Stories about: Science Seen

Science Seen: Using Twitter to map hospitals’ stance toward LGBT patients

Hswen Y et al. Social Science & Medicine Oct 2018. DOI: 10.1016/j.socscimed.2018.08.031  

How sensitive are hospitals to the needs of lesbian, gay, bisexual and transgender (LGBT) patients? In a 2010 survey by Lambda Legal, 70 percent of transgender patients and 56 percent of gay/lesbian/bisexual patients reported discrimination from health care providers. Clinicians refused to provide needed care, refused to touch them or used excessive precautions, blamed them for their health status, were verbally abusive or were physically violent.

A new exploratory study, published in the October issue of Social Science & Medicine, turned to social media for a view from the ground. The researchers, Yulin Hswen of Harvard T.H. Chan School of Public Health and Jared Hawkins, PhD, MMSc, of Boston Children’s Hospital’s Informatics Program, analyzed 1,856 publicly available tweets from 2015-2017.

“Information from social media and other online sources can help us gain authentic and unsolicited accounts from vulnerable patient groups, like LGBT individuals who are not typically represented,” says Hswen.

Based on the tweets, the team determined which hospitals were more supportive of LGBT patients (the blue dots in the above map) and which were less supportive (the red dots).

The identified tweets included Twitter handles from 653 hospitals and contained LGBT-related terms: LGBT, transgender, trans, intersex, sex change, transisbeautiful, tranny, drag queen, preferred pronoun, transhealth, genderodyssey, cis, gay, lesbian, queer, rainbowhealth, gender fluid, homosexual, bisexual, homo, homophob and transphobe. A tweet classed as supportive might read, “@Hospital is hosting a LGBT resource fair;” a negative tweet might read: “Having sex with men does not mean I deserve less @Hospital.”

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Sounding out the protein that enables us to hear

The proposed structure of the TMC1 protein (not to scale), superimposed over rows of hair cells in the mouse inner ear. The yellow portions indicate the amino acid substitutions used to identify the location of the pore that admits ions into the cell. (CREDIT: Bifeng Pan et al., Neuron 2018, https://doi.org/10.1016/j.neuron.2018.07.033)

In 2011, a team led by Jeffrey Holt, PhD, demonstrated that a protein called TMC1 is required for hearing and balance, following the 2002 discovery that mutations in the TMC1 gene cause deafness. Holt’s team proposed that TMC1 proteins form channels that enable electrically charged ions such as calcium and potassium to enter the delicate hair cells of the inner ear. This, in turn, enables the cells to convert sound waves and head movement into electrical signals that talk to the brain.

In a new study published today in Neuron, Holt and colleagues teamed with the lab of David Corey, PhD, at Harvard Medical School. Together, they confirmed TMC1’s essential role in hearing, ending a 40-year quest, and mapped out its working parts.

Working with living hair cells in mice, they made substitutions in 17 amino acids within the TMC1 protein, one at a time, to see which substitutions altered hair cells’ ability to respond to stimuli and allow the flow of ions. Eleven amino acid substitutions altered the influx of ions, and five did so dramatically, reducing ion flow by up to 80 percent. One substitution blocked calcium flow completely, thereby revealing the location of the pore within TMC1 that enables ion influx.

Down the road, the study could have implications for reversing hearing loss, which affects more than 460 million people worldwide.

“To design optimal treatments for hearing loss, we need to know the molecules and their structures where disease-causing malfunctions arise, and our findings are an important step in that direction,” Holt said in this press release from Harvard Medical School.

Read more about Holt’s work.

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Science Seen: An intestinal toxin’s trick, a potential cancer fighter

Crystal structure of the C. difficile toxin bound to its receptor, causing intestinal damage
Adapted from Science May 11, 2018. DOI: 10.1126/science.aar1999

Clostridium difficile, also called “C. diff,” causes severe gastrointestinal tract infections and tops the CDC’s list of urgent drug-resistant threats. In work published in Nature in 2016, Min Dong, PhD, and colleagues found the elusive portal that enables a key C. diff toxin, toxin B, to enter the intestines’ outer cells and break down the intestinal barrier (above right).

Interestingly, the same portal, known as the Frizzled receptor, also receives signals that maintain the intestine’s stem cells. When toxin B docks, it blocks these signals, carried by a molecule known as Wnt. But exactly how it all works remained a puzzle — until new research published today in Science.

