Synthetic Hinge Could Hold Key to Revolutionary “Smart” Insulin Therapy (Medicine)

For people with diabetes who are insulin dependent, glycemic control is a full-time job. But what if their medication could do the work for them—an insulin whose activity in the bloodstream responds to the blood glucose levels and adjusts accordingly? An invention from Indiana University School of Medicine Distinguished Professor Michael A. Weiss, MD, PhD, could lead to just that.

In a breakthrough study published in the peer-reviewed journal PNAS, Weiss and his team describe the use of a synthetic “switch” that can be opened or closed using a simple sugar sensor. The study was in part collaborative with Thermalin, Inc., a small biotech company that Weiss began in 2008.

Their concept exploits a natural mechanism, designated the “protective hinge,” that is built into vertebrate insulins. The protective hinge is a natural structural feature that evolved more than half a billion years ago to keep the hormone stable in its closed state but foldable and functional in its open state.

“The reason a glucose-responsive insulin is important is that the biggest barrier to the effective use of insulin, especially in Type 1 diabetes, is the fear of the consequences of blood sugar going too low,” said Weiss, who is also the Chair of the Department of Biochemistry and Molecular Biology.

Immediate consequences of severely low blood sugar (hypoglycemia) can include delirium, convulsions or loss of consciousness, and repeated episodes of severe hypoglycemia can cause cognitive decline. On the other hand, chronic high blood sugar (hyperglycemia) can lead to blindness, stroke or amputation. Staying in the desired blood glucose range is a delicate balance that insulin-dependent diabetics face every day.

But Weiss said that he envisions a future when people do not have to choose to risk their long-term health to protect themselves from the immediate dangers of severe hypoglycemia.

Image credit Balamurugan Dhayalan, PhD, and Deepak Chatterjee, PhD
Indiana University School of Medicine

“The promise of this kind of ‘smart’ insulin is that it would transform diabetes care, so people wouldn’t have to worry anymore,” said Weiss. “With our invention, we envision that when the blood sugar goes low, the hinge would close. But there will be much work to do to translate our proof of principle to an FDA-approved product.”

In the 100 years since the discovery of insulin, its use as a treatment for diabetes has gone through many significant changes. C. Ronald Kahn, MD, chief academic officer at the Joslin Diabetes Center at Harvard Medical School, said that glucose-responsive insulin could be the next.

“In the recent study from the Weiss laboratory appearing in PNAS, we see an example of the next exciting phase of insulin development, namely development of an insulin analogue which through chemical modification can sense the level of sugar present in the blood,” said Kahn.  “While the current analogue has been designed to sense fructose, it seems likely that this same approach can be used to develop analogues to sense glucose.  Whether these can be sensitive enough to be modulated by changes within the physiological range remains to be determined, but if so, this would be an important new tool in the management of diabetes.”

Other types of glucose-responsive insulins are being developed elsewhere. What makes Weiss’ invention unique is its simplicity. The synthetic hinge exploits naturally occurring processes and introduces fewer external or artificial elements compared to other approaches.

While their study uses fructose as model (representative of a monosaccharide like glucose), it proves that Weiss’ synthetic hinge concept works. His team is already working on glucose-responsive insulin candidates that open and close at the desired high and low glucose thresholds, which are respectively 70 to 180 milligrams per deciliter. By replacing the fructose sensor with glucose sensors, a revolutionary insulin therapy may be closer than we think.

The above referenced study is titled “Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone–receptor activation.” Contributing authors include Yen-Shan Chen, PhD, Yanwu Yang, PhD, Balamurugan Dhayalan, PhD, Mark A. Jarosinski, PhD, and Deepak Chatterjee, PhD, from Indiana University; Nelson B. Phillips, PhD, from Case Western Reserve University; Jeremy Gleaton, PhD, Yule Liu, PhD, Laurie Broadwater, PhD, Thomas Hattier, PhD, and M. Dodson Michael, PhD, from Thermalin, Inc; and Michael C. Lawrence from the University of Melbourne.

This work is supported in part by grants from the JDRF, the Leona M. and Harry B. Helmsley Charitable Trust, and the National Institutes of Health (R01 DK040949 and R01 DK127761).

Featured image: Michael Weiss, MD, PhD © Indiana University School of Medicine

Reference: Yen-Shan Chen et al, Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone–receptor activation, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2103518118

Provided by Indiana University School of Medicine

Retina ‘Hardwired’ to Predict Path of Moving Objects (Neuroscience)

Finding helps explain how baseball players can connect with a 100-mph fastball and how the rest of us manage everyday tasks.

Neural circuits in the primate retina can generate the information needed to predict the path of a moving object before visual signals even leave the eye, UW Medicine researchers demonstrate in a new paper.

