Researchers convert female mosquitoes to nonbiting males with implications for mosquito control

Mosquito biting skin

Virginia Tech researchers have proven that a single gene can convert female Aedes aegypti mosquitoes into fertile male mosquitoes and identified a gene needed for male mosquito flight.

Male mosquitoes do not bite and are unable to transmit pathogens to humans. Female mosquitoes, on the other hand, are able to bite.

Female Aedes aegypti mosquitoes require blood to produce eggs, making them the prime carriers of the pathogens that cause Zika and dengue fever in humans.

"The presence of a male-determining locus (M locus) establishes the male sex in Aedes aegypti and the M locus is only inherited by the male offspring, much like the human Y chromosome," said Zhijian Tu, a professor in the Department of Biochemistry in the College of Agriculture and Life Sciences.

"By inserting Nix, a previously discovered male-determining gene in the M locus of Aedes aegypti, into a chromosomal region that can be inherited by females, we showed that Nix alone was sufficient to convert females to fertile males. This may have implications for developing future mosquito control techniques."

These findings were published in the Proceedings of the National Academy of Sciences.

"We also discovered that a second gene, named myo-sex, was needed for male flight. This work sheds light into the molecular basis of the function of the M locus, which contains at least 30 genes," said Azadeh Aryan, a research scientist in Tu's lab and the first author on the paper.

Aryan and colleagues generated and characterized multiple transgenic mosquito lines that expressed an extra copy of the Nix gene under the control of its own promoter. Maria Sharakhova, an assistant professor of entomology in the College of Agriculture and Life Sciences, and Anastasia Naumencko, a former graduate research assistant, mapped the chromosomal insertion site of the extra copy of Nix.

The Virginia Tech team, in collaboration with Zach Adelman's lab in the Department of Entomology at Texas A&M University and Chunhong Mao of the Biocomplexity Institute & Initiative at the University of Virginia, found that the Nix transgene alone, even without the M locus, was sufficient to convert females into males with male-specific sexually dimorphic features and male-like gene expression.

"Nix-mediated sex conversion was found to be highly penetrant and stable over many generations in the laboratory, meaning that these characteristics will be inherited for generations to come," said Michelle Anderson, a former member of the Adelman and Tu labs and currently a senior research scientist at the Pirbright Institute in the United Kingdom.

Although the Nix gene was able to convert the females into males, the converted males could not fly as they did not inherit the myo-sex gene, which is also located in the M locus.

Knocking out myo-sex in wild-type males confirmed that the lack of myo-sex in the sex-converted males is the reason why they could not fly. Although flight is needed for mating, the sex-converted males were still able to father viable sex-converted progeny when presented with cold-anesthetized wild-type females.

"Nix has great potential for developing mosquito control strategies to reduce vector populations through female-to-male sex conversion, or to aid in the Sterile Insect Technique, which requires releasing only nonbiting males," said James Biedler, a research scientist in the Tu lab.

Genetic methods that rely on mating to control mosquitoes target only one specific species. In this case, the Tu team is targeting Aedes aegypti, a species that invaded the Americas a few hundred years ago and poses a threat to humans.

Lab-made virus mimics COVID-19 virus

Laboratory researcher

Airborne and potentially deadly, the virus that causes COVID-19 can only be studied safely under high-level biosafety conditions. Scientists handling the infectious virus must wear full-body biohazard suits with pressurized respirators, and work inside laboratories with multiple containment levels and specialized ventilation systems. While necessary to protect laboratory workers, these safety precautions slow down efforts to find drugs and vaccines for COVID-19 since many scientists lack access to the required biosafety facilities.

To help remedy that, researchers at Washington University School of Medicine in St. Louis have developed a hybrid virus that will enable more scientists to enter the fight against the pandemic. The researchers genetically modified a mild virus by swapping one of its genes for one from SARS-CoV-2, the virus that causes COVID-19. The resulting hybrid virus infects cells and is recognized by antibodies just like SARS-CoV-2, but can be handled under ordinary laboratory safety conditions.

The study is available online in Cell Host & Microbe.

"I've never had this many requests for a scientific material in such a short period of time," said co-senior author Sean Whelan, PhD, the Marvin A. Brennecke Distinguished Professor and head of the Department of Molecular Microbiology. "We've distributed the virus to researchers in Argentina, Brazil, Mexico, Canada and, of course, all over the U.S. We have requests pending from the U.K. and Germany. Even before we published, people heard that we were working on this and started requesting the material."

