POMC Neuron BBSome Regulation of Body Weight is Independent of its Ciliary Function.

The BBSome, a complex of several Bardet-Biedl syndrome (BBS) proteins including BBS1, has emerged as a critical regulator of energy homeostasis. Although the BBSome is best known for its involvement in cilia trafficking, through a process that involve BBS3, it also regulates the localization of cell membrane receptors underlying metabolic regulation. Here, we show that inducible Bbs1 gene deletion selectively in proopiomelanocortin (POMC) neurons cause a gradual increase in body weight, which was associated with higher fat mass. In contrast, inducible deletion of Bbs3 gene in POMC neurons failed to affect body weight and adiposity. Interestingly, loss of BBS1 in POMC neurons led to glucose intolerance and insulin insensitivity, whereas BBS3 deficiency in these neurons is associated with slight impairment in glucose handling, but normal insulin sensitivity. BBS1 deficiency altered the plasma membrane localization of serotonin 5-HT2C receptor (5-HT2CR) and ciliary trafficking of neuropeptide Y2 receptor (NPY2R).In contrast, BBS3 deficiency, which disrupted the ciliary localization of the BBSome, did not interfere with plasma membrane expression of 5-HT2CR, but reduced the trafficking of NPY2R to cilia. We also show that deficiency in BBS1, but not BBS3, alters mitochondria dynamics and decreased total and phosphorylated levels of dynamin-like protein 1 (DRP1) protein. Importantly, rescuing DRP1 activity restored mitochondria dynamics and localization of 5-HT2CR and NPY2R in BBS1-deficient cells. The contrasting effects on energy and glucose homeostasis evoked by POMC neuron deletion of BBS1 versus BBS3 indicate that BBSome regulation of metabolism is not related to its ciliary function in these neurons.

Extreme laser pulse-energy measurements by means of photon momentum.

Extreme lasers capable of short, high-energy pulses are probing the frontiers of science and advancing practical technology. The utility of such lasers increases with their average power delivery, which enables faster data acquisition, higher flux of laser-driven particle and radiation sources and more efficient material processing. However, the same extreme energies and electric field strengths of these lasers are currently preventing their direct and high accuracy measurement for these experimental applications. To overcome this limitation, we use the momentum of the laser pulses as a measurement proxy for their energy. When light reflects from an ideal mirror, its momentum is transferred to the mirror, but its energy is reflected. We demonstrate here a force-sensing mirror configuration to measure laser pulse energies up to 100 J/pulse (10 ns duration, 10 Hz repetition rate) from a kilowatt-level average power multi-slab laser operated at the HiLASE facility of the Czech Academy of Sciences. We combine a radiation-pressure power meter with a charge integrator photodiode to form what we refer to as a Radiation Pressure Energy Meter. To our knowledge, this is the first demonstration of a high-accuracy, non-absorbing, SI traceable primary standard measurement of both single and average pulse energies of a 1-kW-average-power pulsed laser source. With this, we demonstrate a practical method for in-situ calibration of the traditional thermal instruments (pyroelectric detectors) currently used for indirect measurements of energy and power of such extreme lasers.

Moving beyond More of the Same, but Better - How Campuses of Care Can Transform Long-Term Care.

For decades, there have been calls for innovative care solutions to address the growing numbers of people living with complex health and social needs, including dementia. In 2020-2021, the toll of the COVID-19 pandemic on vulnerable populations exposed many of the same issues and spurred renewed calls for transformative change. As we look forward, it is imperative to consider options not just for improving residential long-term care but also for integrating it into broader continuums of health and social care, where people can receive supports and services in the most appropriate setting. This commentary spotlights campuses of care as one homegrown solution to address individuals' and system needs and contexts.

High amplification laser-pressure optic enables ultra-low uncertainty measurements of the optical laser power at kilowatt levels.

We present the first measurements of kilowatt laser power with an uncertainty less than 1 %. These represent progress toward the most accurate measurements of laser power above 1 kW at 1070 nm wavelength and establish a more precise link between force metrology and laser power metrology. Radiation pressure, or photon momentum, is a relatively new method of non-destructively measuring laser power. We demonstrate how a multiple reflection optical system amplifies the pressure of a kilowatt class laser incoherently to improve the signal to noise ratio in a radiation pressure-based measurement. With 14 incoherent reflections of the laser, we measure a total uncertainty of 0.26 % for an input power of 10 kW and 0.46 % for an input power of 1 kW at the 95 % confidence level. These measurements of absolute power are traceable to the SI kilogram and mark a state-of-the-art improvement in measurement precision by a factor of four.

