function and skiptic exons in ALS patient-derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP-43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.

Bartonella in Rodents and Ectoparasites in the Canary Islands, Spain: New Insights into Host-Vector-Pathogen Relationships.

Bartonella genus is comprised of several species of zoonotic relevance and rodents are reservoirs for some of these Bartonella species. As there were no data about the range of Bartonella species circulating among rodents in the Canary Islands, our main aim was to overcome this lack of knowledge by targeting both the citrate synthase (gltA) and the RNA polymerase beta subunit (rpoB) genes. A total of 181 small mammals and 154 ectoparasites were obtained in three of the Canary Islands, namely Tenerife, La Palma, and Lanzarote. The overall prevalence of Bartonella DNA in rodents was 18.8%, whereas the prevalence in ectoparasites was 13.6%. Bartonella sequences closely related to the zoonotic species Bartonella elizabethae, Bartonella tribocorum, and Bartonella rochalimae were identified in rodents, whereas two different gltA haplotypes similar to B. elizabethae were also detected in fleas. Furthermore, Bartonella queenslandensis DNA was also identified in rodents. A strong host specificity was observed, since B. elizabethae DNA was only found in Mus musculus domesticus, whereas gltA and rpoB sequences closely related to the rest of Bartonella species were only identified in Rattus rattus, which is probably due to the host specificity of the arthropod species that act as vectors in these islands. Our results indicate that humans may contract Bartonella infection by contact with rodents in the Canary Islands.

Erratum: Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.

[This corrects the article DOI: 10.1016/j.isci.2021.103463.].

Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.

Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context.