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AIMS: Maintenance of adequate levels of soil organic carbon (SOC) is crucial for the biological, chemical and physical functioning of soils. This study was conducted (i) to determine the impact of long-term sugarcane monoculture on total SOC stocks and on its labile fractions and (ii) to quantify the loss of original SOC and the accretion of sugarcane-derived C following the adoption of new management practices namely de-rocking/land grading and mechanized harvesting. METHODS: Five study sites representing the five major soil groups under sugarcane in Mauritius were selected with a classical “paired-plot” design adopted. In this design, two sites with similar initial conditions were developed in different ways over time. One represents the reference soil (virgin land with predominantly C₃ type vegetation) and the other represents one of the following cropping treatments: (i) fields continuously cultivated with sugarcane for more than 25 or 50 years without de-rocking or land grading, (ii) fields under long-term sugarcane but having undergone de-rocking and land grading for mechanized harvesting in the last 3 years. Soil samples were taken to a depth of 50 cm and analysed for total organic C, labile C, ¹³C natural abundance, bulk density and stone content. RESULTS: Changes in SOC stock in the 0–50 cm profile following >50 years of cane cropping were not significant (P > 0.05) compared to virgin land at any site. Soil δ¹³C values revealed that long-term sugarcane cultivation resulted in a depletion of original SOC by 34 to 70 %. However, this loss was fully compensated by C input from sugarcane residues at all sites studied resulting in no net change in SOC stock. Adoption of mechanized harvest did not have any detrimental effect on SOC stocks due to C inputs from crop residues. However, long-term sugarcane cultivation resulted in significant decline in a labile C (KMnO₄-oxidizable) fraction. CONCLUSION: Despite the large losses of original C following conversion from forest to sugarcane, long-term sugarcane cultivation resulted in sequestration of sugarcane-derived C which adequately compensated these losses. Moreover, intensive de-rocking and land grading preceding mechanized harvesting did not have any detrimental effect on SOC stocks. However, the quality of sugarcane soils, as indicated by a decline in labile C, could be degraded.

Cancer cachexia is defined as a state of involuntary weight loss, attributed to altered body composition with muscle mass loss and/or loss of adiposity. Identifying the association between cancer cachexia and outcomes may pave the way for novel agents that target the cancer cachexia process. Clinical parameters for measurement of cancer cachexia are needed. We conducted a single-institution retrospective analysis that included 86 NHL patients with the aim of identifying an association between cancer cachexia and outcomes in aggressive lymphomas using the cachexia index (CXI) suggested by Jafri et al. (Clin Med Insights Oncol 9:87–93, 15 ). Impact of cachexia factors on progression-free survival (PFS) and overall survival (OS) were assessed using log-rank test and Cox proportional hazards regression. Patients were dichotomized around the median CXI into “non-cachectic” (CXI ≥49.8, n  = 41) and “cachectic” (CXI <49.8, n  = 40) groups. Cachectic patients had significantly worse PFS (HR 2.18, p  = 0.044) and OS (HR = 4.05, p  = 0.004) than non-cachectic patients. Cachexia as defined by the CXI is prognostic in aggressive lymphomas and implies that novel therapeutic strategies directed at reversing cachexia may improve survival in this population.

Immune checkpoint inhibitors (ICIs) are the current guideline recommended treatment for many malignancies considered to be terminal. Despite considerable advances, their utility remains limited, and the field requires synergistic partners to further improve outcomes. Oncolytic viruses (OV) are emerging as contenders for the role of the synergistic agent of choice due to their multi-mechanistic effect on activating the tumor ‘cold’ immune microenvironment. Herpes simplex virus 1, a naturally selective OV, is the most advanced virotherapeutic compound in clinical applications for use in combination with ICI. We here present the case of a 72 year-old patient with a heavily pre-treated, advanced maxillary sinus squamous cell cancer with distant metastases who developed complete response (CR) with only three administrations of a programmed death 1 inhibitor after treatment interference by a severe herpes zoster infection, based on the related alpha-herpesvirus varicella zoster virus (VZV). This exceptional response has been followed and confirmed with imaging studies over more than 5 years. Although the patient had several favorable predictors for response to immunotherapy, we reason that the exceptional response may in part be secondary to the serendipitous VZV infection. Documented cases of cancer patients that achieved CR after few administrations of treatment with ICI are rare, with most reporting follow up of just over 1 year or less. In this case, it is conceivable that the interference of the infection with VZV, soon after the start of immunotherapy with ICI, led to a lasting antitumor immunity and sustained CR. This hypothesis is supported by the concept of ‘oncolytic immunotherapy’ which is reviewed in this manuscript. In addition, persistence of a TP53 mutation found in a liquid biopsy, despite clinical and radiologic remission, is discussed.