To create a model of SARS-CoV-2 that would be safer to handle, Whelan and colleagues -- including co-senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine, and co-first authors Brett Case, PhD, a postdoctoral researcher in Diamond's laboratory, and Paul W. Rothlauf, a graduate student in Whelan's laboratory -- started with vesicular stomatitis virus (VSV). This virus is a workhorse of virology labs because it is fairly innocuous and easy to manipulate genetically. Primarily a virus of cattle, horses and pigs, VSV occasionally infects people, causing a mild flu-like illness that lasts three to five days.

Viruses have proteins on their surfaces that they use to latch onto and infect cells. The researchers removed VSV's surface-protein gene and replaced it with the one from SARS-CoV-2, known as spike. The switch created a new virus that targets cells like SARS-CoV-2 but lacks the other genes needed to cause severe disease. They dubbed the hybrid virus VSV-SARS-CoV-2.

Using serum from COVID-19 survivors and purified antibodies, the researchers showed that the hybrid virus was recognized by antibodies very much like a real SARS-CoV-2 virus that came from a COVID-19 patient. Antibodies or sera that prevented the hybrid virus from infecting cells also blocked the real SARS-CoV-2 virus from doing so; antibodies or sera that failed to stop the hybrid virus also failed to deter the real SARS-CoV-2. In addition, a decoy molecule was equally effective at misdirecting both viruses and preventing them from infecting cells.

"Humans certainly develop antibodies against other SARS-CoV-2 proteins, but it's the antibodies against spike that seem to be most important for protection," Whelan said. "So as long as a virus has the spike protein, it looks to the human immune system like SARS-CoV-2, for all intents and purposes."

The hybrid virus could help scientists evaluate a range of antibody-based preventives and treatments for COVID-19. The virus could be used to assess whether an experimental vaccine elicits neutralizing antibodies, to measure whether a COVID-19 survivor carries enough neutralizing antibodies to donate plasma to COVID-19 patients, or to identify antibodies with the potential to be developed into antiviral drugs.

"One of the problems in evaluating neutralizing antibodies is that a lot of these tests require a BSL-3 facility, and most clinical labs and companies don't have BSL-3 facilities," said Diamond, who is also a professor of molecular microbiology, and of pathology and immunology. "With this surrogate virus, you can take serum, plasma or antibodies and do high-throughput analyses at BSL-2 levels, which every lab has, without a risk of getting infected. And we know that it correlates almost perfectly with the data we get from bona fide infectious SARS-CoV-2."

Since the hybrid virus looks like SARS-CoV-2 to the immune system but does not cause severe disease, it is a potential vaccine candidate, Diamond added. He, Whelan and colleagues are conducting animal studies to evaluate the possibility.

How COVID-19 causes smell loss

Coronavirus illustration

Temporary loss of smell, or anosmia, is the main neurological symptom and one of the earliest and most commonly reported indicators of COVID-19. Studies suggest it better predicts the disease than other well-known symptoms such as fever and cough, but the underlying mechanisms for loss of smell in patients with COVID-19 have been unclear.

Now, an international team of researchers led by neuroscientists at Harvard Medical School has identified the olfactory cell types most vulnerable to infection by SARS-CoV-2, the virus that causes COVID-19.

Surprisingly, sensory neurons that detect and transmit the sense of smell to the brain are not among the vulnerable cell types.

Reporting in Science Advances on July 24, the research team found that olfactory sensory neurons do not express the gene that encodes the ACE2 receptor protein, which SARS-CoV-2 uses to enter human cells. Instead, ACE2 is expressed in cells that provide metabolic and structural support to olfactory sensory neurons, as well as certain populations of stem cells and blood vessel cells.

The findings suggest that infection of nonneuronal cell types may be responsible for anosmia in COVID-19 patients and help inform efforts to better understand the progression of the disease.

"Our findings indicate that the novel coronavirus changes the sense of smell in patients not by directly infecting neurons but by affecting the function of supporting cells," said senior study author Sandeep Robert Datta, associate professor of neurobiology in the Blavatnik Institute at HMS.

This implies that in most cases, SARS-CoV-2 infection is unlikely to permanently damage olfactory neural circuits and lead to persistent anosmia, Datta added, a condition that is associated with a variety of mental and social health issues, particularly depression and anxiety.