Liang Tao, PhD in Dong’s lab, working with the labs of Rongsheng Jin, PhD, at UC-Irvine, and Xi He, PhD, at Boston Children’s, captured the crystal structure of a fragment of toxin B (in orange above) as it joined to the Frizzled receptor (in green). The structure revealed lipid molecules within the Frizzled receptor (in yellow and red) that play a central role. Normally, when Wnt binds to Frizzled, it nudges these lipids aside. But the team showed that when the toxin fragment binds to Frizzled, it locks these lipids in place, preventing Wnt from engaging with the cell.

Just as stem cells rely on Wnt signaling for growth and regeneration, so do many cancers. Now that its mechanism is known, Dong thinks this toxin B fragment, which by itself isn’t toxic, could be a useful anti-cancer therapeutic. They’re currently developing a new generation of Wnt signaling modulators and testing them in animal models of cancer. (For further information, contact Rajinder.Khunkun@childrens.harvard.edu of Boston Children’s Technology & Innovation Development Office.)

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Science Seen: New microscope reveals biological life as you’ve never seen it before

Various images of cells captured by a new microscope reported in Science
A new microscope allows us to see how cells behave in 3D and real time inside living organisms.

Astronomers developed a “guide star” adaptive optics technique to obtain the most crystal-clear and precise telescopic images of distant galaxies, stars and planets. Now a team of scientists, led by Nobel laureate Eric Betzig, PhD, are borrowing the very same trick. They’ve combined it with lattice light-sheet to create a new microscope that’s able to capture real-time, incredibly detailed and accurate images, along with three-dimensional videos of biology on the cellular and sub-cellular level.

The work — a collaboration between researchers at Howard Hughes Medical Institute, Boston Children’s Hospital and Harvard Medical School —  is detailed in a new paper just published in Science.

“For the first time, we are seeing life itself at all levels inside whole, living organisms,” said Tom Kirchhausen, PhD, co-author on the new study, who is a senior investigator in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital and a professor of cell biology and pediatrics at Harvard Medical School (HMS).

“Every time we’ve done an experiment with this microscope, we’ve observed something novel — and generated new ideas and hypotheses to test,” Kirchhausen said in a news story by HMS. “It can be used to study almost any problem in a biological system or organism I can think of.”

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Science Seen: Imaging early auditory brain development

Auditory brain development - Heschl’s gyrus at 28 and 40 weeks
Copyright © 2018 Monson et al.

Babies can hear and respond to sounds, including language, before birth. In fact, research shows that babies learn to recognize words in the womb. Now, an advanced MRI technique called diffusion tensor imaging is providing a fine-tuned view of when different brain areas mature, including the areas that process sound. And the findings suggest that babies born prematurely may have disruptions in auditory brain development and in speech.

Investigators at Boston Children’s Hospital, Brigham and Women’s Hospital, Washington University School of Medicine in St. Louis and University College London analyzed advanced MRI brain images from 90 preterm infants and 15 infants born at full term (40 weeks). Fifty-six of the preterm infants were imaged at multiple time points. As shown above, the team focused on a particular fold in the brain called Heschl’s gyrus (HG). This area contains the primary auditory cortex, the first part of the auditory cortex to receive sound signals, and the non-primary auditory cortex, which plays a higher-level role in processing those stimuli.

As seen in these sample images, the primary cortex has largely matured at 28 weeks’ postmenstrual age (PMA), whereas the non-primary auditory cortex has had a surge in development between 28 and 40 weeks’ PMA. Both regions appeared underdeveloped in the premature infants as compared with the infants born at term.

The study further found that disturbed maturation of the non-primary cortex was associated with poorer expressive language ability at age 2. The team suggests that this area may be especially vulnerable to disruption in a premature birth because it is undergoing such rapid change.

The study was published in eNeuro, an open-access journal from the Society for Neuroscience. Jeffrey Neil, MD, PhD, of Boston Children’s Department of Neurology, was senior author on the paper. First author Brian Monson, PhD, is now at the University of Illinois at Urbana-Champaign. Read more in the university’s press release.

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Science Seen: To deliver things into cells, do as rotavirus does

rotavirus cell entry - lessons for drug delivery
Courtesy Stephen Harrison

Rotavirus, a major cause of early childhood diarrhea, could have a lot to tell drug developers about how to deliver their products into cells.

Rotavirus doesn’t have an outer membrane, so it’s had to evolve a special system to infect cells. “Viruses with a membrane, like flu or HIV, can simply fuse that membrane with the membrane of the target cell and dump their contents inside the cell,” says Stephen Harrison, PhD, chief of the Laboratory of Molecular Medicine at Boston Children’s Hospital.

