Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of meier-gorlin syndrome

Mutations in ORC1, ORC4, ORC6, CDT1, and CDC6, which encode proteins required for DNA replication origin licensing, cause Meier-Gorlin syndrome (MGS), a disorder conferring microcephaly, primordial dwarfism, underdeveloped ears, and skeletal abnormalities. Mutations in ATR, which also functions during replication, can cause Seckel syndrome, a clinically related disorder. These findings suggest that impaired DNA replication could underlie the developmental defects characteristic of these disorders. Here, we show that although origin licensing capacity is impaired in all patient cells with mutations in origin licensing component proteins, this does not correlate with the rate of progression through S phase. Thus, the replicative capacity in MGS patient cells does not correlate with clinical manifestation. However, ORC1-deficient cells from MGS patients and siRNA-mediated depletion of origin licensing proteins also have impaired centrosome and centriole copy number. As a novel and unexpected finding, we show that they also display a striking defect in the rate of formation of primary cilia. We demonstrate that this impacts sonic hedgehog signalling in ORC1-deficient primary fibroblasts. Additionally, reduced growth factor-dependent signaling via primary cilia affects the kinetics of cell cycle progression following cell cycle exit and re-entry, highlighting an unexpected mechanism whereby origin licensing components can influence cell cycle progression. Finally, using a cell-based model, we show that defects in cilia function impair chondroinduction. Our findings raise the possibility that a reduced efficiency in forming cilia could contribute to the clinical features of MGS, particularly the bone development abnormalities, and could provide a new dimension for considering developmental impacts of licensing deficiency

Colorectal and uterine movement and tension of the inferior hypogastric plexus in cadavers

Background: Hypotheses on somatovisceral dysfunction often assume interference by stretch or compression of the nerve supply to visceral structures. The purpose of this study is to examine the potential of pelvic visceral movement to create tension of the loose connective tissue that contains the fine branches of the inferior hypogastric nerve plexus. Methods: Twenty eight embalmed human cadavers were examined. Pelvic visceral structures were displaced by very gentle 5 N unidirectional tension and the associated movement of the endopelvic fascia containing the inferior hypogastric plexus that this caused was measured. Results: Most movement of the fascia containing the inferior hypogastric plexus was obtained by pulling the rectosigmoid junction or broad ligament of the uterus. The plexus did not cross any vertebral joints and the fascia containing it did not move on pulling the hypogastric nerve. Conclusions: Uterine and rectosigmoid displacement produce most movement of the fascia containing the hypogastric nerve plexus, potentially resulting in nerve tension. In the living this might occur as a consequence of menstruation, pregnancy or constipation. This may be relevant to somatovisceral reflex theories of the effects of manual therapy on visceral conditions.Ian P Johnso

A Nuprl-PVS Connection: Integrating Libraries of Formal Mathematics.

We describe a link between the Nuprl and PVS proof systems that enables users to access PVS from the Nuprl theorem proving environment, to import PVS theories into the Nuprl library, and to browse both Nuprl and PVS theories in a unified formal framework. The combined system is a first step towards a digital library of formalized mathematics that can be shared and used in complex applications

(Table 1) Alkenone concentration, UK'37 index and derived sea surface temperatures for ODP Site 167-1020

Uk'37 sea-surface temperature (SST) estimates obtained at ~2.5-k.y. resolution from Ocean Drilling Program Site 1020 show glacial-interglacial cyclicity with an amplitude of 7°-10°C over the last 780 k.y. This record shows a similar pattern of variability to another alkenone-based SST record obtained previously from the Santa Barbara Basin. Both records show that oxygen isotope Stage (OIS) 5.5 was warmer by ~3°C relative to the present and that glacial Uk'37 temperatures warm in advance of deglaciation, as inferred from benthic d18O records. The alkenone-based SST record at Site 1020 is longer than previously published work along the California margin. We show that warmer than present interglacial stages have occurred frequently during the last 800 k.y. Alkenone concentrations, a proxy for coccolithophorid productivity, indicate that sedimentary marine organic carbon content has also varied significantly over this interval, with higher contents during interglacial periods. A baseline shift to warmer SST and greater alkenone content occurs before OIS 13. We compare our results with those from previous multiproxy studies in this region and conclude that SST has increased by ~5°C since the last glacial period (21 ka). Our data show that maximum alkenone SSTs occur simultaneously with minimum ice volume at Site 1020, which is consistent with data from farther south along the margin. The presence of sea ice in the glacial northeast Pacific, the extent of which is inferred from locations of ice-rafted debris, provides further support for our notion of cold surface water within the northern California Current system, averaging 7°-8°C cooler during peak glacial conditions. The cooling of surface water during glacial stages most likely did not result from enhanced upwelling because alkenone concentrations and terrestrial redwood pollen assemblages are consistently lower during glacial periods

