We analyzed sediment from Ocean Drilling Program (ODP) Site 1144 in the northern South China Sea to examine the weathering response of SE Asia to the strengthening of the East Asian Monsoon (EAM) ...since 14ka. Our high-resolution record highlights the decoupling between continental chemical weathering, physical erosion and summer monsoon intensity. Mass accumulation rates, Ti/Ca, K/Rb, hematite/goethite and 87Sr/86Sr show sharp excursions from 11 to 8ka, peaking at 10ka. Clay minerals show a shorter-lived response with a higher kaolinite/(illite+chlorite) ratio at 10.7–9.5ka. However, not all proxies show a clear response to environmental changes. Magnetic susceptibility rises sharply between 12 and 11ka. Grain-size becomes finer from 14 to 10ka and then coarsens until ~7ka, but is probably controlled by bottom current flow and sealevel. Sr and Nd isotopes show that material is dominantly eroded from Taiwan with a lesser flux from Luzon, while clay mineralogy suggests that the primary sources during the Early Holocene were reworked via the shelf in the Taiwan Strait, rather than directly from Taiwan. Erosion was enhanced during monsoon strengthening and caused reworking of chemically weathered Pleistocene sediment largely from the now flooded Taiwan Strait, which was transgressed by ~8ka, cutting off supply to the deep-water slope. None of the proxies shows an erosional response lasting until ~6ka, when speleothem oxygen isotope records indicate the start of monsoon weakening. Although more weathered sediments were deposited from 11 to 8ka when the monsoon was strong these are reworked and represent more weathering during the last glacial maximum (LGM) when the summer monsoon was weaker but the shelves were exposed.
► First high resolution multi-proxy weathering and erosion study in Holocene East Asia. ► Continental slope records can record environmental change but record is fragmentary. ► Mass accumulation rate, 87Sr/86Sr, K/Rb, clay minerals respond to intensified monsoon. ► Sealevel rise truncates records like hematite/goethite by flooding the source region. ► Stronger early Holocene weathering pulse is reworked from Last Glacial Maximum.
Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to X-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based ...techniques detect deletions, duplications, or point mutations in the dystrophin-encoding DMD gene. However, in a small subset of patients clinically diagnosed with DMD, the molecular cause is not identified with these routine methods. Evaluation of the 60 DMD patients in our center revealed three cases without a known genetic cause. DNA samples of these patients were analyzed using whole-exome sequencing (WES) and, if unconclusive, optical genome mapping (OGM). WES led to a diagnosis in two cases: one patient was found to carry a splice mutation in the DMD gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene (FKTN) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the DMD gene (~1.28 Mb) that was subsequently confirmed with long-read sequencing. These results highlight the importance of reanalyzing unsolved cases using WES and demonstrate that OGM is a useful method for identifying large structural variants in cases with unremarkable exome sequencing.
We present a multi-proxy mineral record based on X-ray diffraction and diffuse reflectance spectrophotometry analysis for two cores from the western Indus Shelf in order to reconstruct changing ...weathering intensities, sediment transport, and provenance variations since 13ka. Core Indus-10 is located northwest of the Indus Canyon and exhibits fluctuations in smectite/(illite+chlorite) ratios that correlate with monsoon intensity. Higher smectite/(illite+chlorite) and lower illite crystallinity, normally associated with stronger weathering, peaked during the Early–Mid Holocene, the period of maximum summer monsoon. Hematite/goethite and magnetic susceptibility do not show clear co-variation, although they both increase at Indus-10 after 10ka, as the monsoon weakened. At Indus-23, located on a clinoform just west of the canyon, hematite/goethite increased during a period of monsoon strengthening from 10 to 8ka, consistent with increased seasonality and/or reworking of sediment deposited prior to or during the glacial maximum. After 2ka terrigenous sediment accumulation rates in both cores increased together with redness and hematite/goethite, which we attribute to widespread cultivation of the floodplain triggering reworking, especially after 200years ago. Over Holocene timescales sediment composition and mineralogy in two localities on the high-energy shelf were controlled by varying degrees of reworking, as well as climatically modulated chemical weathering.