Engineered whole lungs may one day expand therapeutic options for patients with end-stage lung disease. However, the feasibility of ex vivo lung regeneration remains limited by the inability to recapitulate mature, functional alveolar epithelium. Here, we modulate multimodal components of the alveolar epithelial type 2 cell (AEC2) niche in decellularized lung scaffolds in order to guide AEC2 behavior for epithelial regeneration. First, endothelial cells coordinate with fibroblasts, in the presence of soluble growth and maturation factors, to promote alveolar scaffold population with surfactant-secreting AEC2s. Subsequent withdrawal of Wnt and FGF agonism synergizes with tidal-magnitude mechanical strain to induce the differentiation of AEC2s to squamous type 1 AECs (AEC1s) in cultured alveoli, in situ. These results outline a rational strategy to engineer an epithelium of AEC2s and AEC1s contained within epithelial-mesenchymal-endothelial alveolar-like units, and highlight the critical interplay amongst cellular, biochemical, and mechanical niche cues within the reconstituting alveolus.

The heart is a highly adaptable organ, capable of altering its properties over both short and long timescales. Contractility can be modulated within seconds to match increased mechanical loads. If these demands are sustained over a prolonged period, the heart undergoes macroscopic and microscopic changes to achieve an adapted equilibrium. Although cardiac remodeling processes may be adaptive and help to maintain homeostasis, these changes can become maladaptive over time and contribute to the development of heart failure. Understanding the detailed mechanisms by which mechanical loads are transduced to cellular changes is therefore of critical importance, but remains poorly understood. Progress has been elusive in part due to the difficulty of studying cardiomyocytes under defined loading conditions, whether in vivo or in vitro. In this work, we developed a system capable of delivering precise mechanical loads to human engineered heart tissues (EHTs) under chronic culture conditions. Our efforts yielded a design that enables independent regulation of preload, afterload, and contractile work, allowing the impact of each factor on myocardial remodeling to be clearly studied. Using this system, we observed augmented mitochondrial biogenesis in response to increased contractile work. Increases in mitochondrial mass were path independent – regulation of mitochondrial biogenesis and mass occurred independently of shortening regimes and developed tensions. Additionally, we examined the effects of loading on sarcomere regulation and found myosin heavy chain isoform expression to be highly sensitive to the velocity of shortening, yet relatively insensitive to afterload. To our knowledge, these results are the first evidence of the ability of cardiomyocytes to sense and respond to shortening and shortening rate independently of mechanical load. We then used this system to investigate the role of mechanical loading in cardiac pathophysiology. Arrhythmogenic Cardiomyopathy (ACM) is an inherited disease characterized by fibro-fatty replacement of the myocardium, ventricular arrhythmias, heart failure, and elevated risk of sudden cardiac death. A majority of ACM associated mutations are found within genes encoding for a desmosomal protein, however variable disease penetrance indicates the importance of additional factors. Strenuous exercise has been shown to exacerbate disease progression, yet underlying pathomechanisms have not been elucidated. In this work, we focused on a variant of unknown significance in desmoplakin. An extensive single-family ACM cohort was assembled, revealing a pattern of coinheritance for R451G desmoplakin and the ACM phenotype. Molecular dynamic simulations and protein degradation assays of recombinant R451G desmoplakin identified the primary effects of the mutation as increased susceptibility towards calpain-mediated degradation. Cardiomyocytes differentiated from patient-derived induced pluripotent stem cells showed depressed levels of desmoplakin in the absence of abnormal electrical propagation. In order to mimic exercise training, EHTs were either stretched during relaxation (high preload) or contracted against increased resistance (high afterload), modeling dynamic or static exercise respectively. We found that high preloads reduced conduction velocity and levels of gap junction proteins in EHTs expressing R451G desmoplakin. These reductions were not observed during exposure to high afterloads, suggesting that highly static exercises may be better tolerated by ACM patients than highly dynamic exercises. Reduced levels of gap junction proteins resulted from increased lysosome-mediated degradation and inhibition of the ERK pathway was able to partially mitigate this loss. This work represents some of the earliest evidence of mechanical loading giving rise to conduction delays in an in vitro model of ACM. EHTs expressing R451G desmoplakin were hypersensitized to diastolic stretch specifically, while remaining unaffected by increased systolic loads. Overall this body of work provides an increased understanding into the role of mechanical loading in cardiac physiology and pathophysiology.