(Table 2) Revised stacked record on magnetic susceptibility of ODP Site 162-984 sediments

Magnetic field and susceptibility data were collected using the geological high-resolution magnetometer tool string (GHMT) at three sites during Ocean Drilling Program Leg 162. Postcruise processing of the magnetic field data yielded a polarity stratigraphy for Holes 986C and 987E. A magnetic susceptibility record was measured at Hole 984B. Detailed analysis of the core and log susceptibility records at Hole 984B yielded an empirical tool resolution of the susceptibility measurement tool (SUMT) of 53 cm. At Site 984, where sedimentation rates were typically >10 cm/k.y., this gave a resolution of at least ~5000 yr. This data report summarizes the GHMT postcruise processing, method of interpretation, and analysis of the SUMT resolution

Laparoscopic Roux-en-Y Gastric Bypass in the Megaobese .

HYPOTHESIS: Laparoscopic Roux-en-Y gastric bypass is a safe and effective procedure in patients with a body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) of 70 or greater. DESIGN: A retrospective analysis of patients with a BMI of 70 or greater who underwent laparoscopic Roux-en-Y gastric bypass by a single surgeon. SETTING: A university-affiliated community hospital in Allentown, Pa. PATIENTS: A nonconsecutive series of 9 patients with a BMI of 70 or greater who met traditional criteria for a bariatric procedure. INTERVENTION: Laparoscopic approach to Roux-en-Y gastric bypass with stapled anastomoses. RESULTS: Patient medical records were reviewed for length of stay, complications, operative time, comorbidities, and weight loss. Seven patients were women and 2 were men. Comorbidities included dyspnea on exertion, peripheral edema, arthritis, sleep apnea, hypertension, diabetes mellitus, asthma, hypothyroidism, gastroesophageal reflux disease, peptic ulcer disease, and heart disease. Eight of 9 procedures were successfully completed laparoscopically. One patient was converted to an open procedure. One patient developed a marginal ulcer postoperatively. No other complications occurred. Operative time ranged from 122 to 330 minutes (mean, 203 minutes). Length of stay averaged 1.2 days. Overall weight loss was 49% of excess body weight at 1 year after surgery. CONCLUSION: Laparoscopic Roux-en-Y gastric bypass is safe and effective in patients with a BMI of 70 or greater

Horse-related injury patterns: a single center report

Abstract Background For ages, humankind and horses have been closely related to occupational and recreational activities. The dangers of engaging with horses have been previously reported. Among sporting activities, horse riding is well-known for its risks. Despite multiple recommendations to wear protective gear, horse-related activities still comprise the risk of severe injuries. This study aimed to examine: (1) if specific mechanisms are correlated to particular injury patterns and (2) if injury types are related to patient demographics. Methods From one level I trauma center, between July 2019 and July 2022 (3 years) all emergency reports and discharge letters were retrospectively reviewed by full-text search regarding horse-related injuries. Patient demographics, body mass index, trauma mechanism, injury types, and initiated treatment were extracted from medical records and analyzed. Results During the study period, 95 patients with 99 horse-related injuries were included. The overwhelming majority of the patients was female (93.7%). Age averaged 35.3 years (range 6 to 71). BMI was 23.6 kg/m2. Inpatient treatment was required in 60.6%. Length of hospital stay averaged 10 days. Surgical treatment was performed in 55 patients (55.6%). Open reduction and internal fixation was the most common procedure (74.5%). Trauma mechanism was fall from a horse followed by being hit by a horse (60.6% and 23.2%, respectively). Injured upper extremities counted up for 52.5% followed by spinal and pelvic injuries (23.2%). Spinal and pelvic injuries were related to fall from a horse (p < 0.001). Injuries to the lower extremities were predominantly caused by a kick of the horse when the rider was unmounted (p = 0.001) and negatively related to a fall from a horse (p = 0.002). Ten patients got their fingers tangled while holding the reins and suffered from injuries to the upper extremity (p < 0.001). Three of them required an amputation (30%). Conclusion Despite the fact that patients are young and healthy, horse related injuries must not be underestimated. In our study, almost two-thirds of the patients required inpatient treatment and 50% underwent surgery. We could show that patient age was related to injury severity according to the Abbreviated Injury Scale (AIS). Spinal and pelvic injuries were significantly related to a fall from a horse with a significantly greater trauma impact according to the AIS. Therefore, these severe entities need to be ruled out in such events. Accidents caused by holding the reins, may result in serious injuries to the hand with 30% requiring an amputation. Doctors need to be aware of possible horse-related injury patterns to reduce morbidity