"I think it's good news, because once the infection clears, olfactory neurons don't appear to need to be replaced or rebuilt from scratch," he said. "But we need more data and a better understanding of the underlying mechanisms to confirm this conclusion."

A majority of COVID-19 patients experience some level of anosmia, most often temporary, according to emerging data. Analyses of electronic health records indicate that COVID-19 patients are 27 times more likely to have smell loss but are only around 2.2 to 2.6 times more likely to have fever, cough or respiratory difficulty, compared to patients without COVID-19.

Some studies have hinted that anosmia in COVID-19 differs from anosmia caused by other viral infections, including by other coronaviruses.

For example, COVID-19 patients typically recover their sense of smell over the course of weeks -- much faster than the months it can take to recover from anosmia caused by a subset of viral infections known to directly damage olfactory sensory neurons. In addition, many viruses cause temporary loss of smell by triggering upper respiratory issues such as stuffy nose. Some COVID-19 patients, however, experience anosmia without any nasal obstruction.

Pinpointing vulnerability

In the current study, Datta and colleagues set out to better understand how sense of smell is altered in COVID-19 patients by pinpointing cell types most vulnerable to SARS-CoV-2 infection.

They began by analyzing existing single-cell sequencing datasets that in total catalogued the genes expressed by hundreds of thousands of individual cells in the upper nasal cavities of humans, mice and nonhuman primates.

The team focused on the gene ACE2, widely found in cells of the human respiratory tract, which encodes the main receptor protein that SARS-CoV-2 targets to gain entry into human cells. They also looked at another gene, TMPRSS2, which encodes an enzyme thought to be important for SARS-CoV-2 entry into the cell.

The analyses revealed that both ACE2 and TMPRSS2 are expressed by cells in the olfactory epithelium -- a specialized tissue in the roof of the nasal cavity responsible for odor detection that houses olfactory sensory neurons and a variety of supporting cells.

Neither gene, however, was expressed by olfactory sensory neurons. By contrast, these neurons did express genes associated with the ability of other coronaviruses to enter cells.

The researchers found that two specific cell types in the olfactory epithelium expressed ACE2 at similar levels to what has been observed in cells of the lower respiratory tract, the most common targets of SARS-CoV-2, suggesting a vulnerability to infection.

These included sustentacular cells, which wrap around sensory neurons and are thought to provide structural and metabolic support, and basal cells, which act as stem cells that regenerate the olfactory epithelium after damage. The presence of proteins encoded by both genes in these cells was confirmed by immunostaining.

In additional experiments, the researchers found that olfactory epithelium stem cells expressed ACE2 protein at higher levels after artificially induced damage, compared with resting stem cells. This may suggest additional SARS-CoV-2 vulnerability, but it remains unclear whether or how this is important to the clinical course of anosmia in patients with COVID-19, the authors said.

Datta and colleagues also analyzed gene expression in nearly 50,000 individual cells in the mouse olfactory bulb, the structure in the forebrain that receives signals from olfactory sensory neurons and is responsible for initial odor processing.

Neurons in the olfactory bulb did not express ACE2. The gene and associated protein were present only in blood vessel cells, particularly pericytes, which are involved in blood pressure regulation, blood-brain barrier maintenance and inflammatory responses. No cell types in the olfactory bulb expressed the TMPRSS2 gene.

Smell loss clue

Together, these data suggest that COVID-19-related anosmia may arise from a temporary loss of function of supporting cells in the olfactory epithelium, which indirectly causes changes to olfactory sensory neurons, the authors said.

"We don't fully understand what those changes are yet, however," Datta said. "Sustentacular cells have largely been ignored, and it looks like we need to pay attention to them, similar to how we have a growing appreciation of the critical role that glial cells play in the brain."

The findings also offer intriguing clues into COVID-19-associated neurological issues. The observations are consistent with hypotheses that SARS-CoV-2 does not directly infect neurons but may instead interfere with brain function by affecting vascular cells in the nervous system, the authors said. This requires further investigation to verify, they added.

The study results now help accelerate efforts to better understand smell loss in patients with COVID-19, which could in turn lead to treatments for anosmia and the development of improved smell-based diagnostics for the disease.

"Anosmia seems like a curious phenomenon, but it can be devastating for the small fraction of people in whom it's persistent," Datta said. "It can have serious psychological consequences and could be a major public health problem if we have a growing population with permanent loss of smell."