Feedback Control of a Nonlinear Electrostatic Force Transducer.

We document a feedback controller design for a nonlinear electrostatic transducer that exhibits a strong unloaded resonance. Challenging features of this type of transducer include the presence of multiple fixed points (some of which are unstable), nonlinear force-to-deflection transfer, effective spring-constant softening due to electrostatic loading and associated resonance frequency shift. Furthermore, due to the utilization of lowpass filters in the electronic readout circuitry, a significant amount of transport delay is introduced in the feedback loop. To stabilize this electro-mechanical system, we employ an active disturbance-rejecting controller with nonlinear force mapping and delay synchronization. As demonstrated by numerical simulations, the combination of these three control techniques stabilizes the system over a wide range of electrode deflections. The proposed controller shows good setpoint tracking and disturbance rejection, and improved settling time, compared to the sensor alone.

Simplified kilogram traceability for high-power laser measurement using photon momentum radiometers.

Photon momentum radiometers measure the force imparted by a reflected laser beam to determine the laser's optical power. This requires high-accuracy calibration of the force sensors using milligram and microgram mass artifacts. Calibrated test masses can therefore be used to provide traceability of these radiometers to the International System of Units, but low-noise calibration at these mass levels is difficult. Here, we present the improvement in calibration capability that we have gained from implementing a robotic mass delivery system. We quantify this in terms of the specific nuances of force measurements as implemented for laser power metrology.

Miniature force sensor for absolute laser power measurements via radiation pressure at hundreds of watts.

We present a small power meter that detects the radiation pressure of an incident high-power laser. Given its small package and non-destructive interaction with the laser, this power meter is well suited to realizing a robust real-time, high-accuracy power measurement in laser-based manufacturing environments. The incident laser power is determined through interferometric measurement of displacement of a 20 mm diameter high reflectivity mirror, mounted at the center of a dual element spiral flexure. This device can measure laser power from 25 W to 400 W with a 260 m W/H z noise floor and ≤ 3.2% expanded uncertainty. We validate our device against a calibrated thermopile with simultaneous measurements of an unpolarized 1070 nm laser and report good agreement between the two systems. Finally, by referencing to an identical mechanical spring that does not see the incident laser, we suppress vibration noise in the power measurement by 14.8 dB over a 600 Hz measured bandwidth. This is an improvement over other radiation pressure based power meters that have previously been demonstrated.

Dynamic Laser Absorptance Measured in a Geometrically Characterized Stainless-Steel Powder Layer.

The relationship between real powder distributions and optical coupling is a critical building block for developing a deeper physical understanding of laser-additive manufacturing and for creating more reliable and accurate models for predictable manufacturing. Laser-light absorption by a metal powder is distinctly different from that of a solid material, as it is impacted by additional parameters, such as particle size, shape distribution, and packing. Here, we use x-ray computed tomography to experimentally determine these parameters in a thinly spread austenitic stainless-steel powder on a metal substrate, and we combine these results with optical absorptance measurements during a 1 ms stationary laser-light exposure to simulate the additive-manufacturing process. Within the thinly spread powder layer, the particle volume fraction changes continuously from near zero at the powder surface to a peak value of 0.72 at a depth of 235 µm, with the most rapid increase taking place in the first 100 µm. The relationship between this particle volume fraction gradient and optical absorptance is investigated using an analytical model, which shows that depth-averaged absorptance measurements can measure the predicted average value, but will fail to capture local effects that result from a changing powder density. The time-averaged absorptance remains at levels between 0.67 and 0.80 across a two orders of magnitude range in laser power, which is significantly higher than that observed in solid stainless-steel experiments. The dynamic behavior of the absorptance, however, reveals physical phenomena, including oxidation, melting, and vapor cavity (keyhole) formation, as well as quantifying the effect of these on the absorbed energy.

Onsite multikilowatt laser power meter calibration using radiation pressure.