“The ability to predict where moving objects will go is so important for survival that it’s likely hardwired into all sighted animals,” said Michael Manookin, an assistant professor of ophthalmology at the University of Washington School of Medicine. He led the research team with Fred Rieke, professor of physiology and biophysics. 

Manookin and his colleagues report their findings in the journal Nature Neuroscience.  Belle Liu and Arthur Hong, two UW undergraduate students, were the lead authors on the paper.

In the study, the researchers looked at how motion was processed by cellular circuits in the retina. The circuits the researchers focused on are composed of light-sensing photoreceptor cells, called cones; an intermediate layer of cells, called bipolar cells; and ganglion cells that collect signals from bipolar cells and transmit these signals out of the eye to other brain regions. 

Professor Michael Manookin works at a confocal microscope.
Professor Michael Manookin works at a confocal microscope. © Washington University

These circuits are made up of scores of hundreds of photoreceptor cells that connect to dozens of bipolar cells that, in turn, connect to ganglion cells, Manookin said. “The signals from the cones converge on the bipolar cells and the signals from bipolar cells converge onto a single ganglion cell, which has to extract motion information from these signals and relay that information to brain regions tasked with processing motion.” 

To understand how this was done, the researchers projected patterns that appeared to be moving away from, and toward, the retina and recorded the signals being generated by the ganglion cells in response to the movements.

They then analyzed the signals to see if the ganglion cells were generating what is called “predictive motion encoding” – that is, patterns that reflect information that could be used to predict the future motion of an object. 

“For example, if you present a movie of a ball moving across the visual field, you can record the spikes coming from the ganglion cell in response to that movie,” Manookin explains. “Then you can calculate how much information the spikes contain about where the ball is likely to be in the future.” 

To evaluate how effectively the cells were transmitting predictive information, the researchers compared the performance of the ganglion cells to computer programs created to solve such problems. They found that the ganglion cells were nearly as effective at transmitting this predictive information as the best performing computer programs.  

“That the retina, with such simple hardware, is doing these calculations so efficiently is just remarkable,” Manookin said.

The researchers found that the circuits can extract this information because of crosstalk between the bipolar cells. Bipolar cells are in close contact with adjacent bipolar cells. If one becomes excited by signals from its photoreceptor cells, in addition to sending a signal to the ganglion cell, it also passes some of that excitement along to its neighboring bipolar cells. 

The neighboring cells are then “primed” so that, if they also receive signals from their photoreceptor cells, they are more likely to send a strong signal to the ganglion cell. In this way, as a moving object passes over the visual field, the information about that movement “ripples” through the network of bipolar cells.

The ganglion cell ultimately collects the incoming information from the bipolar cells and encodes it in signals that provides the brain with information about the motion of the object. With information from many thousands of these ganglion cells about the path of the object, the brain can then quickly predict its trajectory.

“A 90 or 100 mile per hour fastball can travel more than seven feet before the signals gets out of your retina,” Manookin said. “To hit the baseball, you have to be able to predict where it will be in the future. This ability to predict the movement of objects in our environment is also needed in everyday activities like driving a car or even walking. It’s an ability so important to survival that evolution has hardwired it into our nervous system.”

Ultimately, this knowledge of how the retina processes information can be used to develop technologies for restoring meaningful vision to people suffering from blindness, Manookin said.

This work was supported in part the U.S. National Eye Institute (NEI RO1-EY027323, R01-EY029247, R01-EY028542, P30-EY001730), the Taiwanese Ministry of Science and Technology (108-2813-C-007-085-B), and the Taiwanese Ministry of Education. Tissue was provided by the Tissue Distribution Program at the Washington Primate Research Center (National Institutes of Health grant P51 OD-010425).

Featured image: To hit a baseball, your eyes and brain work in concert to predict its path. © Getty Images

Reference: Liu, B. et al, Predictive encoding of motion begins in the primate retina, Nat Neurosci (2021). DOI: 10.1038/s41593-021-00899-1

Provided by University of Washington

Cryptic Transcription in Mammalian Stem Cells Linked to Aging (Biology)

Although visible signs of aging are usually unmistakable, unraveling what triggers them has been quite a challenge. Researchers at Baylor College of Medicine and collaborating institutions have discovered that a cellular phenomenon called cryptic transcription, which had been previously described and linked to aging in yeasts and worms, is elevated in aging mammalian stem cells.

The team reports in the journal Nature Aging that cryptic transcription occurs because a cellular mechanism that keeps it in check falls apart as cells get old. The findings suggest that strategies that control cryptic transcription could have pro-longevity effects.

“In previous work, we showed that cryptic transcription in yeasts and worms is not only a marker of aging but also a cause,” said corresponding author Dr. Weiwei Dang, assistant professor of molecular and human genetics and the Huffington Center on Aging at Baylor. “Reducing the amount of this aberrant transcription in these organisms prolonged their lifespan.”

