Monica L. Salgado-Lucio, Danelia Ramirez-Ramirez, Coral Y. Jorge-Cruz, Ana L. Roa-Espitia, and Enrique O. Hernandez-Gonzalez

Actin polymerization is a crucial process during sperm capacitation. We have recently described the participation of FAK during actin polymerization in guinea pig spermatozoa. However, the mechanism by which FAK mediates these processes is unknown. Our previous data have shown that MAPK1 (hereafter referred to as ERK2) is activated during the first minutes of capacitation, and inhibition of ERK2 blocked actin polymerization and the acrosome reaction. In this current study, we found that FAK is involved in ERK2 activation – as FAK was phosphorylated at tyrosine residue 925 and bound to Grb2 – and that inhibition of FAK results in a significant decrease of ERK2 activation. We also confirmed the presence of Rho guanine nucleotide exchange factor 2 (ARHGEF2, hereafter referred to as GEF-H1), which is able to associate with RhoA during capacitation. RhoA activation and its participation in actin polymerization were also analyzed. Inhibition of FAK or ERK1/2 impeded GEF-H1 phosphorylation, RhoA activation, and the association between GEF-H1 and RhoA. Finally, we observed the presence of fibronectin on the sperm surface, its role in sperm–sperm interaction as well as participation of β-integrin in the activation of ERK2. Our results show that the signaling pathway downstream of fibronectin, via integrin, FAK, Grb2, MEK1/2, ERK2, GEF-H1 and RhoA regulates the actin polymerization associated with spermatozoa capacitation.

When nutrients become scarce, bacteria can enter an extended state of quiescence. A major challenge of this state is how to preserve ribosomes for the return to favorable conditions. Here, we show that the ribosome dimerization protein hibernation-promoting factor (HPF) functions to protect essential ribosomal proteins. Ribosomes isolated from strains lacking HPF (hpf) or encoding a mutant allele of HPF that binds the ribosome but does not mediate dimerization were substantially depleted of the small subunit proteins S2 and S3. Strikingly, these proteins are located directly at the ribosome dimer interface. We used single-particle cryo-electron microscopy (cryo-EM) to further characterize these ribosomes and observed that a high percentage of ribosomes were missing S2, S3, or both. These data support a model in which the ribosome dimerization activity of HPF evolved to protect labile proteins that are essential for ribosome function. HPF is almost universally conserved in bacteria, and HPF deletions in diverse species exhibit decreased viability during starvation. Our data provide mechanistic insight into this phenotype and establish a mechanism for how HPF protects ribosomes during quiescence.

IMPORTANCE The formation of ribosome dimers during periods of dormancy is widespread among bacteria. Dimerization is typically mediated by a single protein, hibernation-promoting factor (HPF). Bacteria lacking HPF exhibit strong defects in viability and pathogenesis and, in some species, extreme loss of rRNA. The mechanistic basis of these phenotypes has not been determined. Here, we report that HPF from the Gram-positive bacterium Bacillus subtilis preserves ribosomes by preventing the loss of essential ribosomal proteins at the dimer interface. This protection may explain phenotypes associated with the loss of HPF, since ribosome protection would aid survival during nutrient limitation and impart a strong selective advantage when the bacterial cell rapidly reinitiates growth in the presence of sufficient nutrients.