We have demonstrated the calibration of a thermal power meter against a radiation pressure power meter in the range of 20 kW in a manufacturing test environment. The results were compared to a traditional calorimeter-based laboratory calibration undertaken at the National Institute of Standards and Technology. The results are reported, and the effects of nonideal conditions typical of measurements in low-stability environments are discussed.

The endoplasmic reticulum coat protein II transport machinery coordinates cellular lipid secretion and cholesterol biosynthesis.

Triglycerides and cholesterol are essential for life in most organisms. Triglycerides serve as the principal energy storage depot and, where vascular systems exist, as a means of energy transport. Cholesterol is essential for the functional integrity of all cellular membrane systems. The endoplasmic reticulum is the site of secretory lipoprotein production and de novo cholesterol synthesis, yet little is known about how these activities are coordinated with each other or with the activity of the COPII machinery, which transports endoplasmic reticulum cargo to the Golgi. The Sar1B component of this machinery is mutated in chylomicron retention disorder, indicating that this Sar1 isoform secures delivery of dietary lipids into the circulation. However, it is not known why some patients with chylomicron retention disorder develop hepatic steatosis, despite impaired intestinal fat malabsorption, and why very severe hypocholesterolemia develops in this condition. Here, we show that Sar1B also promotes hepatic apolipoprotein (apo) B lipoprotein secretion and that this promoting activity is coordinated with the processes regulating apoB expression and the transfer of triglycerides/cholesterol moieties onto this large lipid transport protein. We also show that although Sar1A antagonizes the lipoprotein secretion-promoting activity of Sar1B, both isoforms modulate the expression of genes encoding cholesterol biosynthetic enzymes and the synthesis of cholesterol de novo. These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions.

Use of radiation pressure for measurement of high-power laser emission.

We demonstrate a paradigm in absolute laser radiometry where a laser beam's power can be measured from its radiation pressure. Using an off-the-shelf high-accuracy mass scale, a 530 W Yb-doped fiber laser, and a 92 kW CO(2) laser, we present preliminary results of absolute optical power measurements with inaccuracies of better than 7% to 13%. We find negligible contribution from radiometric (thermal) forces. We also identify this scale's dynamic-force noise floor for a 0.1 Hz modulation frequency as 4 µN/Hz(1/2) or, as optical power sensitivity, 600 W/Hz(1/2).

Absolute spectroscopy of N2O near 4.5 µm with a comb-calibrated, frequency-swept quantum cascade laser spectrometer.

We present absolute line center frequencies for 24 fundamental ν3 ro-vibrational P-branch transitions near 4.5 µm in N2O with an absolute expanded (multiplied by 2) frequency uncertainty of 800 kHz. The spectra are acquired with a swept laser spectrometer consisting of an external-cavity quantum cascade laser whose instantaneous frequency is continuously tracked against a near-infrared frequency comb. The measured absorbance profiles have a well-calibrated frequency axis, and are fitted to determine absolute line center values. We discuss the main sources of uncertainty.

Frequency characterization of a swept- and fixed-wavelength external-cavity quantum cascade laser by use of a frequency comb.

The instantaneous optical frequency of an external-cavity quantum cascade laser (QCL) is characterized by comparison to a near-infrared frequency comb. Fluctuations in the instantaneous optical frequency are analyzed to determine the frequency-noise power spectral density for the external-cavity QCL both during fixed-wavelength and swept-wavelength operation. The noise performance of a near-infrared external-cavity diode laser is measured for comparison. In addition to providing basic frequency metrology of external-cavity QCLs, this comb-calibrated swept QCL system can be applied to rapid, precise broadband spectroscopy in the mid-infrared spectral region.

Pullout analysis of a lumbar plate with varying screw orientations: experimental and computational analyses.