► We examine a high resolution multi-proxy physical properties from two marine cores. ► Little correlation between physical proxies and climate in early Holocene ► Reworking probable cause of poor correlation in Early Holocene ► Possible anthropogenic influence on sedimentation in the last 200 years
High pre-existing antibodies against viral vectors reduce their functionality and may lead to adverse complications. To circumvent this problem in future gene therapy approaches, we tested the ...seroprevalence of a large range of human adenovirus types in patients with neuromuscular disorders (NMDs) to find appropriate viral vector candidates for gene replacement therapy for NMDs. Binding and neutralizing antibodies against 39 human adenovirus types were tested in the sera of 133 patients with NMDs and 76 healthy controls aged 17-92 years. The influence of age, sex, and NMDs on antibody levels was analyzed. The seroprevalence of different adenoviruses in the cohort varied widely. The highest levels of binding antibodies were detected against HAdV-D27, -C1, -D24, -D70, -B14, -C6, -D13, -B34, and -E4, whereas the lowest reactivity was detected against HAdV-F41, -A31, -B11, -D75, -D8, -D65, -D26, -D80, and -D17. The highest neutralizing reactivity was observed against HAdV-B3, -C2, -E4, -C1, -G52, -C5, and -F41, whereas the lowest neutralizing reactivity was observed against HAdV-D74, -B34, -D73, -B37, -D48, -D13, -D75, -D8, -B35, and -B16. We detected no influence of sex and only minor differences between different age groups. Importantly, there were no significant differences between healthy controls and patients with NMDs. Our data show that patients with NMDs have very similar levels of binding and neutralizing antibodies against HAdV compared to healthy individuals, and we identified HAdV-A31, -B16, -B34, -B35, -D8, -D37, -D48, -D73, -D74, -D75, and -D80 as promising candidates for future vector development due to their low binding and neutralizing antibody prevalence.
New techniques in molecular genetic diagnostics now allow for accurate diagnosis in a large proportion of patients with muscular diseases. Nevertheless, many patients remain unsolved, although the ...clinical history and/or the muscle biopsy give a clear indication of the involved genes. In many cases, there is a strong suspicion that the cause must lie in unexplored gene areas, such as deep-intronic or other non-coding regions. In order to find these changes, next-generation sequencing (NGS) methods are constantly evolving, making it possible to sequence entire genomes to reveal these previously uninvestigated regions. Here, we present a young woman who was strongly suspected of having a so far genetically unsolved sarcoglycanopathy based on her clinical history and muscle biopsy. Using short read whole genome sequencing (WGS), a homozygous inversion on chromosome 13 involving
and
was detected. The breakpoint in intron 2 of
led to the absence of γ-sarcoglycan, resulting in the manifestation of autosomal recessive limb-girdle muscular dystrophy 5 (LGMDR5) in the young woman.
Myopathies comprise a heterogeneous group of disorders characterized by variable phenotypes. The increasing use of next-generation sequencing allows identification of the causative genes in a much ...higher percentage of patients with hereditary muscle disorders and also illustrates a considerable degree of overlap with other clinical entities, including connective tissue disorders. Here, we present a 14-year-old German patient who was initially suspected to suffer from myopathy based on his clinical, radiological, and muscle biopsy findings. Exome sequencing revealed a novel homozygous nonsense mutation in the
gene, causative for spondylocheiro dysplastic Ehlers Danlos syndrome (SCD-EDS), suggesting a connective tissue disorder. Including our patient, only 9 affected individuals from 4 families have been described for SCD-EDS so far. The previously reported patients did not show obvious evidence of myopathy, suggesting a broader clinical presentation than originally suspected. We summarize herein the current knowledge on clinical features as well as pathophysiological pathways for this rare connective tissue disease and discuss the high degree of clinical overlap between myopathic and connective tissue disorders.
Mutations in the DARS2 gene are known to cause leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), a rare autosomal recessive neurological disorder. It was ...originally described as juvenile-onset slowly progressive ataxia and spasticity, but recent reports suggest a broader clinical spectrum. Most patients were found to carry compound heterozygous DARS2 mutations, and only very few patients with homozygous mutations have been described so far. We present here an 8-month-old boy carrying a homozygous missense mutation in DARS2 who clinically showed severe neurological deterioration after a respiratory tract infection, followed by an almost complete remission of symptoms. This report further extends the knowledge about the clinical and molecular genetic spectrum of LBSL.
•We present a boy with leukoencephalopathy due to a homozygous DARS2 mutation.•Homozygous mutations in the DARS2 gene are rarely described.•The favourable outcome of the young boy is unusual for DARS2 mutations.•The MRI pattern is not typical for the DARS2 associated leukoencephalopathy (LBSL).