Cryptic transcription is a phenomenon that interferes with normal cellular processes. Normal gene transcription is a first step in the production of proteins. It begins in a specific location on the DNA called the promoter. This is where the protein coding gene begins to be transcribed into RNA, which is eventually translated into protein. Gene transcription is a well-regulated
cellular process, but as cells age, they lose their ability to control it.

“Promoters have a specific DNA sequence that identifies the starting point of the transcription process that is usually located preceding the actual protein coding sequence,” explained Dang. “But promoter look-alike sequences do exist in other locations, including along the actual protein coding sequence, and they could start transcription and generate shorter transcripts, called cryptic transcripts. Here we investigated whether cryptic transcription increased with age in mammals and potential mechanisms involved in this phenomenon.”

The team worked with mammalian stem cells, which have shown to play a significant role in aging. They adapted a method to detect cryptic transcription to determine the level of this transcription in mice and human stem cells and cultured cells. When compared to young stem cells, older ones had increased cryptic transcription. They also looked into other aging cells and found that, in the majority of cells spanning a range of tissues, cryptic transcription was also elevated with age.

“Altogether, our findings indicate that elevated cryptic transcription is a hallmark of mammalian aging,” Dang said.

Young cells have mechanisms in place to prevent cryptic transcription. In aged mammalian cells, the researchers found that one such mechanisms, which involves limiting the access to chromatin, the material that makes up the chromosomes, is failing, facilitating the production of cryptic transcripts.

“It is still not clear how elevated cryptic transcription contributes to aging, but the evidence is accumulating that it is detrimental to mammals as it is for yeast and worms,” Dang said. “Future studies may result in ways of reduce the pro-aging effects of cryptic transcription.”

Other contributors to this work include Brenna S. McCauley, Luyang Sun, Ruofan Yu, Minjung Lee, Haiying Liu, Dena S. Leeman, Yun Huang and Ashley E. Webb. The authors are associated with one or more of the following institutions: Baylor College of Medicine, Texas A&M University, University of Texas MD Anderson Cancer Center, Stanford University, Genentech and Brown University.

This work was funded by NIH grants R01AG052507, R01AG053268, R01HL134780, R01HL146852 and T32AG000183; CPRIT award R1306 and a Ted Nash Long Life Foundation research grant.

Reference: McCauley, B.S., Sun, L., Yu, R. et al. Altered chromatin states drive cryptic transcription in aging mammalian stem cells. Nat Aging (2021).

Provided by BCM

Imagined Music And Silence Trigger Similar Brain Activity (Neuroscience)

Imagining a song triggers similar brain activity as moments of silence in music, according to a pair of studies recently published in JNeurosci. The results reveal how the brain continues responding to music, even when none is playing.null

When we listen to music, the brain attempts to predict what comes next. A surprise, such as a loud note or disharmonious chord, increases brain activity. Yet it is difficult to isolate the brain’s prediction signal because it also responds to the actual sensory experience.

Di Liberto, Marion, and Shamma used EEG to measure the brain activity of musicians while they listened to or imagined Bach piano melodies. Activity while imagining music had the opposite polarity of activity while listening to music, meaning when one was positive, the other was negative. The same type of activity occurred in silent moments of the songs when statistically there could have been a note, but there wasn’t.

There is no sensory input during silence and imagined music, so this activity comes from the brain’s predictions. The research team also decoded the brain activity to determine which song someone was imagining.

The researchers find music is more than a sensory experience for the brain. Instead, the brain keeps making predictions even when music is not playing.

Featured image: Silence and imagined music triggered brain activity with an inverted polarity to activity from listening to music. Credit: Di Liberto, Marion, and Shamma, JNeurosci 2021

Reference: The Music of Silence. Part I: Responses to Musical Imagery Encode Melodic Expectations, JNeurosci (2021). DOI: 10.1523/JNEUROSCI.0183-21.2021

Provided by Society for Neuroscience

Indometacin Is More Effective In Treating COVID-19 Than Paracetamol (Medicine)

A randomized clinical trial, recently conducted by Dr. Rajan Ravichandran and colleagues on the safety and efficacy of NSAID Indometacin, revealed that it is not only safe but also very effective drug which can be used for the treatment of COVID-19 patients. Their study recently appeared in MedRxiv.

Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. 

Now, Dr. Rajan Ravichandran and colleagues conducted a randomized clinical trial at Panimalar Medical College, Chennai, India in order to test the efficacy and safety of Indometacin in RT-PCR positive covid patients.

“Our primary aim is to understand the efficacy of indomethacin in preventing desaturation and deterioration in mild and moderate Covid-19 patients and compare this with a paracetamol based arm. While, secondary aim is to evaluate symptomatic relief in indometacin patients compared to patients on paracetamol.”

— they said.

They recruited a total of 300 patients using a block randomization parallel group protocol after obtaining the Ethics Committee clearance and consent from the patients. Finally, they presented results for 210 patients with 102 in the indomethacin arm and 108 in the paracetamol arm.

