Intermountain bunchgrass prairie is one of North America’s most endangered ecosystems, now covering less than 1 percent of the area it once did. Over the past century, bunchgrass prairies have become warmer and drier, and human-driven climate change is expected to continue that trend, with potential impacts on bunchgrass ecosystems. However, bunchgrass is often overlooked in studies of grasslands.

To better understand the effects of climate change on bunchgrass prairies, Belovsky and Slade studied the National Bison Range, a bunchgrass prairie in Montana, for 40 years. They made repeated observations of plant growth and production, abundances of different plant species, and availability of nitrogen (an important nutrient for plants), generating a comprehensive timeline of ecosystem changes.

Over the course of the study, annual temperatures rose and precipitation declined in the prairie, making it more susceptible to fire. Surprisingly, the researchers found that annual aboveground primary production — the amount of plant material produced every year — rose by 110 percent, associated with increased precipitation and cooler temperatures during the important growth period of late May through June. However, this was associated with a change in plant composition, with a 108 percent increase in invasive species, more drought-tolerant species being favored overall, and declines in dicot non-grass plants (decreasing by 65 percent) over the 40-year study period.

The researchers also found that other ecosystem changes followed seasonal climate trends, instead of annual trends. For instance, summer temperatures were higher than might be expected from annual trends, boosting summer senescence — the yearly “browning” of green plant material.

These findings highlight the importance of considering local and seasonal changes when forecasting the effects of climate change on a given ecosystem. The authors report that intermountain bunchgrass prairie could be morphing into a different type of grassland that may be previously unknown.

Dr. Belovsky adds: “Forecasting climate change effects on plant production based on expected average annual increased temperature and decreased precipitation may not be appropriate, because seasonal climate changes may be more important and may not follow average annual expectations.”

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Tsunamis are a relatively common event along the eastern Mediterranean coastline, with historical records and geographic data showing one tsunami occurring per century for the last six thousand years. The record for earlier tsunami events, however, is less defined. In this study, Shtienberg and colleagues describe a large early Holocene tsunami deposit (between 9,910 to 9,290 years ago) in coastal sediments at Tel Dor in northwest Israel, a maritime city-mound occupied from the Middle Bronze II period (2000-1550 BCE) through the Crusader period.

To conduct their analysis, the authors used photogrammetric remote sensing techniques to create a digital model of the Tel Dor site, combined with underwater excavation and terrestrial borehole drilling to a depth of nine meters.

Along the coast of the study area, the authors found an abrupt marine shell and sand layer with an age of constraint 9,910 to 9,290 years ago, in the middle of a large ancient wetland layer spanning from 15,000 to 7,800 years ago. The authors estimate the wave capable of depositing seashells and sand in the middle of what was at the time fresh to brackish wetland must have travelled 1.5 to 3.5 km, with a coastal wave height of 16 to 40 m. For comparison, previously documented tsunami events in the eastern Mediterranean have travelled inland only around 300 m — suggesting the tsunami at Dor was generated by a far stronger mechanism. Local tsunamis tend to arise due to earthquakes in the Dead Sea Fault system and submarine landslides; the authors note that an earthquake contemporary to the Dor paleo-tsunami (dating to around 10,000 years ago) has already been identified using cave damage in the nearby Carmel ridge, suggesting this specific earthquake could have triggered an underwater landslide causing the massive tsunami at Dor.

This paleo-tsunami would have occurred during the Early to Middle Pre-Pottery Neolithic B cultural period of the region (10,700-9,250 years ago 11,700-10,500 cal BP), and potentially wiped out evidence of previous Natufian (12,500-12,000 years ago) and Pre-Pottery Neolithic coastal villages (previous surveys and excavations show a near absence of low-lying coastal villages in this region). The re-appearance of abundant Late Neolithic archaeological sites (ca. 6,000 BCE) along the coast in the years after the Dor tsunami coincides with the resumption of wetland deposition in the Dor core samples and indicates resettlement followed the event — highlighting residents’ resilience in the face of massive disruption.

According to Gilad Shtienberg, a postdoc at the Scripps Center for Marine Archaeology at UC San Diego who is studying the sediment cores, “Our project focuses on reconstructing ancient climate and environmental change over the past 12,000 years along the Israeli coast; and we never dreamed of finding evidence of a prehistoric tsunami in Israel. Scholars know that at the beginning of the Neolithic, around 10,000 years ago, the seashore was 4 kilometers from where it is today. When we cut the cores open in San Diego and started seeing a marine shell layer embedded in the dry Neolithic landscape, we knew we hit the jackpot.”

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In a paper published in the December 23, 2020 online issue of Nature, researchers at University of California San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research, with colleagues in New York and the United Kingdom, describe how a phenomenon known as “chromothripsis” breaks up chromosomes, which then reassemble in ways that ultimately promote cancer cell growth.

Chromothripsis is a catastrophic mutational event in a cell’s history that involves massive rearrangement of its genome, as opposed to a gradual acquisition of rearrangements and mutations over time. Genomic rearrangement is a key characteristic of many cancers, allowing mutated cells to grow or grow faster, unaffected by anti-cancer therapies.

“These rearrangements can occur in a single step,” said first author Ofer Shoshani, PhD, a postdoctoral fellow in the lab of the paper’s co-senior author Don Cleveland, PhD, professor of medicine, neurosciences and cellular and molecular medicine at UC San Diego School of Medicine.