The sandstone-hosted McArthur River Zone 4 U ore body and alteration system, located in the Athabasca Basin, are the focus of a detailed mineralogical and geochemical study aimed at reconstructing its evolution. The oxidation state of Fe in clay alteration from Zone 4 is measured using 57Fe Mössbauer spectroscopy and compared with other mineralized and barren sandstone-hosted alteration systems in the Athabasca Basin. The aim is to ascertain the role of Fe in forming U deposits and determine whether Fe oxidation state in alteration minerals can indicate proximity to mineralization. At Zone 4, early diagenetic kaolin is overprinted by zones of dravite, illite, chlorite, and late kaolinite forming around the P2 fault. Uranium mineralization occurred at ca. 1600 Ma and was triggered by mixing between oxidizing U-bearing basinal fluids and reducing basement-modified basinal fluids, the latter forming when basinal fluids interacted with basement lithologies. Early pre-ore silicification in the lower 200 metres of the Manitou Falls Formation above the ore body created favourable conditions for mineralization by focusing basinal fluids into the reduction site and enhancing ore preservation. However, it obstructed the post-ore migration of radiogenic Pb and U pathfinder elements from the deposit and limited the extent of hydrothermal sudoite alteration in the overlying strata. Sandstone-hosted alteration systems in the Athabasca Basin are commonly surrounded by an outer illite and an inner chlorite zone. Illites have high Fe3+/ΣFe ratios characteristic of formation from oxidizing basinal fluids, whereas, chlorites have lower and more varied Fe3+ /ΣFe ratios, reflecting their origin from reducing, Fe 2+-bearing basement-derived fluids having undergone variable mixing with oxidizing basinal fluids. Chlorites in mineralized systems where fluid-mixing occurred, such as at McArthur River Zone 4 and Maurice Bay, record higher Fe3+/ΣFe ratios than barren systems where fluid-mixing did not, such as at Wheeler River Zone K and Spring Point. The scarcity of U-bearing basinal fluids available for mixing with Fe2+-bearing basement fluids is a critical geochemical factor precluding mineralization in barren sandstone-hosted systems. The Fe3+/ΣFe ratio of chlorites has potential applications for discriminating barren and mineralized systems and as spatial vectors to ore when coupled with Pb isotope ratios.

This dissertation examines the function of photographs in W. G. Sebald's The Emigrants. I argue that images in the book encourage the reader to identify with those depicted in them and simultaneously discourage this identification. Dissecting the mechanism and motivations of this inherent contradiction, an ethics of viewing and writing about the past emerges. Sebald engages the readers with these photographs, I argue, to champion a cautious and qualified identification. Sebald's interactions with the past are indicative of his historical background. Having missed the catastrophic events of the Second World War, he is motivated by a historical compunction to depict the past and a personal desire to be present in it. The photographs discussed in this dissertation both fulfill and frustrate this desire. They demonstrate how the momentous events can be transmitted to and worked through by Sebald's generation. For this reason, The Emigrants contributes vitally to the work of Vergangenheitsbewältigung; it attempts to grapple with and overcome the legacy of the Holocaust by encouraging a form of nuanced, and therefore ethical, identification. To explore Sebald's relationship with this legacy, I examine photographs that put the viewer in four different subject positions: family member, researcher, victim, and perpetrator. This diversity of perspectives constitutes precisely the \"synoptic and artificial view\" that Sebald advocates. Images of each subject position reveal different insights on how his generation views the past. Almost twenty-five years after the publication of The Emigrants, the book continues to be the topic of rigorous scholarly discussion, testifying to its relevance to present German society and beyond.

Both in terms of area and population, the fifteen changwads of the North-east constitute the largest of the four basic regions in the Kingdom of Thailand. Recent census data indicate that 37.9 per cent of the 3.2 million Thai farm households live in this region cultivating a similar proportion of the country's 69.7 million rai (I rai = 0.395 acre) of land in agricultural holdings. However, the region seems to have more than its fair share of the problems which stand in the way of the Government's efforts to accelerate the country's economic development. At present, the solution to the ‘North-east Problem’ remains as elusive as it was a decade ago. In spite of the impressive amount of public expenditure already poured into the region for improving the infra-structure and providing a wide range of rural facilities, together with an ever-increasing amount of services rendered by national and international agencies for planning and implementing the processes of growth, the per caput income of the North-easterner still lags as far behind that of his fellow countryman residing elsewhere in the kingdom as it did in the recent past. This article attempts to analyse the interaction of the physical conditions and socio-economic problems which are bound up in the existing land-use system of the North-east.

The cardiac progenitor cells （CPCs） in the anterior heart field （AHF） are located in the pharyngeal mesoderm （PM）, where they expand, migrate and eventually differentiate into major cell types found in the heart, including cardio- myocytes. The mechanisms by which these progenitors are able to expand within the PM microenvironment without premature differentiation remain largely unknown. Through in silico data mining, genetic loss-of-function studies, and in vivo genetic rescue studies, we identified N-cadherin and interaction with canonical Wnt signals as a critical component of the microenvironment that facilitates the expansion of AHF-CPCs in the PM. CPCs in N-cadherin mutant embryos were observed to be less proliferative and undergo premature differentiation in the PM. Notably, the phenotype of N-cadherin deficiency could be partially rescued by activating Wnt signaling, suggesting a delicate functional interaction between the adhesion role of N-cadherin and Wnt signaling in the early PM microenviron- ment. This study suggests a new mechanism for the early renewal of AHF progenitors where N-cadherin provides ad- ditional adhesion for progenitor cells in the PM, thereby allowing Wnt paracrine signals to expand the cells without premature differentiation.