Mutation and translocation of fibroblast growth factor receptors often lead to aberrant signaling and cancer. This work focuses on the t(8;22)(p11;q11) chromosomal translocation which creates the breakpoint cluster region (BCR) fibroblast growth factor receptor1 (FGFR1) (BCR-FGFR1) fusion protein. This fusion occurs in stem cell leukemia/lymphoma, which can progress to atypical chronic myeloid leukemia, acute myeloid leukemia, or B-cell lymphoma. This work focuses on the biochemical characterization of BCR-FGFR1 and identification of novel therapeutic targets. The tyrosine kinase activity of FGFR1 is required for biological activity as shown using transformation assays, interleukin-3 independent cell proliferation, and liquid chromatography/mass spectroscopy analyses. Furthermore, BCR contributes a coiled-coil oligomerization domain, also essential for oncogenic transformation by BCR-FGFR1. The importance of salt bridge formation within the coiled-coil domain is demonstrated, as disruption of three salt bridges abrogates cellular transforming ability. Lastly, BCR-FGFR1 acts as a client of the chaperonin heat shock protein 90 (Hsp90), suggesting that BCR-FGFR1 relies on Hsp90 complex to evade proteasomal degradation. Transformed cells expressing BCR-FGFR1 are sensitive to the Hsp90 inhibitor Ganetespib, and also respond to combined treatment with Ganetespib plus the FGFR inhibitor BGJ398. Collectively, these data suggest novel therapeutic approaches for future stem cell leukemia/lymphoma treatment: inhibition of BCR oligomerization by disruption of required salt bridges; and inhibition of the chaperonin Hsp90 complex.

Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease (SCD) may provide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lacking. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T lymphocytes, monocytes, granulocytes and red blood cells (RBC). Thirty-four patients with mixed chimerism and ≥12 months of follow-up were included. A selective advantage of donor RBC and their progenitors/precursors led to full chimerism in mature RBC (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism <50% had hemolysis (reticulocytosis) and higher HbS than their donor. Four of them had donor chimerism <30%, including a patient with AA donor (hemoglobin >10 g/dL) and three with AS donors (hemoglobin <10 g/dL). However, only one vaso-occlusive crisis occurred with 68.7% HbS. Except in the patients with the lowest chimerism, the donor engraftment was lower for T cells than for the other lineages. In a context of mixed chimerism after hematopoietic stem cell transplantation for SCD, myeloid (rather than T cell) engraftment was the key efficacy criterion. Results show that myeloid chimerism as low as 30% was sufficient to prevent a vaso-occlusive crisis in transplants from an AA donor but not constantly from an AS donor. However, the correction of hemolysis requires higher donor chimerism levels (i.e. ≥50%) in both AA and AS recipients. In the future, this group of patients may need a different therapeutic approach.

Background:

Asian Americans are at higher risk for noncardia gastric cancers (NCGC) relative to non-Hispanic Whites (NHW). Asian Americans are genetically, linguistically, and culturally heterogeneous, yet have mostly been treated as a single population in prior studies. This aggregation may obscure important subgroup-specific cancer patterns.

The 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Score was developed to establish a simple, standardized scoring system for researchers to quantify adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations and assess its impact on cancer risk and other health-related outcomes. The aim of this commentary is to clarify potential points of ambiguity in its application, focusing on aspects related to specific subscore components (physical activity, fast foods, alcohol, and sugar-sweetened drinks), how to address different data needs due to varied data collection instruments, and future exploratory score approaches. Overall, we encourage researchers to utilize the standardized score to enhance comparability across populations and countries. Researchers who may adapt or augment the 2018 WCRF/AICR Score are strongly encouraged to provide detailed descriptions of their methods to promote transparency and reproducibility.

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07–1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer.Significance:The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.

Will Flynn be the right wing's Nelson Mandela? Of course that's insulting - but so is this entire presidency

New labor economy data paints a fuller - and bleaker - picture of the economy.

Hindsight is 20/20, even if you’re smizing.

A new national U.S. survey finds that nearly 80 percent of respondents would be concerned about themselves or an expectant mother in their life in the midst of the current COVID-19 outbreak, with almost half expressing fear of going to a scheduled prenatal appointment.

The remains of three slaves found in Mexico contain the earliest signs of the hepatitis B virus and yaws bacteria in the Americas, suggesting transatlantic slavery introduced these diseases

Lucianne Walkowicz says the American Girl doll 'Luciana Vega' stole her name and likeness

The U.S. space agency selected Blue Origin, SpaceX, and Dynetics as contenders to design and manufacture the next moon-landing spacecraft.

The Simpsons officials have yet to respond to The Weeknd's public proposal.

The bee species has been under the looming threat of...