Fig.1 Profile of the recruited patients © Rajan Ravichandran et al.

They found that, no patients developed hypoxia/desaturation in the indomethacin arm, while nearly 20 per cent of the patients in the paracetamol arm developed desaturation.

“When the SpO2 level dips below 93, the patient is managed with low-flow oxygen or by placing him/her in prone position to enhance breathing. In this study, no one showed further deterioration.”

— they said.

The noticeable point is that in the indomethacin arm, the SpO2 improved just after one or two doses. Many patients in the marginal level of 94 improved.

At the end of the seventh day, a further 13 patients in the paracetamol arm were at a SpO2 level of 94. In the indomethacin arm, only two patients had a SpO2 levels of 94, while 97 of the 102 patients recorded an SpO2 level higher than 97.

Additionally, the symptomatic relief is even more salient. The median time for becoming afebrile in the indomethacin arm was three days compared to seven in the paracetamol arm. The median time for cough reduction was four days in the indomethacin arm compared to seven in the case of the paracetamol arm. In fact, 59 out of 108 patients in the paracetamol arm had fever on the seventh day but none in the indomethacin arm. Forty-nine out of 75 patients taking paracetamol took seven or more days to recover from cough. Only nine out of 70 patients took seven days and beyond in the indomethacin arm.

“The median time for becoming afebrile, cough reduction and myalgia relief in the indomethacin arm was four and three and four days respectively. On the other hand, in the paracetamol arm, the median time was seven and eight and seven days, respectively.”

— they said.

One of the most important conclusion comes from analysing the IQR. One can notice in figs 2a to 2e, a very thin IQR band for fever and cough reduction along with a small error bar, compared to paracetamol. This clearly shows that indomethacin acts independent of the patient profile. A marginally broader IQR brand in myalgia may be because of the subjective nature of the relief.

Figure 2 © Rajan Ravichandran et al.

They also monitored CRP, a marker of inflammation, on admission and discharge and found that, indomethacin is very effective in reducing CRP in patients with higher CRP in admission (more than 41 mg/L). R² value for indomethacin was much higher at 0.85, compared to 0.1. One may, hence, conclude that the consistency of indomethacin in reducing inflammation is very high.

Figure 3. Number of patients desaturated © Rajan Ravichandran et al.

A fourteen-day follow-up further reveals the efficacy of the drug. In the indomethacin arm nearly 50 per cent had fully recovered compared to 28 % in the paracetamol arm. The only complaint by patients who took indomethacin was tiredness. Many of these patients had gone back to normal work, too. While, the paracetamol arm patients had several discomfort including myalgia, joint pain and tiredness.

“The use of Indomethacin, alongside the standard treatment protocol in hospitalised Covid-19 patients, was associated with marked symptomatic relief and the oxygen saturation level being maintained at a high level. There were no adverse effects. Indomethacin, instead of paracetamol, should be a preferred drug for the treatment of mild and moderate Covid-19 patients.”

— they concluded.

Reference: Rajan Ravichandran, Surapaneni Krishna Mohan, Suresh Kumar Sukumaran, Devakumar Kamaraj, Sumetha Suga Daivasuga, Samson Oliver Abraham Samuel Ravi, Sivakumar Vijayaraghavalu, Ramarathnam Krishna Kumar, “Use of Indomethacin for mild and moderate Covid -19 patients A Randomized Control Trial”, medRxiv 2021.07.24.21261007; doi:

Note for editors of other websites: To reuse this article fully or partially kindly give credit either to our author/editor S. Aman or provide a link of our article

Learning Foreign Languages Can Affect The Processing Of Music in the Brain (Neuroscience)

Research has shown that a music-related hobby boosts language skills and affects the processing of speech in the brain. According to a new study, the reverse also happens – learning foreign languages can affect the processing of music in the brain.

Research Director Mari Tervaniemi from the University of Helsinki’s Faculty of Educational Sciences  investigated, in cooperation with researchers from the Beijing Normal University (BNU)  and the University of Turku, the link in the brain between language acquisition and music processing in Chinese elementary school pupils aged 8–11 by monitoring, for one school year, children who attended a music training programme and a similar programme for the English language. Brain responses associated with auditory processing were measured in the children before and after the programmes. Tervaniemi compared the results to those of children who attended other training programmes.

“The results demonstrated that both the music and the language programme had an impact on the neural processing of auditory signals,” Tervaniemi says. 

Learning achievements extend from language acquisition to music 

Surprisingly, attendance in the English training programme enhanced the processing of musically relevant sounds, particularly in terms of pitch processing. 

“A possible explanation for the finding is the language background of the children, as understanding Chinese, which is a tonal language, is largely based on the perception of pitch, which potentially equipped the study subjects with the ability to utilise precisely that trait when learning new things. That’s why attending the language training programme facilitated the early neural auditory processes more than the musical training.”

