Heterogeneity of proliferative markers in pancreatic β-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass.

Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilitating complication of Roux-en-Y gastric bypass (RYGB) surgery. Increased secretion of insulin and incretin hormones is implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who underwent pancreatectomy for severe refractory hypoglycemia with neuroglycopenia (RYGB + NG). We aimed to determine whether β-cell proliferation or apoptosis is altered in RYGB + NG. We performed an observational study to analyze markers of proliferation, apoptosis, cell cycle, and transcription factor expression in pancreatic tissue from affected RYGB + NG patients (n = 12), normoglycemic patients undergoing pancreatic surgery for benign lesions (controls, n = 6), and individuals with hypoglycemia due to insulinoma (n = 52). Proliferative cell nuclear antigen (PCNA) expression was increased in insulin-positive cells in RYGB + NG patients (4.5-fold increase, p < 0.001 vs. controls) and correlated with β-cell mass. Ki-67 immunoreactivity was low in both RYGB + NG and controls, but did not differ between groups. Phospho-histone H3 levels did not differ between RYGB + NG and controls. PCNA and Ki-67 were both significantly lower in both controls and RYGB + NG than insulinomas. Markers of apoptosis and cell cycle (M30, p27, and p21) did not differ between groups. PDX1 and menin exhibited similar expression patterns, while FOXO1 appeared to be more cytosolic in RYGB + NG. Markers of proliferation are heterogeneous in patients with severe post-RYGB hypoglycemia. Increased β-cell proliferation in some individuals may contribute to increased β-cell mass observed in severely affected patients

Heterogeneity in multistage carcinogenesis and mixture modeling

Carcinogenesis is commonly described as a multistage process, in which stem cells are transformed into cancer cells via a series of mutations. In this article, we consider extensions of the multistage carcinogenesis model by mixture modeling. This approach allows us to describe population heterogeneity in a biologically meaningful way. We focus on finite mixture models, for which we prove identifiability. These models are applied to human lung cancer data from several birth cohorts. Maximum likelihood estimation does not perform well in this application due to the heavy censoring in our data. We thus use analytic graduation instead. Very good fits are achieved for models that combine a small high risk group with a large group that is quasi immune

Late Eocene to late Oligocene terrestrial climate and vegetation change in the western Tasmanian region

While many palaeoclimate studies have focussed on the Eocene-Oligocene transition (EOT), little is known about the timing and drivers of the post-EOT climate recovery. To better understand and reconstruct terrestrial climate and vegetation dynamics from the late Eocene to late Oligocene (35.5–27.46 Ma), we use a new, high-resolution palynological record and quantitative sporomorph-based climate estimates recovered from ODP Site 1168 on the western Tasmanian margin. Late Eocene (35.50–34.81 Ma) floras reveal Nothofagus-dominated temperate forests with secondary Gymnostoma and minor thermophilic plant elements growing under wet conditions, with mean annual temperatures (MATs) of ∼13 °C. This is followed by a small decrease in terrestrial temperatures across the EOT by ∼2 °C. Apart from a slight decline in abundance of Gymnostoma, increases in the Fuscospora and Lophozonia-type Nothofagus, and the disappearance of palms (Arecaceae), vegetation remained relatively stable across the EOT. However, a prolonged interval of warm-temperate conditions after 33.0 Ma, independent of fluctuations in the current pCO2 record, imply additional regional controls on local climate. Changes in surface oceanographic currents, due to sustained deepening of the Tasmanian Gateway, may have played a significant role in sustaining warm-temperate vegetation in southern Australia post-EOT. The early Oligocene (PZ 3; 30.5–27.46 Ma) vegetation record still maintains the Nothofagus-dominated forest with a recovery in Gymnostoma. Gymnosperms (especially Araucariaceae, Dacrydium, and Podocarpus) and cryptogams expanded alongside an increase in overall species diversity. Sporomorph-based MATs averaged ∼11 °C in this interval. The expansion of cool-temperate forest (sustained cool-temperate climate conditions in our terrestrial records) matches the general declining pCO2 concentrations in the early Oligocene. The synchroneity between terrestrial and marine temperatures (MATs and SSTs gradually decline) and atmospheric pCO2 highlight the importance of pCO2 in driving terrestrial climate and vegetation change in the Tasmanian region during the early Oligocene

Lipid-biomarker-based sea surface temperature record offshore Tasmania over the last 23 million years

The Neogene (23.04–2.58 Ma) is characterised by progressive buildup of ice volume and climate cooling in the Antarctic and the Northern Hemisphere. Heat and moisture delivery to Antarctica is, to a large extent, regulated by the strength of meridional temperature gradients. However, the evolution of the Southern Ocean frontal systems remains scarcely studied in the Neogene. Here, we present the first long-term continuous sea surface temperature (SST) record of the subtropical front area in the Southern Ocean at Ocean Drilling Program (ODP) Site 1168 off western Tasmania. This site is, at present, located near the subtropical front (STF), as it was during the Neogene, despite a 10∘ northward tectonic drift of Tasmania. We analysed glycerol dialkyl glycerol tetraethers (GDGTs – on 433 samples) and alkenones (on 163 samples) and reconstructed the paleotemperature evolution using TEX86 and U37k′ as two independent quantitative proxies. Both proxies indicate that Site 1168 experienced a temperate ∼ 25 ∘C during the early Miocene (23–17 Ma), reaching ∼ 29 ∘C during the mid-Miocene climatic optimum. The stepwise ∼ 10 ∘C cooling (20–10 ∘C) in the mid-to-late Miocene (12.5–5.0 Ma) is larger than that observed in records from lower and higher latitudes. From the Pliocene to modern (5.3–0 Ma), STF SST first plateaus at ∼ 15 ∘C (3 Ma), then decreases to ∼ 6 ∘C (1.3 Ma), and eventually increases to the modern levels around ∼ 16 ∘C (0 Ma), with a higher variability of 5∘ compared to the Miocene. Our results imply that the latitudinal temperature gradient between the Pacific Equator and the STF during late Miocene cooling increased from 4 to 14 ∘C. Meanwhile, the SST gradient between the STF and the Antarctic margin decreased due to amplified STF cooling compared to the Antarctic margin. This implies a narrowing SST gradient in the Neogene, with contraction of warm SSTs and northward expansion of subpolar conditions.</p