STUDY DESIGN: Experimental and finite element analysis of anterior lumbar interbody fixation (ALIF) plate pullout. OBJECTIVE: The objective of this study was to determine the effect of screw angle and orientation on ALIF plate pullout strength. SUMMARY OF BACKGROUND DATA: It has been thought that angling the screws in an ALIF plate leads to better fixation strength; however, a few studies are published on this question, which produced conflicting results. METHODS: Using custom guides, screws were configured in 9 different orientations to affix ALIF plates to polyurethane foam blocks. Pullout tests were performed at a rate of 1 mm/min. In addition, finite element analyses were performed on a 2-dimensional screw-block model to gain insight into the internal stress during pullout. RESULTS: The pullout load was the greatest, with screws positioned 12° outward sagittaly and 6° inward coronally (936 ± 72 N). This orientation was statistically greater than the orientation with the lowest pullout load (812 ± 45 N, P < 0.05); however, no group was statistically different than placing the screws straight in (868 ± 86 N, P > 0.05). Finite elements analysis showed some gain in pullout strength at 12° followed by some loss at greater angles. As the screw insertion angle increased, stress levels elevated within the block even in the regions away from the screw. CONCLUSION: Significant difference was found between certain screw-angle configurations; however, when compared with simply placing the screws straight in, the difference was never more than 8%. This implies that there is greater freedom in the angle and placement of screws than previously thought. Our results show that there is little change in fixation strength when placing the screw in a different direction.

Pullout of a lumbar plate with varying screw lengths.

BACKGROUND: Screw length pertains to stability in various orthopedic fixation devices. There is little or no information on the relationship between plate pullout strength and screw length in anterior lumbar interbody fusion (ALIF) plate constructs in the literature. Such a description may prove useful, especially in the treatment of osteoporotic patients where maximizing construct stability is of utmost importance. Our purpose is to describe the influence of screw length on ALIF plate stability in severely and mildly osteoporotic bone foam models. METHODS: Testing was performed on polyurethane foam blocks with densities of 0.08 g/cm(3) and 0.16 g/cm(3). Four-screw, single-level ALIF plate constructs were secured to the polyurethane foam blocks by use of sets of self-tapping cancellous bone screws that were 20, 24, 28, 32, and 36 mm in length and 6.0 mm in diameter. Plates were pulled out at 1 mm/min to failure, as defined by consistently decreasing load despite increasing displacement. RESULTS: Pullout loads in 0.08-g/cm(3) foam for 20-, 24-, 28-, 32-, and 36-mm screws averaged 303, 388, 479, 586, and 708 N, respectively, increasing at a mean of 25.2 N/mm. In 0.16-g/cm(3) foam, pullout loads for 20-, 24-, 28-, 32-, and 36-mm screws averaged 1004, 1335, 1569, 1907, and 2162 N, respectively, increasing at a mean of 72.2 N/mm. CONCLUSIONS: The use of longer screws in ALIF plate installation is expected to increase construct stability. Stabilization from screw length in osteoporotic patients, however, is limited.

Multilevel magnetic resonance imaging analysis of multifidus-longissimus cleavage planes in the lumbar spine and potential clinical applications to Wiltse's paraspinal approach.

STUDY DESIGN: Retrospective magnetic resonance imaging (MRI)-based study. OBJECTIVE: Our goal was to develop Wiltse's paraspinal surgical approach by determining the precise anatomic locations of the intermuscular cleavage planes formed by the multifidus and longissimus muscles. The primary objective was to measure the distances between the midline and the intermuscular planes, bilaterally, on MRI scans at each of the five disc levels between L1 and S1. Secondary objectives included identifying the existence of any correlations between patient demographics and the measured outcomes. SUMMARY OF BACKGROUND DATA: In 1968, Wiltse described an approach to the spine using the natural cleavage plane of the multifidus and longissimus muscles as an entry to the posterior spinal elements. The small direct incisions lessened bleeding, tissue violation, and muscle retraction, which popularized Wiltse's approach among surgeons. A detailed description of the locations of the intermuscular cleavage planes at each lumbar disc level, however, is not available. METHODS: MRI scans of 200 patients taken during routine care (2007-2009) were retrospectively reviewed to gather measurements of the distances from the intermuscular cleavage planes to the midline, bilaterally, at each disc level from L1 to S1. Age, sex, and BMI (body mass index) were obtained to determine correlations. RESULTS: Mean measurements significantly differed between all disc levels. At L5-S1, the mean distance was 37.8 mm; at L4-L5, 28.4 mm; at L3-L4, 16.2 mm; at L2-L3, 10.4 mm; and at L1-L2, 7.9 mm. The mean female distances were significantly greater than males (2 mm) on both sides of L5-S1 only. No correlation was discovered between BMI, age, height (N = 50), or weight (N = 50) with respect to measured distances. CONCLUSION: In the absence of any significant clinical correlation between patient demographics and the entry site in Wiltse's approach, the spine surgeon may use distances described in this paper to apply to a broad base of spine patients regardless of BMI, sex, or age.