Tervaniemi says that the results support the notion that musical and linguistic brain functions are closely linked in the developing brain. Both music and language acquisition modulate auditory perception. However, whether they produce similar or different results in the developing brain of school-age children has not been systematically investigated in prior studies. 

At the beginning of the training programmes, the number of children studied using electroencephalogram (EEG) recordings was 120, of whom more than 80 also took part in EEG recordings a year later, after the programme.

In the music training, the children had the opportunity to sing a lot: they were taught to sing from both hand signs and sheet music. The language training programme emphasised the combination of spoken and written English, that is, simultaneous learning. At the same time, the English language employs an orthography that is different from Chinese. The one-hour programme sessions were held twice a week after school on school premises throughout the school year, with roughly 20 children and two teachers attending at a time. 

“In both programmes the children liked the content of the lessons which was very interactive and had many means to support communication between the children and the teacher” says Professor Sha Tao who led the study in Beijing. 

The article entitled Improved auditory functions caused by music versus foreign-language training at school age – is there a difference? was recently published in the esteemed Cerebral Cortex journal. 

Authors of the article: Tervaniemi, M., Putkinen, V., Nie, P., Wang, C., Du, B., Lu, J., Li, S., Cowley, B., Tammi, T., Tao, S. Cerebral Cortex. 

Featured image: Children attending the after school music club. (Image: Mari Tervaniemi)

Provided by University of Helsinki

New Evidence Shows the COVID-19 Delta Variant Rapidly Rising (Biology)

The University’s coronavirus sequencing effort uncovered that there are several variants present in its patient population, but Delta is chief among them and easily transmitted. And its presence is likely triggering a local surge in the infectious disease.

Dr. Andrews
Andrews © University of Miami

University of Miami researchers and physicians are seeing firsthand how rapidly the Delta variant of COVID-19 is spreading through the local population.

While just a month ago University researchers had identified just two cases of the Delta variant in Miami-Dade County, new sequencing data from the second week of July reveals that 63 percent of a sampling of COVID-19 patients in Jackson Memorial Health System and at University of Miami’s UHealth Tower had the highly transmissible form of the virus. This sequencing data also revealed that 20 percent of patients had the Brazilian variant (now known as Gamma), 9 percent had the Colombian variant (B.1.621), which is dominating that country, and 3 percent had the Lambda variant that is currently the dominant COVID-19 strain in Peru.

“The Colombian variant and the Lambda variant share many of the properties of the other bad players we have seen emerging—like Delta—such as increased transmissibility and a potential to escape the immunity provided by vaccines,” said Dr. David Andrews, associate professor in the Department of Pathology and Laboratory Medicine, who is leading the University’s effort to sequence COVID-19 positive samples.

Research assistants Marissa Brooks and Yoslayma Cardentey review sequencing results produced by the NovoSeq instrument at the Sylvester Comprehensive Cancer Center Onco-Genomics Shared Resource.
Research assistants Marissa Brooks and Yoslayma Cardentey review sequencing results produced by the NovoSeq instrument at the Sylvester Comprehensive Cancer Center Onco-Genomics Shared Resource. © University of Miami

Dr. Lilian Abbo, a professor in the Miller School of Medicine’s Division of Infectious Diseases, said the data affirms recent case spikes she has noticed at Jackson Memorial Hospital, but suspects that the number of patients with the Delta variant today is much higher. In short order, the Delta variant has permeated the United States, pushing the nation into another COVID-19 surge, particularly among the unvaccinated. It now accounts for at least 83 percent of COVID-19 cases nationally, the U.S. Centers for Disease Control and Prevention (CDC) estimated last week.

“I’m seeing a more than 350 percent increase in COVID-19 hospitalizations,” said Abbo, who is also chief of infection prevention and microbial stewardship at Jackson Memorial Health System. “At Jackson Memorial Hospital, I suspect we are seeing more than 80 percent Delta already.”

Andrews, who gathered a team this past January to sequence COVID-19 samples, agreed.

“It’s obvious to me we will be at 80 to 90 percent Delta by next week,” said Andrews, who is also vice chief of pathology for Jackson Health System.

Since the Delta variant is much more easily transmitted than earlier variants, the Miller School is ramping up its sequencing efforts and will now be gathering samples weekly to survey the variants circulating locally, according to Andrews. While the Florida Department of Health is doing some COVID-19 sequencing that they share with the CDC, reports indicate that only 2,688 positive COVID-19 samples have been sequenced in Florida since the pandemic began, or about 0.1 percent of cases.

Through the sequencing process, researchers can determine the genetic origins of each positive COVID-19 sample, but the process is time-consuming and costly. So, only a fraction of the samples is sequenced. University researchers want to contribute to the effort to monitor the variants in South Florida because this knowledge could help guide medical treatment. Andrews is also working with researchers at the Miller School to develop a rapid test that could determine if a positive COVID-19 sample contains the Delta variant.