“During chromothripsis, a chromosome in a cell is shattered into many pieces, hundreds in some cases, followed by reassembly in a shuffled order. Some pieces get lost while others persist as extra-chromosomal DNA (ecDNA). Some of these ecDNA elements promote cancer cell growth and form minute-sized chromosomes called ‘double minutes.'”

Research published last year by scientists at the UC San Diego branch of the Ludwig Institute for Cancer Research found that up to half of all cancer cells in many types of cancers contain ecDNA carrying cancer-promoting genes.

In the latest study, Cleveland, Shoshani and colleagues employed direct visualization of chromosome structure to identify the steps in gene amplification and the mechanism underlying resistance to methotrexate, one of the earliest chemotherapy drugs and still widely used.

In collaboration with co-senior author Peter J. Campbell, PhD, head of cancer, aging and somatic mutation at Wellcome Sanger Institute in the United Kingdom, the team sequenced the entire genomes of cells developing drug resistance, revealing that chromosome shattering jump-starts formation of ecDNA-carrying genes that confer anti-cancer therapy resistance.

The scientists also identified how chromothripsis drives ecDNA formation after gene amplification inside a chromosome.

“Chromothripsis converts intra-chromosomal amplifications (internal) into extra-chromosomal (external) amplifications and that amplified ecDNA can then reintegrate into chromosomal locations in response to DNA damage from chemotherapy or radiotherapy,” said Shoshani. “The new work highlights the role of chromothripsis at all critical stages in the life cycle of amplified DNA in cancer cells, explaining how cancer cells can become more aggressive or drug-resistant.”

Said Cleveland: “Our identifications of repetitive DNA shattering as a driver of anti-cancer drug resistance and of DNA repair pathways necessary for reassembling the shattered chromosomal pieces has enabled rational design of combination drug therapies to prevent development of drug resistance in cancer patients, thereby improving their outcome.”

The findings address one of the so-called nine Grand Challenges for cancer therapy development, a joint partnership between the National Cancer Institute in the United States and Cancer Research UK, the world’s largest independent cancer research and awareness charity.

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The World Health Organization (WHO) has declared AMR as one of the top 10 global public health threats against humanity. It is estimated that by 2050, antibiotic-resistant infections could claim 10 million lives each year and impose a cumulative $100 trillion burden on the global economy. The list of bacteria that are becoming resistant to treatment with all available antibiotic options is growing and few new drugs are in the pipeline, creating a pressing need for new classes of antibiotics to prevent public health crises.

“We took a creative, double-pronged strategy to develop new molecules that can kill difficult-to-treat infections while enhancing the natural host immune response,” said Farokh Dotiwala, M.B.B.S., Ph.D., assistant professor in the Vaccine & Immunotherapy Center and lead author of the effort to identify a new generation of antimicrobials named dual-acting immuno-antibiotics (DAIAs).

Existing antibiotics target essential bacterial functions, including nucleic acid and protein synthesis, building of the cell membrane, and metabolic pathways. However, bacteria can acquire drug resistance by mutating the bacterial target the antibiotic is directed against, inactivating the drugs or pumping them out.

“We reasoned that harnessing the immune system to simultaneously attack bacteria on two different fronts makes it hard for them to develop resistance,” said Dotiwala.

He and colleagues focused on a metabolic pathway that is essential for most bacteria but absent in humans, making it an ideal target for antibiotic development. This pathway, called methyl-D-erythritol phosphate (MEP) or non-mevalonate pathway, is responsible for biosynthesis of isoprenoids — molecules required for cell survival in most pathogenic bacteria. The lab targeted the IspH enzyme, an essential enzyme in isoprenoid biosynthesis, as a way to block this pathway and kill the microbes. Given the broad presence of IspH in the bacterial world, this approach may target a wide range of bacteria.

Researchers used computer modeling to screen several million commercially available compounds for their ability to bind with the enzyme, and selected the most potent ones that inhibited IspH function as starting points for drug discovery.

Since previously available IspH inhibitors could not penetrate the bacterial cell wall, Dotiwala collaborated with Wistar’s medicinal chemist Joseph Salvino, Ph.D., professor in The Wistar Institute Cancer Center and a co-senior author on the study, to identify and synthesize novel IspH inhibitor molecules that were able to get inside the bacteria.

The team demonstrated that the IspH inhibitors stimulated the immune system with more potent bacterial killing activity and specificity than current best-in-class antibiotics when tested in vitro on clinical isolates of antibiotic-resistant bacteria, including a wide range of pathogenic gram negative and gram positive bacteria. In preclinical models of gram negative bacterial infection, the bactericidal effects of the IspH inhibitors outperformed traditional pan antibiotics. All compounds tested were shown to be nontoxic to human cells.

“Immune activation represents the second line of attack of the DAIA strategy,” said Kumar Singh, Ph.D., Dotiwala lab postdoctoral fellow and first author of the study.

“We believe this innovative DAIA strategy may represent a potential landmark in the world’s fight against AMR, creating a synergy between the direct killing ability of antibiotics and the natural power of the immune system,” echoed Dotiwala.

Work supported by: The G. Harold and Leila Y. Mathers Foundation, funds from the Commonwealth Universal Research Enhancement (CURE) Program and the Wistar Science Discovery Fund; The Pew Charitable Trusts supported Farokh Dotiwala with a Wistar Institute recruitment grant; Additional support was provided by the Adelson Medical Research Foundation and the Department of Defense. Support for The Wistar Institute facilities was provided by Cancer Center Support Grant P30 CA010815 and National Institutes of Health instrument grant S10 OD023586.

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