The circadian clock system (from Latin “circa diem,” about a day) allows the organisms to anticipate periodical changes of geophysical time, and to adjust to these changes. Nearly all the cells in our body comprise molecular clocks that regulate and synchronize metabolic functions to a 24-hour cycle of day-night changes. Today, increasing evidence show that disturbances in our internal clocks stemming from frequent time zone changes, irregular working schedules or ageing, have a significant impact on the development of metabolic diseases in human beings, including type-2 diabetes. Such disturbances seem to prevent the proper functioning of the cells in the pancreatic islet that secrete insulin and glucagon, the hormones that regulate blood sugar levels. By comparing the pancreatic cells of type 2 diabetic human donors with those of healthy people, researchers at the University of Geneva (UNIGE) and at the University Hospitals of Geneva (HUG), Switzerland, were able to demonstrate, for the first time, that the pancreatic islet cells derived from the Type 2 Diabetic human donors bear compromised circadian oscillators. The disruption of the circadian clocks was concomitant with the perturbation of hormone secretion. Moreover, using clock modulator molecule dubbed Nobiletin, extracted from lemon peel, the researchers succeeded in “repairing” the disrupted cellular clocks and in partial restoring of the islet cell function. These results, published in the Proceedings of the National Academy of Sciences of the United States, provide a first insight into innovative approach for diabetes care.

Two years ago, the team led by Charna Dibner, Principle Investigator in the Departments of Medicine and of Cell Physiology and Metabolism, and Diabetes Centre at UNIGE Faculty of Medicine, and at HUG, has already shown that in rodents the perturbation of pancreatic cellular clocks led to disrupted insulin and glucagon secretion, thus promoting the onset of diabetes. But what is the situation in human beings? “We had also previously observed that if the clocks of human pancreatic cells were artificially disrupted in the cellular culture in vitro, secretion of the key islet hormones — insulin and glucagon — was compromised,” says Volodymyr Petrenko, a researcher in Dr. Dibner’s lab and the first author of these publications. Hence our next step, that we report here, was to unravel whether the circadian rhythms were perturbed in human pancreatic islets in type 2 diabetes, and, if so, how would this perturbation affect the islet function.”

Using combined bioluminescence-fluorescence time-lapse microscopy, a technology that allows tracking the molecular clock activity in living cells very precisely over time, the scientists compared the behaviour of pancreatic cell of type-2 diabetic donors and those of healthy subjects throughout the day. “The verdict is indisputable,” says Charna Dibner. The biological rhythms of the islet cells in type-2 diabetes exhibit both reduced amplitudes of circadian oscillations and poor synchronization capacity. “As a result, hormone secretion is no longer coordinated. Moreover, the defects in temporal coordination of insulin and glucagon secretion observed in patients with type-2 diabetes were comparable to those measured in healthy islet cells with artificially-disrupted circadian clock.”

It’s all in the timing!

Circadian clocks represent the daily cycles governing the various cellular functions. There are several interlocking levels of synchronization of these clocks, the main one being light, which in particular regulates the central clock located in the cerebral hypothalamus. Like a conductor in the orchestra, it regulates peripheral clocks present in organs and cells. The latter are therefore partly centrally regulated, but function differently in each organ, and even in each cell, depending on their functions. “Pancreatic cells are also subject to the rhythm of fasting and food intake, and to a tight hormonal regulation,” says Charna Dibner. “Coordinating all levels of regulation therefore allows the optimization of metabolic functions. Clocks deregulation in pancreatic islet leads to a compromised function: they are not anymore anticipating food-derived signals. Indeed, if you eat the same food but at night rather than during the day, you may gain weight much faster, due to a suboptimal response of your metabolism.”

Setting the right time again

Step two of their research: the Geneva scientists used Nobiletin, a small clock modulator molecule — a natural ingredient of lemon peel whose impact on circadian clocks has been recently discovered — in order to resynchronize the clocks. “By acting on one of the core-clock components, it resets efficiently the amplitude of the oscillations in the human islets” says Volodymyr Petrenko. “And as soon as we got the clocks back in sync, we also observed an improvement in insulin secretion.”

“This is the first proof of principle that repairing compromised circadian clocks may help improving the function of the pancreatic islet hormone secretion,” says Charna Dibner. “We will continue by exploring this repair mechanism in vivo, first in animal models. Our society experiences epidemic growth in metabolic diseases, concomitant with shifted working and eating schedules, and lack of sleep. By re-synchronizing the perturbed molecular clocks, either by personalized eating and exercise schedules or with the help of clock modulator molecules, we hope to ultimately be able to provide an innovative solution to an epidemical metabolic problem affecting an ever-increasing proportion of the world’s population. .”