Meanwhile, Abbo is observing the severity of the Delta variant firsthand. She said that in UHealth and Jackson Health System urgent care clinics, Jackson Health System emergency rooms, hospitals, and the correctional facilities, she is seeing a spike in COVID-19 positive rates. She attributes this to the more contagious Delta variant, along with people working closely together at the tragic building collapse in Surfside, many gathering for massive demonstrations in support of protesters in Cuba, and the Miami heat keeping residents indoors.

Abbo © University of Miami

As an example of the Delta variant’s contagious nature, Abbo cited a recent study out of China where researchers swabbed COVID-19 patients with the Delta variant and found that the amount of virus in each sample was on average 1,000 times higher than the original Wuhan strain of COVID-19. “Therefore, the Delta variant is highly infectious and infected people are spreading a lot more virus,” she warned.

Abbo also described the type of COVID-19 patients she is seeing at Jackson Health System’s three hospitals. First of all, Abbo noted, 90 percent of them are unvaccinated. And of those in the intensive care unit, 95 percent are unvaccinated. She has also noticed that this summer’s COVID-19 patients are typically younger than those infected before and often fall within the age range of 30 to 60.

“Vaccinated people with good immune systems are typically able to neutralize the virus, so they aren’t getting as sick as people who are not vaccinated,” she said. “But we are also noticing that unvaccinated people with the Delta variant seem to deteriorate much faster, even with treatment.”

However, in what are called breakthrough cases, people who are vaccinated are still able to get COVID-19, particularly the Delta variant. Even though most of these people are not hospitalized, up to 15 percent of the COVID-19 cases in Miami-Dade County now are breakthrough cases, according to  a Miami-Dade division of the Florida Department of Health report. While only about 10 percent of the COVID-19 patients in Jackson Health System are vaccinated, Abbo explained that these patients are typically elderly, immunocompromised, diabetic, or have another preexisting medical condition.

All of the unfortunate outcomes she is seeing right now point to one solution, Abbo said. “For anyone right now who is not vaccinated, I urge you to go and get vaccinated and believe in science,” she urged. “We need to control the pandemic and we will be able to control it with science and by taking responsible actions.”

Abbo also pointed out that she is seeing reinfection cases among unvaccinated young adults who had COVID-19 once. Because previous infection is not providing a lasting immunity in most people who had “mild COVID-19″ before, it is extremely important to get vaccinated because it is the most powerful form of protection for everyone and prevents severe disease or death, she added.

According to the CDC, Miami-Dade County is now at 12.6 percent positivity rate for COVID-19 and Broward County is at 14.8 percent. The Florida Department of Health reports that last week 73,199 Floridians were infected with COVID-19. Of those, 9.5 percent of COVID-19 cases were found in children younger than 12 and 19.6 percent of the state’s caseload contains people younger than 19 years old. Adults between 20 and 49 made up the bulk of the COVID-19 cases, or 53 percent. Just 14 percent of cases occurred in people older than 60.

For South Florida’s entire population—vaccinated or not—Abbo recommends wearing a mask any time you are indoors and not at home. She also suggests dining outdoors only at restaurants and avoiding crowded, cramped settings like bars.

“We are at very high numbers of infection in our community, and you can no longer trust who is vaccinated or not,” she said. “Everyone is infected until proven otherwise.”

Featured image: More than 73,000 new coronavirus cases were reported in Florida over the previous week, according to the Florida Department of Health. Photo: The Associated Press

Reference: Baisheng Li et al. “Viral infection and transmission in a large well-traced outbreak caused by the Delta SARS-CoV-2 variant”, 2021. Link to paper

Provided by University of Miami Health System, Miller School of Medicine

Physicists Show That a Quantum Particle Made of Light and Matter Can Be Dragged by a Current of Electrons (Physics)

A pair of studies in Nature show that a quasiparticle, known as a plasmon polariton, can be pulled with and against a flow of electrons, a finding that could lead to more efficient ways of manipulating light at the nanoscale.

Light was thought to move at a fixed rate until 1851, when a French physicist—the first to accurately clock the speed of light—showed it could also be slowed or accelerated simply by shining a light beam with or against the flow of moving water. Decades later, Einstein seized on Hippolyte Fizeau’s landmark water-pipe experiments in developing his theory of relativity.

Now, new research in Nature shows that a quasiparticle made of waves of photons and electrons—a plasmon polariton—has a similar ability to change speeds when immersed in an electrical current flowing through a sheet of graphene. But there’s a hitch: the polaritons appear to more easily shift gears in one direction—to a slightly slower speed—when traveling against the flow of electrons.