Rotavirus does something different, Harrison’s lab has found. First, each virion attaches itself to the cell membrane and wraps itself inside it. Next, its outer proteins, VP4 (the red spikes above) and VP7 (in yellow), disrupt that membrane — and are stripped off in a matter of seconds.

“If you will, they’re the booster the rocket has to shed so the payload can continue,” says Harrison.

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Science Seen: Tackling S. aureus by eavesdropping on infections

S. aureus vaccine messenger RNA transcriptome
This messenger RNA ‘heat map,’ generated from 50 patient samples, shows potential target proteins for a more effective S. aureus vaccine. The color scale indicates the magnitude of the transcription level, with red highest.

Staphylococcus aureus causes 11,000 deaths annually in the U.S. alone and is frequently antibiotic-resistant. It’s a leading cause of pneumonia, bloodstream infections, bone/joint infections and surgical site infections and the #1 cause of skin and soft tissue infections. Efforts to develop an S. aureus vaccine have so far failed: the vaccines don’t seem to be capturing the right ingredients to make people immune.

Kristin Moffitt, MD, in Boston Children’s Hospital’s Division of Infectious Diseases, took a step back and asked: “What proteins does S. aureus need to make to establish infection?” The answer, she reasoned, could point to new antigens to include in a vaccine.

The above image shows an early result from Moffitt’s investigation. It’s a “heat map” of the messenger RNA signature — a snapshot of the proteins S. aureus is potentially up-regulating during infection.

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Science Seen: Disrupted developmental genes cause ‘split brain’

split brain syndrome
The two halves of the brain on the right, from a patient with the DCC mutation, are almost completely disconnected. The mutation — first recognized in worms — prevents axons (nerve fibers) from crossing the midline of the brain by interfering with guidance cues. Image courtesy Ellen Grant, MD, director, Fetal-Neonatal Neuroimaging and Developmental Science Center.

Tim Yu, MD, PhD, a neurologist and genomics researcher at Boston Children’s Hospital, was studying autism genes when he saw something on a list that rang a bell. It was a mutation that completely knocked out the so-called Deleted in Colorectal Carcinoma gene (DCC), originally identified in cancer patients. The mutation wasn’t in a patient with autism, but in a control group of patients with brain malformations he’d been studying in the lab of Chris Walsh, MD, PhD.

Yu’s mind went back more than 20 years. As a graduate student at University of California, San Francisco, he’d conducted research in roundworms, studying genetic mutations that made the worms, which normally move in smooth S-shaped undulations, move awkwardly and erratically.

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Science Seen: Brain myelination in tuberous sclerosis complex

tuberous sclerosis brain myelination improved with CTGF deletion

Tuberous sclerosis complex (TSC) strikes about 1 in 6,000 people and is marked by numerous benign tumors in the brain, kidneys, heart, lungs and other tissues. Children with TSC often have epilepsy, intellectual disability and/or autism, showing disorganized white matter in their brains. Work in the lab of Mustafa Sahin, MD, PhD, has shown that the TSC1 mutation disrupts the brain’s ability to adequately wrap its nerve fibers in myelin, the insulating coating that enhances nerves’ ability to conduct signals. A new study from the lab shows why: neurons lacking functional TSC1 secrete increased amounts of connective tissue growth factor (CTGF). This impairs the development of oligodendrocytes, the cells that do the myelinating. Here, electron microscopy in a TSC mouse model shows a decreased number of nerve fibers wrapped in myelin (dark ovals) on the left. On the right, genetic deletion of CTGF increases myelination. Sahin plans to delve further to develop potential pharmaceutical approaches to restore myelination in TSC. Read more in the Journal of Experimental Medicine. (Image: Ebru Ercan et al.)

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Rainbow-hued blood stem cells shed new light on cancer, blood disorders

color-coded blood stem cells
These red blood cells bear color tags made from random combinations of red, green and blue fluorescent proteins. Same-color cells originate from the same blood stem cell (Nature Cell Biology 2016, Henninger et al).

A new color-coding tool is enabling scientists to better track live blood stem cells over time, a key part of understanding how blood disorders and cancers like leukemia arise, report researchers in Boston Children’s Hospital’s Stem Cell Research Program.

In Nature Cell Biology today, they describe the use of their tool in zebrafish to track blood stem cells the fish are born with, the clones (copies) these cells make of themselves and the types of specialized blood cells they give rise to (red cells, white cells and platelets). Leonard Zon, MD, director of the Stem Cell Research Program and a senior author on the paper, believes the tool has many implications for hematology and cancer medicine since zebrafish are surprisingly similar to humans genetically.

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