The post Bee-Killing Murder Hornets Have Somehow Landed In America For The First Time appeared first on Man's World India.

America can take its next steps toward reopening by placing an emphasis on emerging health data and closely examining how early states are performing, Housing and Urban Development Secretary Dr. Ben Carson asserted Saturday.

It’s been 180 years since Charles Wilkes voyaged to the Antarctic continent and his journey has never been more relevant

Past public health crises inspired innovations in infrastructure, education, fundraising and civic debate

Fossil teeth uncovered in Peru reveal that an extinct family of primates, thought to have lived only in Africa, made it across the ocean

A new study of ancient climate has a dire warning about today's dry conditions

Meet the hugely influential polymath, who foretold of climate change and inspired artists, writers and even the founder of the Smithsonian

(This May 7 story changes monthly to weekly in paragraph 35)

"You can use a scarf," the US Leader said as he addressed the demand for face masks. "A lot of people have scarves... scarves would be very good.

With elite sport across the globe on pause due to the coronavirus pandemic, Americans are turning to competitive eating to fill the void.

The US coronavirus death toll has now exceeded the 58,220 American lives lost during the Vietnam War, as cases in the country topped one million.

American astronauts will be back on the Moon within five years "by any means necessary," the US Vice President has announced.

Twin sisters Nishita and Atisha Lulla talk about recording a previous single in Mumbai, the country-folk influence and more

The post Indo-American Sister Duo LULLANAS Drop Debut EP ‘Before Everything Got Real’ appeared first on My Site.

Map-makers insert fake towns or trap-streets to catch out plagiarists, but Agloe, in New York state, took on a strange life of its own

In 2008, Argleton village in west Lancashire appeared on Google, complete with weather reports, a job site and an estate agent advertising houses for sale. Argleton vanished two years later. While its site was – and still is – a damp field in the middle of nowhere, it’s worth noting that Argleton is an anagram of G Not Real. Although Google never admitted to having created it, Argleton was a phantom settlement, planted as a trap.

In the world of digital mapping and cartography, snares to catch unwary plagiarists take the form of fake roads or places, known as “trap streets” or “paper towns”. For some, such as Lye Close or Noereal Road, the clue is in the name. (A real alleyway in Cardiff that served as a trap street in the 2014 Dr Who episode Face the Raven may, conversely, be the world’s only fictional fictional street.)

Tom Tomorrow

The post Reopening America Is Only Safe in Trump’s Dreams appeared first on The Nation.

Corey Robin

The post The Inner Life of American Communism appeared first on The Nation.

Based on evidence provided by customer receipts, the investigation confirmed that the pricing of several food items exceeded the 10-per cent increase allowed during a state of emergency, with some prices being as much as 200 per cent more.

Phyllis Schlafly was motivated by her family, not a hunger for power. She was politically involved because of her desire for her children to succeed.

A trio of Senate Democrats wants to give $2,000 per month to individuals through the end of the health emergency. One Senate Republican suggests covering payroll for companies that rehire workers.

Canada has backed an American-led effort to allow Taiwan to be granted observer status at the World Health Organization because of its early success in containing COVID-19.

Tyra Banks agrees that America's Next Top Model has aged, well, poorly. The Sports Illustrated covergirl and host of ANTM came under fire this week when resurfaced clips from the...

Immigrants in the U.S. sent an estimated $150 billion to their home countries in 2019 — half to Latin America and the Caribbean. The World Bank is predicting a sharp decline in remittances this year.

The latest news and information on the pandemic from Yahoo News reporters in the United States and around the world.

The unfavorable comparison between the current president and his predecessor is one of the clearest signs to date of an emerging dynamic that will define the remainder of Trump’s term and the presidential election.

Modern dating techniques are providing new time frames for indigenous settlements in Northeast North America, free from the Eurocentric bias that previously led to incorrect assumptions.

Live shows will begin this month

TV host dedicated an episode of her show to virus's deadly toll on black America

'Do you want your freedom or Covid-19? Because you're going to end up with both'

It's unknown which of its many stars will play show's iconic figure