The finding is a big deal for plasmonics, a field with a rock-star name dedicated to finding new and efficient ways of controlling light down at the nearly invisible scale of individual atoms—for optical computing, nanolasers, and other applications, including imprinting patterns into semiconductors. Polaritons have two perks. Their relatively slow speed compared to photons makes them a good proxy for manipulating light. Polariton waves are also minuscule; dozens can squeeze into the wavelength of one photon.

Dmitri Basov, a physics professor at Columbia, has devoted most of his lab to studying their behavior. “Polaritons possess the best virtues of electrons and photons,” he said. “They’re compact but still quantum, which means they can be manipulated on ultra-fast time scales.”   

Illustration of polariton waves interacting with drifting electrons in a sheet of graphene.
In this illustration, a set of polariton waves (at left), interact with drifting electrons in a sheet of graphene. The warped fabric of space-time (upper left) represents the related concept of relativity. Credit: Yinan Dong, Denis Bandurin, and Ella Maru Studio

In the recent Nature study, Basov and his colleagues recreated Fizeau’s experiments on a speck of graphene made up of a single layer of carbon atoms. Hooking up the graphene to a battery, they created an electrical current reminiscent of Fizeau’s water streaming through a pipe. But instead of shining light on the moving water and measuring its speed in both directions, as Fizeau did, they generated an electromagnetic wave with a compressed wavelength—a polariton—by focusing infrared light on a gold nub in the graphene. The activated stream of polaritons look like light but are physically more compact due to their short wavelengths.

The researchers clocked the polaritons’ speed in both directions. When they traveled with the flow of the electrical current, they maintained their original speed. But when launched against the current, they slowed by a few percentage points.

An Unexpected Result

“We were surprised when we saw it,” said study co-author Denis Bandurin, a physics researcher at MIT. “First, the device was still alive, despite the heavy current we passed through it—it hadn’t blown up. Then we noticed the one-way effect, which was different from Fizeau’s original experiments.”

The researchers repeated the experiments over and over, led by the study’s first-author, Yinan Dong, a Columbia graduate student. Finally, it dawned on them. “Graphene is a material that turns electrons into relativistic particles,” Dong said. “We needed to account for their spectrum.”

A group at Berkeley Lab found a similar result, published in the same issue of Nature. Beyond reproducing the Fizeau effect in graphene, both studies have practical applications. Most natural systems are symmetric, but here, researchers found an intriguing exception. Basov said he hopes to slow down, and ultimately, cut off the flow of polaritons in one direction. It’s not an easy task, but it could hold big rewards.

“Engineering a system with a one-way flow of light is very difficult to achieve,” said Milan Delor, a physical chemist working on light-matter interactions at Columbia who was not involved in the research. “As soon as you can control the speed and direction of polaritons, you can transmit information in nanoscale circuits on ultrafast timescales. It’s one of the ingredients currently missing in photon-based circuits.”

An invitation to a lecture series at Columbia in 1906, which helped to popularize the work of physicist Hippolyte Fizeau and his discovery that light can move at different speeds.
A lecture series at Columbia in 1906 helped to popularize the work of physicist Hippolyte Fizeau, which included his discovery that light can move at different speeds. © Columbia University

Optical isolators are currently used to limit the bounce-back of light in everything from lasers to the fiber optic cables in broadband. But they’re bulky and incompatible with modern nanocircuits, making polaritons, with their potential to be shut off in one direction, so appealing.

Plasmonics researchers are also excited about the detailed images to come out of the experiments. They show that polaritons can serve as nanoscale probes, they said, triggering and recording electron-electron interactions in a system. This information provides clues about how graphene and other quantum materials will behave in the real world.

“The images are effectively a read-out of the material properties of graphene,” Delor said.

‘The Enablers of Nanoptics’

“I like to call polaritons the enablers of nanoptics,” says James Schuck, a mechanical engineer and plasmonics researcher at Columbia Engineering who was not involved in the work. “They’re useful for probing all sorts of materials at the nanoscale.”

Most of the experiments were done during the pandemic; the researchers wore masks and gloves and disinfected the lab after each visit. “There was no slow-down for quantum physics,” says Basov, with a laugh, evoking Fizeau.

The French physicist’s name was later inscribed on the Eiffel Tower; not for the effect that bears his name, but for precisely measuring the speed of light. Fizeau’s work was popularized in a lecture series at Columbia in 1906, as Basov likes to remind students. Fizeau was also an early photographic experimenter. Some of his ghostly daguerreotype views of the rooftops of Paris are held by The Metropolitan Museum of Art, not far from the Columbia campus.

Featured image: Columbia University graduate students Lin Xiong (left) and Yinan Dong image polaritons using a cryogenic microscope. (Credit: Yinan Dong)

Reference: Dong, Y., Xiong, L., Phinney, I.Y. et al. Fizeau drag in graphene plasmonics. Nature 594, 513–516 (2021).