Characterization of protein degradation in serum-based lubricants during simulation wear testing of metal-on-metal hip prostheses.

A size exclusion high performance liquid chromatography (SEC-HPLC) method has been developed which is capable of separation and quantitation of bovine serum albumin (BSA) and bovine serum globulin (BSG) components of serum-based lubricant (SBL) solutions. This allowed characterization of the stability profiles of these proteins when acting as lubricants during hip wear simulation, and identification of wear-specific mechanisms of degradation. Using cobalt-chromium metal-on-metal (MOM) hip joints, it was observed that BSA remained stable for up to 3 days (215K cycles) of wear testing after which the protein degraded in a fairly linear fashion. BSG on the other hand, began to degrade immediately and in a linear fashion with a rate constant of 5% per day. Loss of both proteins occurred via the formation of high molecular weight aggregates which precipitated out of solution. No fragmentation of the polypeptide backbone of either protein was observed. Data obtained suggest that protein degradation was not due to microbial contamination, denaturation at the air-water interface, or frictional heating of articulating joint surfaces in these studies. We conclude that the primary source of protein degradation during MOM simulation testing occurs via high shear rates experienced by SBL solutions at articulating surfaces, possibly coupled with metal-protein interactions occurring as new and reactive metal surfaces are generated during wear testing. The development of this analytical methodology will allow new studies to clarify the role of SBL solutions in wear simulation studies and the interactions and lubricating properties of serum proteins with prosthetic surfaces other than MOM.

Polyethylene wear debris produced in a knee simulator model: effect of crosslinking and counterface material.

Polyethylene (PE) debris has been well studied in clinical retrievals and laboratory wear simulations of total hip replacements. However, little is known about PE debris from total knee replacements. In this study, we investigated the effects of crosslinking PE bearings and alternate counterface material. Mildly (35 kGy) and highly (70 kGy) crosslinked PE were studied in combination with CoCr and zirconia femoral counterfaces. Wear debris was isolated and its morphology characterized. Except for changes in PE debris size with the zirconia bearings, there were no morphological changes greater than 10%. The average submicron volume fraction decreased from about 65% to 45% with both increased crosslinking and changing counterface material from CoCr to zirconia. The averaged number of generated particles decreased by approximately fourfold with increased crosslinking and threefold with changing counterface material from CoCr to zirconia. This showed that the degree of PE crosslinking and the choice of counterface material were important factors in the PE wear debris production in total knee simulator replacements.

Surface damage after multiple dislocations of a 38-mm-diameter, metal-on-metal hip prosthesis.

We present, for the first time, a detailed damage assessment of a large-diameter metal-on-metal (L-MOM) hip prosthesis to show the extent of surface damage that can occur in a patient after multiple dislocations. The patient was a man (51 years old) who dislocated 8 times and was finally revised at 27 months. Radiographically, the cup was malpositioned with 65 degrees lateral opening and 15 degrees retroversion. The retrieved cup was a 1-piece, 38-mm Co-Cr-Mo (M2a; Biomet, Warsaw, Ind) with a titanium-alloy backing. The retrieved components demonstrated all known modes of wear, including a polished wear scar, multidirectional scratching, "stripe" wear, surface contamination of titanium-alloy, front face wear, and backside wear. The clinical significance is that cup positioning remains critical regardless of whether a large diameter head is used or not.

Ceramic total hip arthroplasty in the United States: safety and risk issues revisited.

The advantages of all-alumina bearings are superb wear resistance, stability, and inertness demonstrated over 3 decades. The disadvantage is a small risk for brittle fracture, as described in this paper. Surveying the latest ceramic hip series reported in recent journal articles or presented at the 6th World Biomaterials Congress, we found 11 studies representing more than 35,000 cases followed for 3 to 25 years. There were 24 reported fractures. A unique survey of hip complications in the 1990s found a fracture risk of approximately 1.4 per 1000 ceramic balls used in the United States. A company database holding more than 2.5 million records described the overall fracture risk as 1 per 10,000 cases. Initial use of ceramic cup inserts indicated a 2% to 3% incidence of chipping during surgery. Beginning in 1997, the number of ceramic-metal cup-locking cases entered into a US Food and Drug Administration ceramics database was more than 2400, with no fractures reported by the FDA in July 2003.