The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with ...persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals.
Interpretation of U-series disequilibria in midocean ridge basalts is highly dependent on the bulk partition coefficients for U and Th and therefore the mineralogy of the mantle source. ...Distinguishing between the effect of melting processes and variable source compositions on measured disequilibria (
238U-
230Th-
226Ra and
235U-
231Pa) requires measurement of the radiogenic isotopes Hf, Nd, Sr, and Pb. Here, we report measurements of
238U-
230Th-
226Ra and
235U-
231Pa disequilibria; Hf, Nd, Sr, and Pb isotopic; and major and trace element compositions for a suite of 20 young midocean ridge basalts from the East Pacific Rise axis between 9°28′ and 9°52′N. All of the samples were collected within the axial summit trough using the submersible Alvin. The geological setting and observational data collected during sampling operations indicate that all the rocks are likely to have been erupted from 1991 to 1992 or within a few decades of that time. In these samples,
230Th excesses and
226Ra excesses are variable and inversely correlated. Because the eruption ages of the samples are much less than the half-life of
226Ra, this inverse correlation between
230Th and
226Ra excesses can be considered a primary feature of these lavas. For the lava suite analyzed in this study,
226Ra and
230Th excesses also vary with lava composition:
226Ra excesses are negatively correlated with Na
8 and La/Yb and positively correlated with Mg#. Conversely,
230Th excesses are positively correlated with Na
8 and La/Yb and negatively correlated with Mg#. Th/U,
230Th/
232Th, and
230Th excesses are also variable and correlated to one another.
231Pa excesses are large but relatively constant and independent of Mg#, La/Yb, Th/U, and Na
8. The isotope ratios
143Nd/
144Nd,
176Hf/
177Hf,
87Sr/
86Sr, and
208Pb/
206Pb are constant within analytical uncertainty, indicating that they were derived from a common source. The source is homogeneous with respect to parent/daughter ratios Lu/Hf, Sm/Nd, Rb/Sr, and Th/U; therefore, the measured variations of Th/U,
230Th, and
226Ra excesses and major and trace element compositions in these samples are best explained by polybaric melting of a homogeneous source, not by mixing of compositionally distinct sources.
In the Tyrrhenian region of central Italy, late Quaternary fossil travertines are widespread along two major regional structures: the Tiber Valley and the Ancona–Anzio line. The origin and transport ...of spring waters from which travertines precipitate are elucidated by chemical and isotopic studies of the travertines and associated thermal springs and gas vents. There are consistent differences in the geochemical and isotopic signatures of thermal spring waters, gas vents and present and fossil travertines between east and west of the Tiber Valley. West of the Tiber Valley, δ
13C of CO
2 discharged from gas vents and δ
13C of fossil travertines are higher than those to the east. To the west the travertines have higher strontium contents, and gases emitted from vents have higher
3He/
4He ratios and lower N
2 contents, than to the east. Fossil travertines to the west have characteristics typical of thermogene (thermal spring) origin, whereas those to the east have meteogene (low-temperature) characteristics (including abundant plant casts and organic impurities). The regional geochemical differences in travertines and fluid compositions across the Tiber Valley are interpreted with a model of regional fluid flow. The regional Mesozoic limestone aquifer is recharged in the main axis of the Apennine chain, and the groundwater flows westward and is discharged at springs. The travertine-precipitating waters east of the Tiber Valley have shallower flow paths than those to the west. Because of the comparatively short fluid flow paths and low (normal) heat flow, the groundwaters to the east of the Tiber Valley are cold and have CO
2 isotopic signatures, indicating a significant biogenic contribution acquired from soils in the recharge area and limited deeply derived CO
2. In contrast, spring waters west of the Tiber Valley have been conductively heated during transit in these high heat-flow areas and have incorporated a comparatively large quantity of CO
2 derived from decarbonation of limestone. The elevated strontium content of the thermal spring water west of the Tiber Valley is attributed to deep circulation and dissolution of a Triassic evaporite unit that is stratigraphically beneath the Mesozoic limestone. U-series age dates of fossil travertines indicate three main periods of travertine formation (ka): 220–240, 120–140 and 60–70. Based on the regional flow model correlating travertine deposition at thermal springs and precipitation in the recharge area, we suggest that pluvial activity was enhanced during these periods. Our study suggests that travertines preserve a valuable record of paleofluid composition and paleoprecipitation and are thus useful for reconstructing paleohydrology and paleoclimate.
Postoperative pulmonary complications (PPC) may result in longer duration of in-hospital stay and even mortality. Both thoracic surgery and intraoperative mechanical ventilation settings add ...considerably to the risk of PPC. It is unclear if one-lung ventilation (OLV) for thoracic surgery with a strategy of intraoperative high positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM) reduces PPC, compared to low PEEP without RM.
PROTHOR is an international, multicenter, randomized, controlled, assessor-blinded, two-arm trial initiated by investigators of the PROtective VEntilation NETwork. In total, 2378 patients will be randomly assigned to one of two different intraoperative mechanical ventilation strategies. Investigators screen patients aged 18 years or older, scheduled for open thoracic or video-assisted thoracoscopic surgery under general anesthesia requiring OLV, with a maximal body mass index of 35 kg/m
, and a planned duration of surgery of more than 60 min. Further, the expected duration of OLV shall be longer than two-lung ventilation, and lung separation is planned with a double lumen tube. Patients will be randomly assigned to PEEP of 10 cmH
O with lung RM, or PEEP of 5 cmH
O without RM. During two-lung ventilation tidal volume is set at 7 mL/kg predicted body weight and, during OLV, it will be decreased to 5 mL/kg. The occurrence of PPC will be recorded as a collapsed composite of single adverse pulmonary events and represents the primary endpoint.