The team also hope the data can help pave inroads for questions on disease progression such as whether the nose acts as a reservoir for SARS-CoV-2. Such efforts will require studies in facilities that allow experiments with live coronavirus and analyses of human autopsy data, the authors said, which are still difficult to come by. However, the collaborative spirit of pandemic-era scientific research calls for optimism.

"We initiated this work because my lab had a couple of datasets ready to analyze when the pandemic hit, and we published an initial preprint," Datta said. "What happened after that was amazing, researchers across the globe offered to share and merge their data with us in a kind of impromptu global consortium. This was a real collaborative achievement."

New connection between the eyes and touch discovered

Closeup of eye

Tiny eye movements can be used as an index of humans' ability to anticipate relevant information in the environment independent of the information's sensory modality, a team of scientists has found. The work reveals a connection between eye movements and the sense of touch.

"The fact that tiny eye movements can hinder our ability to discriminate tactile stimuli, and that the suppression of those eye movements before an anticipated tactile stimulus can enhance that same ability, may reflect that common brain areas, as well as common neural and cognitive resources, underlie both eye movements and the processing of tactile stimuli," explains Marisa Carrasco, a professor of psychology and neural science at New York University and the senior author of the paper, which appears in the latest issue of the journal Nature Communications.

"This connection between the eyes and touch reveals a surprising link across perception, cognition, and action," adds Stephanie Badde, an NYU post-doctoral researcher and first author of the paper.

The study asked human participants to distinguish between two kinds of vibrations ("fast" -- high frequency vs. "slow" -- low frequency) that were produced by a device connected to their finger. The researchers then tracked even the tiniest of their involuntary eye movements, known as micro-saccades. These small, rapid eye-movements are known to occur even when we try to fixate our gaze on one spot. Here, participants were instructed to focus their vision on a fixation spot on a computer screen. A cue -- a tap elicited by the device at their finger -- would announce the next imminent vibration. What the participants did not know is that the time interval between that cue and the tactile vibration was a central part of the experimental design.

The manipulation of that interval allowed participants in some blocks to predict with more accuracy precisely when the vibration would happen. Notably, when they had that precise information, the researchers could see not only how the participants' microsaccade rates would decrease just before the vibration stimulus, but also how their ability to distinguish between fast and slow vibrations was enhanced by the suppression of micro-saccades.

Like humans, beluga whales form social networks beyond family ties

Beluga whales 

A groundbreaking study using molecular genetic techniques and field studies brings together decades of research into the complex relationships among beluga whales (Delphinapterus leucas) that spans 10 locations across the Arctic from Alaska to Canada and Russia to Norway. The behavior of these highly gregarious whales, which include sophisticated vocal repertoires, suggest that this marine mammal lives in complex societies. Like killer whales (Orcinus orca) and African elephants (Loxodonta Africana), belugas were thought to form social bonds around females that primarily comprise closely related individuals from the same maternal lineage. However, this hypothesis had not been formally tested.

The study, led by Florida Atlantic University's Harbor Branch Oceanographic Institute, is the first to analyze the relationship between group behaviors, group type, group dynamics, and kinship in beluga whales. Findings, just published in Scientific Reports, reveal several unexpected results. Not only do beluga whales regularly interact with close kin, including close maternal kin, they also frequently associate with more distantly related and unrelated individuals.

Findings indicate that evolutionary explanations for group living and cooperation in beluga whales must expand beyond strict inclusive fitness arguments to include other evolutionary mechanisms. Belugas likely form multi-scale societies from mother-calf dyads to entire communities. From these perspectives, beluga communities have similarities to human societies where social networks, support structures, cooperation and cultures involve interactions between kin and non-kin. Given their long lifespan (approximately 70 years) and tendency to remain within their natal community, these findings reveal that beluga whales may form long-term affiliations with unrelated as well as related individuals.

"This research will improve our understanding of why some species are social, how individuals learn from group members and how animal cultures emerge," said Greg O'Corry-Crowe, Ph.D., lead author and a research professor at FAU's Harbor Branch. "It also has implications for traditional explanations based on matrilineal care for a very rare life-history trait in nature, menopause, which has only been documented in a handful of mammals, including beluga whales and humans."

Researchers found that belugas formed a limited number of group types, from mother-calf dyads to adult male groups, and from mixed-age groups to large herds. These same group types were consistently observed across population and habitats. Furthermore, certain behaviors were associated with group type, and group membership was found to often be dynamic.