Provided by Columbia University

Researchers Uncover a Way to Harness the Power of Immunotherapy for Advanced Prostate Cancer (Medicine)

It’s a scientific riddle tangled up in a complex web. How do you turn an immune cold cancer into one that responds to immunotherapy?

Researchers led by the University of Michigan Rogel Cancer Center started with a simple thread: an inhibitor that showed promise against metastatic castration-resistant prostate cancer cells. This is the most challenging type of prostate cancer – advanced disease that has become resistant to hormone-based treatment.

From there, they continued to untangle the web to discover multiple levels of cellular processes that were preventing the immune system from mounting a response. Break past them with this inhibitor and suddenly what’s considered an immune cold tumor turns red hot.

Immunotherapy has dramatically improved outcomes for some types of cancer. But prostate cancers are typically immune cold, which means these patients have benefited little from immunotherapies. Finding a way to rev up the immune response would create tremendous opportunity to improve patient outcomes,” says Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine. Chinnaiyan is senior author of the paper published in Nature Cancer.

Researchers started by screening a library of 167 inhibitors against prostate cancer cells. They found one, ESK981, had the most impact.

ESK981 is a class of drugs called multi-tyrosine kinase inhibitors, which are designed to hit multiple targets. This means it functions like a combination therapy, able to block cancer on more than one front. It was originally developed to check blood vessel growth and has already been tested in phase 1 clinical trials, which found it to be safe and well-tolerated.

In cell lines and mice with metastatic castration-resistant prostate cancer, researchers found ESK981 inhibited tumor growth.

“The response was intriguing, but we wanted to understand the mechanism at play with ESK981 in prostate cancer cells,” Chinnaiyan says.

They discovered several cellular processes were occurring. First was the role of a type of cell death called autophagy. The authors surprisingly found that ESK981 was a potent inhibitor of autophagy in tumor cells. This caused the cancer cells to produce a protein called CXCL10, which led to recruitment of immune T cells to the tumor.

But there was one more layer to go. Ultimately, they traced it back to PIKfyve, a type of protein called a lipid kinase. The authors discovered that ESK981 directly targets PIKfyve, affecting these multiple processes involved in metabolism and cell death.

The researchers confirmed this by knocking down PIKfyve in cell lines and mice. They saw the same processes occur: tumors stopped growing, autophagy was controlled and more T cells were recruited to the tumor. When they added an immune checkpoint inhibitor to the PIKfyve knockdown, the impact was even greater, significantly reducing tumors.

“Overcoming resistance to immunotherapy is an urgent need in prostate cancer. PIKfyve is a promising target, especially combined with an immune checkpoint inhibitor. This combination has potential to extend the benefit of immunotherapy to patients whose tumors have previously not responded,” Chinnaiyan says.

Based on these findings, researchers have begun phase 2 clinical trials using ESK981 alone or in combination with the immunotherapy nivolumab for metastatic castration-resistant prostate cancer.

Additional authors: Yuanyuan Qiao, Jae Eun Choi, Jean C. Tien, Stephanie A. Simko, Thekkelnaycke Rajendiran, Josh N. Vo, Andrew D. Delekta, Lisha Wang, Lanbo Xiao, Nathan B. Hodge, Parth Desai, Sergio Mendoza, Kristin Juckette, Alice Xu, Tanu Soni, Fengyun Su, Rui Wang, Xuhong Cao, Jiali Yu, Ilona Kryczek, Xiao-Ming Wang, Xiaoju Wang, Javed Siddiqui, Zhen Wang, Amelie Bernard, Ester Fernandez-Salas, Nora M. Navone, Stephanie J. Ellison, Ke Ding, Eeva-Liisa Eskelinen, Elisabeth I. Heath, Daniel J. Klionsky, Weiping Zou

Funding: Prostate Cancer Foundation Challenge Award, National Cancer Institute Prostate SPORE Grant P50CA186786, Department of Defense grant PC130151P1, National Institutes of Health grant GM131919.

In addition, individual researchers are supported by NCI grant R35CA231996, Howard Hughes Medical Institute, A. Alfred Taubman Institute, American Cancer Society, PCF Young Investigator Awards, DoD Postdoctoral Award W81XWH-16-1-0195, and the Academy of Finland.

Disclosure: The University of Michigan has filed a disclosure on the findings based on this study. Chinnaiyan and Qiao are named as co-inventors. Esanik Therapeutics Inc. licensed ESK981 from Teva Pharmaceuticals. Chinnaiyan is a co-founder and serves on the scientific advisory board of Esanik Therapeutics Inc. Esanik Therapeutics or Teva Pharmaceuticals were not involved in the design or approval of this study, nor was this study funded by them.

Featured image: Researchers in the Chinnaiyan Lab © Credit: University of Michigan Rogel Cancer Center

Paper cited: “Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer,” Nature Cancer. DOI: 10.1038/s43018-021-00237-1

Provided by University of Michigan