“If a docking station is more than two or three blocks away, they just won’t go there,” said Karan Girotra, professor of operations, technology and innovation at Cornell Tech and the Cornell SC Johnson College of Business. “And if they encounter a station without bikes, it’s very unlikely they will go to the next station.”

Girotra co-authored “Bike-Share Systems: Accessibility and Availability,” published in November by Management Science, with Elena Belavina, associate professor at the School of Hotel Administration in the SC Johnson College, and Ashish Kabra, assistant professor at the University of Maryland’s Robert H. Smith School of Business.

Their findings imply that, outside of a few big stations at major transit hubs, cities and bike-share operators should strive to create denser networks with many smaller stations, Girotra and Belavina said, and keep them stocked.

“It’s no surprise that people want stations close to them, but it’s much closer than most planners and bike-share systems thought they needed,” Belavina said. “Most systems are nowhere close to their optimal density.”

Bike sharing systems hold the potential to reduce traffic and pollution in dense, flat cities such as London, New York, Paris and Shanghai, the researchers noted. They encourage and enhance public transit use by providing “last mile” connections to bus and train stations.

But “their promise of urban transformation is far from being fully realized,” according to the paper. Many systems were established quickly, sometimes through public-private partnerships, and with less rigorous planning than higher-cost transit systems, Girotra said.

“There was perhaps an opportunity to put a little more thought into how a bike-share system can be introduced in a city,” he said.

To that end, the research team built a model to produce the first estimates of how station proximity and bike availability influence bike-share operations.

The structural demand model analyzed data from Paris’ Vélib’ system — the largest outside China with roughly 17,000 bikes and 950 stations — during four months of 2013, a period that included nearly 4.4 million trips. The data provided snapshots of system usage every two minutes, showing how stations changed throughout each day.

The researchers blended that information with data about population density in different city districts, metro ridership, attendance at top tourist destinations and weather conditions. The team also logged the locations of thousands of points of interest such as transit stations, parks, libraries, hotels, grocery stores, restaurants and cafes.

“Put together,” Belavina said, “that gave us some ability to disentangle what guides people’s decisions in choosing bike sharing and different bike-share stations.”

The model determined that someone roughly 300 meters (nearly 1,000 feet) from a docking station is 60% less likely to use the service than someone very near the station. The odds decrease slightly with every additional meter, such that someone 500 meters away — about one-third of a mile — is “highly unlikely to use the system.”

But a 10% increase in bike availability — the likelihood of finding a bicycle at a station — would grow ridership by roughly 12%, the study found, thanks to fewer lost sales at out-of-stock stations and improved expectations of the system.

Among the various points of interest, placing stations near grocery stores provides the most benefit, the model showed.

Generating the study’s findings required methodological advances to adapt demand modeling to a bike-share context, the researchers said.

Models have long predicted shifts in usage patterns when considering new locations for transit stations, retail outlets or bank ATMs. But bike-share demand in a major city, with hundreds of stations changing inventory throughout each day, involved studying a more dynamic system with much finer resolution, Girotra said.

The team’s huge volume of data might have required completing more than a quadrillion calculations to generate the best estimates, likely taking over a year, according to the paper. Instead, the researchers developed new computational techniques, Belavina said, to condense some data and make the process more manageable.

The resulting model, according to the co-authors, can be applied not only to bike-share systems but other micro-mobility services: scooters, powered bikes, local food delivery and ride-sharing. The researchers plan to look more broadly at micro-mobility in a future study partnering with London’s transit agency.

Regarding bike sharing, the study’s advice was clear: “Make bikes and stations more available,” Girotra said. “People don’t like walking to access a bike-share system.”

“This is the first in-depth analysis of ovarian aging at a single-cell resolution in a non-human primate model,” says Juan Carlos Izpisua Belmonte, one of the co-corresponding authors, professor in Salk’s Gene Expression Laboratory and holder of the Roger Guillemin Chair. “We found that oxidative stress, the cellular stress that damages cells, is a key player in ovarian aging. This discovery provides valuable insight into the mechanisms by which ovaries age and eventually become infertile.”

The ovary is a complex reproductive organ in which an ovarian cell, called an oocyte, undergoes meiosis to become an egg. Current research suggests that women are born with a set number of oocytes that start to become less functional once women turn 35, leading to infertility. A better understanding of the ovarian environment as well as the mechanisms of healthy aging could inform new therapies for women with fertility issues.