Leigh syndrome (MIM 25600), also known as infantile subacute necrotizing encephalomyelopathy, is a neurodegenerative disorder with characteristic bilateral symmetric lesions in basal ganglia and ...subcortical brain regions. It is commonly associated with systemic cytochrome c oxidase (COX) deficiency and mutations in the SURF1 gene (MIM 185620), encoding a putative assembly or maintenance factor of COX. The clinical course is dominated by neurodevelopmental regression, brain stem, and basal ganglia involvement (e.g., dystonia, apnea) with death often occurring before the age of 10 years. Herein, we present three sisters carrying a previously reported homozygous SURF1 mutation (c.868_869insT) that is predicted to result in a truncated protein with loss of function. Our patients show heterogeneous clinical findings with different distribution patterns of metabolic lesions in brain magnetic resonance imaging (MRI) as well as a Chiari malformation with hydrocephalus in one patient. However, all three siblings show an unusual long survival (12 years and>16 years). COX activity was not detectable in one patient and strongly reduced in the other two. We discuss these findings with respect to a review of the literature. A total of 15 additional patients with survival>14 years have been reported so far. Overall, no clear genotype-phenotype correlations are detectable among these patients.
Diagnosis of neuromuscular diseases in primary care is often challenging. Rare diseases such as Pompe disease are easily overlooked by the general practitioner. We therefore aimed to develop a ...diagnostic support tool using patient-oriented questions and combined data mining algorithms recognizing answer patterns in individuals with selected neuromuscular diseases. A multicenter prospective study for the proof of concept was conducted thereafter.
First, 16 interviews with patients were conducted focusing on their pre-diagnostic observations and experiences. From these interviews, we developed a questionnaire with 46 items. Then, patients with diagnosed neuromuscular diseases as well as patients without such a disease answered the questionnaire to establish a database for data mining. For proof of concept, initially only six diagnoses were chosen (myotonic dystrophy and myotonia (MdMy), Pompe disease (MP), amyotrophic lateral sclerosis (ALS), polyneuropathy (PNP), spinal muscular atrophy (SMA), other neuromuscular diseases, and no neuromuscular disease (NND). A prospective study was performed to validate the automated malleable system, which included six different classification methods combined in a fusion algorithm proposing a final diagnosis. Finally, new diagnoses were incorporated into the system.
In total, questionnaires from 210 individuals were used to train the system. 89.5 % correct diagnoses were achieved during cross-validation. The sensitivity of the system was 93-97 % for individuals with MP, with MdMy and without neuromuscular diseases, but only 69 % in SMA and 81 % in ALS patients. In the prospective trial, 57/64 (89 %) diagnoses were predicted correctly by the computerized system. All questions, or rather all answers, increased the diagnostic accuracy of the system, with the best results reached by the fusion of different classifier methods. Receiver operating curve (ROC) and p-value analyses confirmed the results.
A questionnaire-based diagnostic support tool using data mining methods exhibited good results in predicting selected neuromuscular diseases. Due to the variety of neuromuscular diseases, additional studies are required to measure beneficial effects in the clinical setting.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present a multiproxy geochemical analysis of two cores recovered from the Indus Shelf spanning the Early Holocene to Recent (<14 ka). Indus‐23 is located close to the modern Indus River, while ...Indus‐10 is positioned ∼100 km further west. The Holocene transgression at Indus‐10 was over a surface that was strongly weathered during the last glacial sea level lowstand. Lower Holocene sediments at Indus‐10 have higherεNdvalues compared to those at the river mouth indicating some sediment supply from the Makran coast, either during the deposition or via reworking of older sediments outcropping on the shelf. Sediment transport from Makran occurred during transgressive intervals when sea level crossed the mid shelf. The sediment flux from non‐Indus sources to Indus‐10 peaked between 11 ka and 8 ka. A hiatus at Indus‐23 from 8 ka until 1.3 ka indicates non‐deposition or erosion of existing Indus Shelf sequences. HigherεNdvalues seen on the shelf compared to the delta imply reworking of older delta sediments in building Holocene clinoforms. Chemical Index of Alteration (CIA), Mg/Al and Sr isotopes are all affected by erosion of detrital carbonate, which reduced through the Holocene. K/Al data suggest that silicate weathering peaked ca. 4–6 ka and was higher at Indus‐10 compared to Indus‐23. Fine‐grained sediments that make up the shelf have geochemical signatures that are different from the coarser grained bulk sediments measured in the delta plain. The Indus Shelf data highlight the complexity of reconstructing records of continental erosion and provenance in marine settings.
Key Points
Some widely used geochemical proxies not suitable for weathering
Reworking is an important process in the Indus region
Continental shelves not necessarily good places for continental weathering
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