CHROMOSOMAL BASIS OF DOSAGE COMPENSATION IN DROSOPHILA : III. Early Completion of Replication by the Polytene X-Chromosome in Male: Further Evidence and Its Implications

Thymidine-3H labeling patterns on the X (section 1 A to 12 E of Bridges' map) and 2 R (section 56 F to 60 F of Bridges' map) segments in the salivary gland chromosomes of Drosophila melanogaster have been analyzed in male and female separately. The observed patterns fit, with a few exceptions, in a continuous to discontinuous labeling sequence. In nuclei with similar labeling patterns on the 2R segment in both sexes, the number of labeled sites on the X in male is always less than in female X's. The labeling frequency of the different sites on the male X is considerably lower than those on the female X's, while the sites on the 2R segment have very similar frequency in the two sexes. The rate of thymidine-3H incorporation (as judged by visual grain counting) is relatively higher in male X than in female X's. It is concluded that the model sequence of replication in polytene chromosomes follows a continuous to discontinuous labeling sequence, and that the single X in male completes its replication earlier than either the autosomes in male or the X's in female. This asynchronous and faster rate of replication by the polytene X-chromosome in male substantiates the hypothesis of hyperactivity of the single X in male as the chromosomal basis of dosage compensation in Drosophila

Synchrony of replication in sister salivary glands of Drosophila kikkawai

Intergland synchrony of replication in the larval salivary glands of D. kikkawai bas been studied by 3H-thymidine pulse labelling and very light squashing. It is observed that there is a striking synchrony of replication between the 2 sister glands with respect to the position of the replicating nuclei and the frequency of different labelling patterns. There is also considerable synchrony within a gland where a group of neighbouring nuclei show similar kind of labelling. These observations suggest that the replication cycles of different polytene nuclei in the two sister salivary glands of a Iarva are developmentally determined

A novel set of heat shock polypeptides in malpighian tubules of Drosophila melanogaster

In contrast to the general notion of induction of a common set of heat shock polypeptides (HSP) in all cell types, heat shocked malpighian tubules (MT) ofDrosophila melanogaster larvae did not synthesize the common set of HSP induced in salivary glands or brain ganglia of larvae and in gonads (testis or ovary) of adult flies. Instead, heat shocked MT of late 3rd instar larvae and freshly eclosed adults synthesized a novel set of polypeptides (MT-specific HSP) with a major induced band at 58 kd. Surprisingly, the MT of older flies synthesized both the MT-specific as well as the common set of HSP in response to heat shock. Fusion genes with hsp70 or hsp26 promoter linked to the lac-Z (beta galactosidase) or to ADH (alcohol dehydrogenase) reporter gene were also not induced in larval MT but showed good induction in the MT of older flies. This unexpected finding raises intriguing issues regarding the nature of MT-specific HSP, their genes and the cell type dependent induction of the two sets of HSP

Abdominal Ultrasound and Abdominal Radiograph to Diagnose Necrotizing Enterocolitis in Extremely Preterm Infants

Necrotizing enterocolitis (NEC) is an important contributor towardmortality in extremely premature infants and Very Low Birth Weight(VLBW) infants. The incidence of NEC was 9% in VLBW infants(birth weight 401 to 1,500 grams) in the Vermont Oxford Network(VON, 2006 to 2010, n = 188,703).1 The incidence of NEC was 7%in 1993, increased to 13% in 2008, and decreased to 9% in extremelypreterm infants (22 to 28 weeks gestation) in the Neonatal ResearchNetwork Centers (1993 to 2012).2 The incidence of surgically treatedNEC varies from 28 to 50% in all infants who develop NEC.3 SurgicalNEC occurred in 52% in the VON cohort.1 In this cohort, the odds ofsurgery decreased by 5% for each 100 gram increase in birth.The incidence of surgical NEC has not decreased in the pastdecade.4 The mortality from NEC is significantly higher in infantswho need surgery compared to those who did not (35% versus 21%).1The case fatality rate among patients with NEC is higher in thosesurgically treated (23 to 36%) compared to those medically treated (5to 24%).3 In addition to surgery, NEC mortality rates are influencedby gestational age, birth weight,1,2,5 assisted ventilation on the day ofdiagnosis of NEC, treatment with vasopressors at diagnosis of NEC,and black race.6,7Extremely preterm infants who survive NEC are at risk for severeneurodevelopmental disability and those with surgical NEC have asignificantly higher risk of such delays (38% surgical NEC versus 24%medical NEC).8 Diagnosis of necrotizing enterocolitis is challengingand it is usually suspected based on non-specific clinical signs. Bell’scriteria and Vermont-Oxford Network criteria help in the diagnosisof NEC.Bell’s criteria, commonly used for diagnosis, staging, and planningtreatment of NEC, were described in 1978 and modified in 1986.9,10Bell’s stage I signs are non-specific: temperature instability, lethargy,decreased perfusion, emesis or regurgitation of food, abdominal distension,recurrent apnea, and on occasion, increased support withmechanical ventilation. Abdominal distension and emesis are morecommon than bloody stools in very preterm infants compared to terminfants.7 Abdominal radiographic findings are an integral part of Bell’scriteria. Identification of Bell’s stage I NEC (early NEC) with abdominalradiograph is challenging, as the features on abdominal radiograph(normal gas pattern or mild ileus) are non-specific. With progressionof NEC to Bell Stage IIA, the symptoms (grossly bloody stools,prominent abdominal distension, absent bowel sounds) and featureson abdominal radiographs (one or more dilated loops and focal pneumatosis)are more specific.On the other hand, the Vermont Oxford Network criteria for NECconsist of at least one physical finding (bilious gastric aspirate oremesis, abdominal distension or occult/gross blood in the stool inthe absence of anal fissure) and at least one feature on abdominalradiograph (pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum).1 These features correspond to Bell Stage IIA or StageIIB and are not features of early NEC. Thus relying solely on abdominalradiograph for diagnosis of early NEC, as is practiced currently,has significant drawbacks especially in extremely premature infants.7Ultrasound has been suggested to improve the percentage of infantsdiagnosed with early NEC.11 However, this imaging modality is notused routinely in the diagnosis or management of NEC.As the incidence of surgical NEC and mortality from NEC continuesto be high, the literature to demonstrate the shortcomings ofabdominal radiographs and promise of abdominal ultrasound in diagnosisof NEC is reviewed