"Unlike killer and pilot whales, and like some human societies, beluga whales don't solely or even primarily interact and associate with close kin. Across a wide variety of habitats and among both migratory and resident populations, they form communities of individuals of all ages and both sexes that regularly number in the hundreds and possibly the thousands," said O'Corry-Crowe. "It may be that their highly developed vocal communication enables them to remain in regular acoustic contact with close relatives even when not associating together."

Beluga whale groupings (beyond mother-calf dyads) were not usually organized around close maternal relatives. The smaller social groups, as well as the larger herds, routinely comprised multiple matrilines. Even where group members shared the same mtDNA lineage, microsatellite analysis often revealed that they were not closely related, and many genealogical links among group members involved paternal rather than maternal relatives. These results differ from earlier predictions that belugas have a matrilineal social system of closely associating female relatives. They also differ from the association behavior of the larger toothed whales that informed those predictions. In 'resident' killer whales, for example, both males and females form groups with close maternal kin where they remain for their entire lives.

"Beluga whales exhibit a wide range of grouping patterns from small groups of two to 10 individuals to large herds of 2,000 or more, from apparently single sex and age-class pods to mixed-age and sex groupings, and from brief associations to multi-year affiliations," said O'Corry-Crowe. "This variation suggests a fission-fusion society where group composition and size are context-specific, but it may also reflect a more rigid multi-level society comprised of stable social units that regularly coalesce and separate. The role kinship plays in these groupings has been largely unknown."

Scientists propose plan to determine if Planet Nine is a primordial black hole

Black hole abstract 

Scientists at Harvard University and the Black Hole Initiative (BHI) have developed a new method to find black holes in the outer solar system, and along with it, determine once-and-for-all the true nature of the hypothesized Planet Nine. The paper, accepted to The Astrophysical Journal Letters, highlights the ability of the future Legacy Survey of Space and Time (LSST) mission to observe accretion flares, the presence of which could prove or rule out Planet Nine as a black hole.

Dr. Avi Loeb, Frank B. Baird Jr. Professor of Science at Harvard, and Amir Siraj, a Harvard undergraduate student, have developed the new method to search for black holes in the outer solar system, based on flares that result from the disruption of intercepted comets. The study suggests that the LSST has the capability to find black holes by observing for accretion flares resulting from the impact of small Oort cloud objects.

"In the vicinity of a black hole, small bodies that approach it will melt as a result of heating from the background accretion of gas from the interstellar medium onto the black hole," said Siraj. "Once they melt, the small bodies are subject to tidal disruption by the black hole, followed by accretion from the tidally disrupted body onto the black hole." Loeb added, "Because black holes are intrinsically dark, the radiation that matter emits on its way to the mouth of the black hole is our only way to illuminate this dark environment."

Future searches for primordial black holes could be informed by the new calculation. "This method can detect or rule out trapped planet-mass black holes out to the edge of the Oort cloud, or about a hundred thousand astronomical units," said Siraj. "It could be capable of placing new limits on the fraction of dark matter contained in primordial black holes."

The upcoming LSST is expected to have the sensitivity required to detect accretion flares, while current technology isn't able to do so without guidance. "LSST has a wide field of view, covering the entire sky again and again, and searching for transient flares," said Loeb. "Other telescopes are good at pointing at a known target but we do not know exactly where to look for Planet Nine. We only know the broad region in which it may reside." Siraj added, "LSST's ability to survey the sky twice per week is extremely valuable. In addition, its unprecedented depth will allow for the detection of flares resulting from relatively small impactors, which are more frequent than large ones."

The new paper focuses on the famed Planet Nine as a prime first candidate for detection. The subject of much speculation, most theories suggest that Planet Nine is a previously undetected planet, but it may also flag the existence of a planet-mass black hole.

"Planet Nine is a compelling explanation for the observed clustering of some objects beyond the orbit of Neptune. If the existence of Planet Nine is confirmed through a direct electromagnetic search, it will be the first detection of a new planet in the solar system in two centuries, not counting Pluto, said Siraj, adding that a failure to detect light from Planet Nine -- or other recent models, such as the suggestion to send probes to measure gravitational influence -- would make the black hole model intriguing. "There has been a great deal of speculation concerning alternative explanations for the anomalous orbits observed in the outer solar system. One of the ideas put forth was the possibility that Planet Nine could be a grapefruit-sized black hole with a mass of five to ten times that of the Earth."