“Our goal was to analyze each ovarian cell type along with patterns in gene expression in order to better understand exactly how ovaries age,” says Jing Qu, co-corresponding author, professor at the Chinese Academy of Sciences and former Salk research associate. “This systematic approach provides a better understanding of the mechanisms of healthy ovarian aging.”

The scientists compared 2,601 ovarian cells from young and old non-human primates, and identified gene activity patterns for every type of primate ovarian cell including ooctyes and granulosa cells, which surround the oocytes as they develop. Similar to previous studies in rodents, the scientists observed changes in gene function related to cellular stress and cell division across the non-human primates. As the oocytes and granulosa cells aged, some of the genes that fight cellular stress became less active which led to damage and impairment in function.

The scientists then compared the primate data with granulosa cells from healthy women ranging in age from 21 to 46 years. They observed age-associated damage from cellular stress as well as cell death in the women’s cells. Two key antioxidant genes (IDH1 and NDUFB10) showed decreased function, as seen in the non-human primate cells. To better understand the connection between ovarian aging and the antioxidant genes, the scientists tested what happened to the human cells when the antioxidant genes were made non-functional. They found that without IDH1 or NDUFB10, the cells appeared old and similar to the old non-human primate cells.

The results suggest that IDH1 and NDUFB10 play a critical role in protecting both human and non-human primate ovarian cells from cellular stress during aging. These genes represent promising biomarkers or therapeutic targets for the diagnosis and treatment of age-related decline of the ovaries.

“This study provides a comprehensive understanding of the specific mechanisms of primate ovarian aging at single-cell resolution,” says Guang-Hui Liu, co-corresponding author, professor at the Chinese Academy of Sciences and former Salk research associate. “Our results will hopefully lead to the development of new tools to aid in the rejuvenation of aged ovarian cells.”

“Our research is enabling the identification of new biomarkers for the diagnosis and treatment of female infertility as well as aging-associated human ovarian disorders,” says Concepcion Rodriguez Esteban, an author on the paper and senior staff researcher in the Izpisua Belmonte lab. “These genes could possibly be targeted for the development of therapies to assist with fertility preservation.”

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Molecular motors are chemical compounds that convert energy into directed motions. For example, it is possible to cause a substituent attached to a specific chemical bond to rotate unidirectionally when exposed to light of a certain wavelength. Molecules of this sort are therefore of great interest as driving units for nanomachines. However, in order to perform useful work, these motors must be integrated into larger assemblies in such a way that their mechanical motions can be effectively coupled to other molecular units. So far, this goal has remained out of reach. LMU chemist Dr. Henry Dube is a noted specialist in the field of molecular motors. Now he and his team have taken an important step towards achievement of this aim. As they report in the journal Angewandte Chemie, they have succeeded in coupling the unidirectional motion of a chemical motor to a receiver unit, and demonstrated that motor can not only cause the receiver to rotate in the same direction but at the same time significantly accelerate its rotation.

The molecular motor in Dube’s setup is based on the molecule hemithioindigo, which contains a mobile carbon double bond (-C=C-). When the compound is exposed to light of a specific wavelength, this bond rotates unidirectionally. “In a paper published in 2018, we were able to show that this directional double bond rotation could be transmitted by means of a molecular ‘cable’ to the single carbon bond rotation of a secondary molecular unit.” says Dube. “This single bond itself rotates randomly under the influence of temperature fluctuations. But, thanks to the physical coupling between them, the unidirectional motion of the light-driven motor is transmitted to the single bond, which is forced to rotate in the same direction.”

To verify that the ‘motorized’ bond was actively driving the motion of the single bond, and not simply biasing its direction of rotation, Dube and colleagues added a brake to the system that reduced the thermal motion of the single bond. The modification ensured that the motor would have to expend energy to overcome the effect of the brake in order to cause the single bond to rotate. “This experiment enabled us to confirm that the motor really does determine the rate of rotation of the single bond — and in fact increases it by several orders of magnitude,” Dube explains.

Taken together, these results provide unprecedentedly detailed insights into the mode of operation of an integrated molecular machine. In addition, the experimental setup allowed the authors to quantify the potential energy available to drive useful work, thus yielding the first indication of how much work can effectively be done by a single molecular motor under realistic conditions. “Our next challenge will be to demonstrate that the energy transmitted in this system can indeed be used to perform useful work on the molecular scale,” says Dube.

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Materials provided by Ludwig-Maximilians-Universität München. Note: Content may be edited for style and length.