Domain-matched Pre-training Tasks for Dense Retrieval

Pre-training on larger datasets with ever increasing model size is now a proven recipe for increased performance across almost all NLP tasks. A notable exception is information retrieval, where additional pre-training has so far failed to produce convincing results. We show that, with the right pre-training setup, this barrier can be overcome. We demonstrate this by pre-training large bi-encoder models on 1) a recently released set of 65 million synthetically generated questions, and 2) 200 million post-comment pairs from a preexisting dataset of Reddit conversations. We evaluate on a set of information retrieval and dialogue retrieval benchmarks, showing substantial improvements over supervised baselines

Finding the Optimal Balance between Over and Under Approximation of Models Inferred from Execution Logs

Models inferred from execution traces (logs) may admit more behaviours than those possible in the real system (over-approximation) or may exclude behaviours that can indeed occur in the real system (under-approximation). Both problems negatively affect model based testing. In fact, over-approximation results in infeasible test cases, i.e., test cases that cannot be activated by any input data. Under-approximation results in missing test cases, i.e., system behaviours that are not represented in the model are also never tested. In this paper we balance over- and under-approximation of inferred models by resorting to multi-objective optimization achieved by means of two search-based algorithms: A multi-objective Genetic Algorithm (GA) and the NSGA-II. We report the results on two open-source web applications and compare the multi-objective optimization to the state-of-the-art KLFA tool. We show that it is possible to identify regions in the Pareto front that contain models which violate fewer application constraints and have a higher bug detection ratio. The Pareto fronts generated by the multi-objective GA contain a region where models violate on average 2% of an application's constraints, compared to 2.8% for NSGA-II and 28.3% for the KLFA models. Similarly, it is possible to identify a region on the Pareto front where the multi-objective GA inferred models have an average bug detection ratio of 110: 3 and the NSGA-II inferred models have an average bug detection ratio of 101: 6. This compares to a bug detection ratio of 310928: 13 for the KLFA tool. © 2012 IEEE

Specializing Interpreters using Offline Partial Deduction

We present the latest version of the Logen partial evaluation system for logic programs. In particular we present new binding-types, and show how they can be used to effectively specialise a wide variety of interpreters.We show how to achieve Jones-optimality in a systematic way for several interpreters. Finally, we present and specialise a non-trivial interpreter for a small functional programming language. Experimental results are also presented, highlighting that the Logen system can be a good basis for generating compilers for high-level languages

Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS. METHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed. RESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2 variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2 variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1 ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1 and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS. CONCLUSIONS: SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further

Adaptive Evolution of a Stress Response Protein

Some cancers are mediated by an interplay between tissue damage, pathogens and localised innate immune responses, but the mechanisms that underlie these linkages are only beginning to be unravelled.Here we identify a strong signature of adaptive evolution on the DNA sequence of the mammalian stress response gene SEP53, a member of the epidermal differentiation complex fused-gene family known for its role in suppressing cancers. The SEP53 gene appears to have been subject to adaptive evolution of a type that is commonly (though not exclusively) associated with coevolutionary arms races. A similar pattern of molecular evolution was not evident in the p53 cancer-suppressing gene.Our data thus raises the possibility that SEP53 is a component of the mucosal/epithelial innate immune response engaged in an ongoing interaction with a pathogen. Although the pathogenic stress mediating adaptive evolution of SEP53 is not known, there are a number of well-known candidates, in particular viruses with established links to carcinoma

Functional Conservation of Cis-Regulatory Elements of Heat-Shock Genes over Long Evolutionary Distances

Transcriptional control of gene regulation is an intricate process that requires precise orchestration of a number of molecular components. Studying its evolution can serve as a useful model for understanding how complex molecular machines evolve. One way to investigate evolution of transcriptional regulation is to test the functions of cis-elements from one species in a distant relative. Previous results suggested that few, if any, tissue-specific promoters from Drosophila are faithfully expressed in C. elegans. Here we show that, in contrast, promoters of fly and human heat-shock genes are upregulated in C. elegans upon exposure to heat. Inducibility under conditions of heat shock may represent a relatively simple “on-off” response, whereas complex expression patterns require integration of multiple signals. Our results suggest that simpler aspects of regulatory logic may be retained over longer periods of evolutionary time, while more complex ones may be diverging more rapidly