The conserved XPF:ERCC1-like Zip2:Spo16 complex controls meiotic crossover formation through structure-specific DNA binding.

In eukaryotic meiosis, generation of haploid gametes depends on the formation of inter-homolog crossovers, which enable the pairing, physical linkage, and eventual segregation of homologs in the meiosis I division. A class of conserved meiosis-specific proteins, collectively termed ZMMs, are required for formation and spatial control of crossovers throughout eukaryotes. Here, we show that three Saccharomyces cerevisiae ZMM proteins-Zip2, Zip4 and Spo16-interact with one another and form a DNA-binding complex critical for crossover formation and control. We determined the crystal structure of a Zip2:Spo16 subcomplex, revealing a heterodimer structurally related to the XPF:ERCC1 endonuclease complex. Zip2:Spo16 lacks an endonuclease active site, but binds specific DNA structures found in early meiotic recombination intermediates. Mutations in multiple DNA-binding surfaces on Zip2:Spo16 severely compromise DNA binding, supporting a model in which the complex's central and HhH domains cooperate to bind DNA. Overall, our data support a model in which the Zip2:Zip4:Spo16 complex binds and stabilizes early meiotic recombination intermediates, then coordinates additional factors to promote crossover formation and license downstream events including synaptonemal complex assembly

Three Essays on the Supply of Long-Term Care Services to the Elderly in the U.S.

Situated in the context of a rapidly aging population, this dissertation examines the implications of supplying long-term care (LTC) services to the elderly in the United States. The first two essays investigate private costs of LTC assistance borne by adult children of elderly parents. In contrast, the third essay focuses on the cost of publicly-provided, formal LTC services. The first essay analyzes whether adult children devote less time to exercise as time allocation in parental caregiving increases. The empirical model is a system of four correlated equations, where the dependent variables are hours spent caregiving, frequency of moderate and vigorous physical activity, and hours spent in paid work. I use pooled cross-sectional data from the Health and Retirement Study (HRS) for this analysis. Results from joint estimation of the four equations indicate limited evidence of a competition between time spent in caregiving and frequency of physical activity. Parental factors that increase allocation of care time to parents do not comprehensively induce reductions in the frequency of any type of physical activity, nor in hours of work, among either men or women. The second essay goes beyond time resources and examines whether dementia onset in parents leads to a reduction in adult children’s household wealth. Towards this, I construct a longitudinal dataset from seven waves of HRS. Estimates from unconditional quantile regressions indicate that parental dementia substantially reduces household wealth of an unmarried adult child in the upper quantiles of the wealth change distribution in the first two years after parental diagnosis. These effects are more pronounced for unmarried adult children without siblings. Further, this response is observed to persist in the subsequent time period as well. An examination of mechanisms suggests that both, losses in labor income and nursing home expenditures, may play a role in leading to wealth declines. This paper makes two contributions: first, it focuses on a broader outcome of private cost, and second, unlike previous studies, it does not limit the analysis to adult children who are informal caregivers. The final essay examines the cost implications of publicly provided formal care services. Medicaid’s Personal Care Services (PCS) State Plan benefit is a key mechanism through which states provide personal assistance services to eligible beneficiaries. But, it is widely claimed that states are reluctant to adopt the program over fears of runaway spending. Surprisingly, there has been very little empirical work on examining the effect of the PCS State Plan benefit on Medicaid expenditures. Using aggregate state-level data from 1975 through 2009, this study finds that PCS State Plan adoption had no overall effect on Medicaid expenditures, except briefly during the early-growth years in 1980s. Further, findings suggest that states make decisions to adopt the program based on financial experiences of other adopting states. This study provides evidence consistent with the interpretation that when faced with the dilemma of balancing increased access and uncontrolled expenditures, state officials adapt the design of an entitlement benefit in an effort to make it less expensive. In its entirety, the dissertation provides new thinking on two dominant themes in conventional long-term care research: “caregiver burden” and “woodwork effect.” In particular, the results of the first and third essay question the presence of “caregiver burden” and “woodwork effect” respectively, while the third essay challenges the pervasiveness of “caregiver burden” among unmarried adult children. These findings, which in some aspect are unexpected in the context of existing literature, have important implications for policy intervention and the direction of future research efforts in this area