Strength and variability of the Oligocene Southern Ocean surface temperature gradient

Large Oligocene Antarctic ice sheets co-existed with warm proximal waters offshore Wilkes Land. Here we provide a broader Southern Ocean perspective to such warmth by reconstructing the strength and variability of the Oligocene Australian-Antarctic latitudinal sea surface temperature gradient. Our Oligocene TEX86-based sea surface temperature record from offshore southern Australia shows temperate (20–29 °C) conditions throughout, despite northward tectonic drift. A persistent sea surface temperature gradient (~5–10 °C) exists between Australia and Antarctica, which increases during glacial intervals. The sea surface temperature gradient increases from ~26 Ma, due to Antarctic-proximal cooling. Meanwhile, benthic foraminiferal oxygen isotope decline indicates ice loss/deep-sea warming. These contrasting patterns are difficult to explain by greenhouse gas forcing alone. Timing of the sea surface temperature cooling coincides with deepening of Drake Passage and matches results of ocean model experiments that demonstrate that Drake Passage opening cools Antarctic proximal waters. We conclude that Drake Passage deepening cooled Antarctic coasts which enhanced thermal isolation of Antarctica

Absence of a strong, deep-reaching Antarctic Circumpolar Current zonal flow across the Tasmanian gateway during the Oligocene to early Miocene

The vigorous eastward flow of the Antarctic Circumpolar Current (ACC) connects all major ocean basins and plays a prominent role in the transport of heat, carbon and nutrients around the globe. However, the establishment of a deep circumpolar flow, similar to the present-day ACC, remains controversial thereby obscuring our understanding of its climatic impact. Deciphering the chemical composition of Circumpolar Deep Water (CDW) within the ACC can provide critical insights about its development and evolution. Here we present new fossil fish teeth/bone debris neodymium isotope (ε) records from Deep Sea Drilling Project (DSDP) Sites 278 and 274 in the southwest Pacific Ocean, with the aim to trace changes in deep water masses across the Tasmanian Gateway between the early Oligocene and early Miocene (~ 33–22 Ma). Site 274 provides the first Nd isotope record proximal to the Ross Sea during the Oligocene (33.5–23.4 Ma). Its Nd isotope composition shows excursions to very radiogenic values, ε = −3.1 and ε − 3.7, at 33.5 Ma and 23.8 Ma, respectively, in response to major steps in Antarctic ice sheet expansion. A shift to lower, more unradiogenic ε values between 29.7 and 29.1 Ma is linked to an increased influence of proto-CDW upwelling at the site. In contrast, the Nd isotope record from Site 278 in the southern Emerald Basin shows little variability (ε = −6.0 to −6.7) throughout the Oligocene and early Miocene (30.9–21.8 Ma). Comparison with published data north of the ACC path, demonstrates the presence of two deep water masses in the South Pacific prior to the inferred onset of the ACC (33–30 Ma), one occupying depths between ~2500 and 3000 m (ε ~ −3 to −5) and a deep/bottom water mass (> 3000 m) with a more unradiogenic Nd isotope composition (ε ~ −6). Site 278 located close to the proto-polar front (proto-PF) indicates that following the inferred onset of the ACC, deep waters bathing the southern Emerald Basin remained more radiogenic in the Southwest Pacific compared to sites along the proto-PF in the South Atlantic and Indian Ocean (ε ~ −8.1). This indicates a provinciality in Nd isotope compositions of deep waters along the proto-PF across the Tasmanian Gateway. Our data are incompatible with the existence of a modern-like homogenous (lateral and vertical) Nd isotope composition of CDW along the main flow path of the ACC in all oceanic basins in the Oligocene to early Miocene. We attribute distinct Nd isotope compositions of deep waters across the Tasmanian Gateway to reflect a less deep reaching and weaker ACC (proto-ACC) than today. Our findings suggest that the modern strong and deep-reaching ACC flow must have been developed at a later point in the Neogene.Funding to this research is provided by the Alexander S. Onassis Public Benefit Foundation Ph.D. research grant: F ZL 016-1/2015-2016; the Spanish Ministry of Economy, Industry and Competitivity (grants CTM2017-89711-C2-1/2-P), co-funded by the European Union through FEDER funds; and an ECORD Research grant awarded to DE. PKB and FH acknowledge funding through the European Research Council starting grant #802835 OceaNice and NWO polar programme grant ALWPP2016.001. This paper is a contribution to the SCAR PAIS Programme