PROTHOR is the first randomized controlled trial in patients undergoing thoracic surgery with OLV that is adequately powered to compare the effects of intraoperative high PEEP with RM versus low PEEP without RM on PPC. The results of the PROTHOR trial will support anesthesiologists in their decision to set intraoperative PEEP during protective ventilation for OLV in thoracic surgery.
The trial was registered in clinicaltrials.gov ( NCT02963025 ) on 15 November 2016.
After publication of the original article 1, the authors have notified us that two of the collaborator first and last names have been inverted in the "PROTHOR Investigators" table.
Measurement of protactinium-231 ($^{231}$Pa) in carbonates by thermal ionization mass spectroscopy yields $^{231}$Pa ages that are more than 10 times more precise than those determined by decay ...counting. Carbonates between 10 and 250,000 years old can now be dated with $^{231}$Pa methods. Barbados corals that have identical $^{231}$Pa and thorium-230 ($^{230}$Th) ages indicate that the timing of sea level change over parts of the last glacial cycle is consistent with the predictions of the Astronomical Theory. Two Devils Hole calcite subsamples record identical $^{231}$Pa and $^{230}$Th ages, suggesting that the chronology of this climate record is accurate.
Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration ...in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.
Recent advances in high-resolution, rapid, in situ microanalytical techniques present numerous opportunities for the analytical community, provided accurately characterized reference materials are ...available. Here, we present multicollector thermal ionization mass spectrometry (MC-TIMS) and multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS) uranium and thorium concentration and isotopic data obtained by isotope dilution for a suite of newly available Chinese Geological Standard Glasses (CGSG) designed for microanalysis. These glasses exhibit a range of compositions including basalt, syenite, andesite, and a soil. Uranium concentrations for these glasses range from ∼2 to 14 μg g–1, Th/U weight ratios range from ∼4 to 6, 234U/238U activity ratios range from 0.93 to 1.02, and 230Th/238U activity ratios range from 0.98 to 1.12. Uranium and thorium concentration and isotopic data are also presented for a rhyolitic obsidian from Macusani, SE Peru (macusanite). This glass can also be used as a rhyolitic reference material, has a very low Th/U weight ratio (around 0.077), and is approximately in 238U–234U–230Th secular equilibrium. The U–Th concentration data agree with but are significantly more precise than those previously measured. U–Th concentration and isotopic data agree within estimated errors for the two measurement techniques, providing validation of the two methods. The large 238U–234U–230Th disequilibria for some of the glasses, along with the wide range in their chemical compositions and Th/U ratios should provide useful reference points for the U-series analytical community.
HIV reservoirs persist in anatomic compartments despite antiretroviral therapy (ART). Characterizing archival HIV DNA in the central nervous system (CNS) and other tissues is crucial to inform cure ...strategies. We evaluated paired autopsy brain-frontal cortex (FC), occipital cortex (OCC), and basal ganglia (BG)-and peripheral lymphoid tissues from 63 people with HIV. Participants passed away while virally suppressed on ART at the last visit and without evidence of CNS opportunistic disease. We quantified total HIV DNA in all participants and obtained full-length HIV-envelope (FL HIV-
) sequences from a subset of 14 participants. We detected HIV DNA (
) in most brain (65.1%) and all lymphoid tissues. Lymphoid tissues had higher HIV DNA levels than the brain (
< 0.01). Levels of HIV
between BG and FC were similar (
> 0.2), while OCC had the lowest levels (
= 0.01). Females had higher HIV DNA levels in tissues than males (
,
= 0.03; 2-LTR,
= 0.05), suggesting possible sex-associated mechanisms for HIV reservoir persistence. Most FL HIV-
sequences (
= 143) were intact, while 42 were defective. Clonal sequences were found in 8 out of 14 participants, and 1 participant had clonal defective sequences in the brain and spleen, suggestive of cell migration. From 10 donors with paired brain and lymphoid sequences, we observed evidence of compartmentalized sequences in 2 donors. Our data further the idea that the brain is a site for archival HIV DNA during ART where compartmentalized provirus may occur in a subset of people. Future studies assessing FL HIV-provirus and replication competence are needed to further evaluate the HIV reservoirs in tissues.
HIV infection of the brain is associated with adverse neuropsychiatric outcomes, despite efficient antiretroviral treatment. HIV may persist in reservoirs in the brain and other tissues, which can seed virus replication if treatment is interrupted, representing a major challenge to cure HIV. We evaluated reservoirs and genetic features in postmortem brain and lymphoid tissues from people with HIV who passed away during suppressed HIV replication. We found a differential distribution of HIV reservoirs across brain regions which was lower than that in lymphoid tissues. We observed that most HIV reservoirs in tissues had intact envelope sequences, suggesting they could potentially generate replicative viruses. We found that women had higher HIV reservoir levels in brain and lymphoid tissues than men, suggesting possible sex-based mechanisms of maintenance of HIV reservoirs in tissues, warranting further investigation. Characterizing the archival HIV DNA in tissues is important to inform future HIV cure strategies.
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