Clinicopathological analysis of ovarian tumors: a two year retrospective study

Background: Ovarian tumours are a heterogeneous neoplasm with a varied clinical, morphological and histological feature. Increasing mortality rate due to ovarian cancers has been reported in recent years. Ovarian tumours in post-menopausal females have high risk of malignancy and it has a very poor outcome. The aim and objective of this study was to determine clinical and histopathological spectrum and the frequency and age distribution of various ovarian tumors.Methods: It is a retrospective observational study of patients with ovarian tumors in the department of obstetrics and gynecology, SGRRI of Medical Health & Sciences and Hospital from January 2016 to December 2017 in a total number of 86 patients. All specimens were sent to pathology department and categorised according to WHO  hispathological classification.Results: Out of 86 cases examined, 64 cases were benign (74.4%), 3 cases were borderline (3.4%) and 19 cases were malignant (22.2%). Majority of the ovarian tumors (73.4%) were seen in the age group of 20 to 50 years. Most commonly encountered benign ovarian tumour was serous cystadenoma (58.1%). Surface epithelial tumors were the commonest tumors (64%) followed by germ cell tumors (29%).Conclusions: A variety of benign and malignant tumours of ovary were reported in this study. Early diagnosis and appropriate treatment of ovarian neoplasms favour the good prognosis. Most common benign tumour encountered in this study was serous cystadenoma

Replica Placement on Directed Acyclic Graphs

The replica placement problem has been well studied on trees. In this paper, we study this problem on directed acyclic graphs. The replica placement problem on general DAGs generalizes the set cover problem. We present a constant factor approximation algorithm for the special case of DAGs having bounded degree and bounded tree-width (BDBT-DAGs). We also present a constant factor approximation algorithm for DAGs composed of local BDBT-DAGs connected in a tree like manner (TBDBT-DAGs). The latter class of DAGs generalizes trees as well; we improve upon the previously best known approximation ratio for the problem on trees. Our algorithms are based on the LP rounding technique; the core component of our algorithm exploits the structural properties of tree-decompositions to massage the LP solution into an integral solution

Pathological Staging of Renal Cell Carcinoma: A Review of 300 Consecutive Cases

Aims: Pathological staging of renal cell carcinoma (RCC) can be challenging compared to other cancer types, as invasion often manifests as finger‐like protrusions into vascular spaces or renal sinus tissue. Although prior studies have shown larger tumour size to be correlated highly with renal sinus invasion, prospective data on evaluating pathological stage are limited. We evaluated a large series reported by one urological pathologist. Methods and results: Three hundred consecutive specimens were reviewed. Tumours larger than 5 cm were routinely sampled extensively or grossly re‐reviewed when no extrarenal extension was identified on initial examination. Apparent multifocal disease was assessed critically for intravascular spread. Retrograde venous invasion was reported in 15 of 300 (5%) cases, 13 of 15 of which were clear cell RCC. Of a total of 163 specimens with clear cell histology, only five of 34 (15%) tumours 7 cm or larger were reported as pT2, all of which had an explanatory comment indicating the absence of definitive extrarenal spread. In contrast, 15 of 20 (75%) pT2 tumours were non‐clear cell histology (papillary, chromophobe and translocation‐associated). Comparing pT3a or higher tumours, the median tumour size in cases with retrograde venous invasion was 8.0 cm, compared to 6.2 cm in cases without retrograde venous invasion (P = 0.005). ConclusionsOur findings support that retrograde venous invasion should be considered carefully before diagnosing multifocal clear cell RCC, which is rare in the sporadic setting. In the absence of vascular invasion, multifocal clear cell papillary RCC can be a mimic. pT2 occurs more frequently with non‐clear cell histology (particularly papillary or chromophobe RCC).https://scholarlycommons.henryford.com/merf2019basicsci/1002/thumbnail.jp

Correlation of PD-L1 expression, clinicopathologic and molecular characteristics in an array of solid tumors: A large-scale real world study

Background: Programmed death ligand-1 (PD-L1) is a predictive marker of anti-programmed death protein 1 (PD- 1)/PD-L1 therapies for solid tumors. Limited literature exists correlating PD-L1 expression, clinicopathological & molecular profiles. We aimed to 1) correlate PD-L1 immunohistochemistry (IHC) results with these profile across multiple solid tumors & 2) assess clinical outcomes (overall survival (OS) & disease-free survival (DFS)) of PD-L1 status with / without anti-PD-L1 immunotherapy (IT). Design: All cases tested for PD-L1 IHC over 2 years (Aug 2019-Sep 2020) were retrieved for this study. Clinicopathological variables recorded included age, race, tumor type, type of PD-L1 clone, PD-L1 status (Tumor Proportion Score (TPS): negative:50%), Combined Positive Score (CPS): negative10), clinical stage, anti-PD-L1 IT. Microsatellite instability (MSI) status using IHC & Ploymerase chain reaction (PCR) assays was recorded. High PD-L1 was defined as PD-L1 expression of TPS \u3e50%/CPS\u3e10. Outcome studies included OS and DFS after generating Kaplan-Meier curves & compared using log rank test. Univariate analysis using Cox regression models were also used. Results: There were 205 cases tested for PD-L1 by IHC. Cohort included non-small cell lung cancers (127), head & neck carcinomas (37), gastric or gastroesophageal carcinoma (20), kidney or urothelial carcinoma (16), cervical carcinomas (5). Median age was 70 years (range 28-90). Most were high stage cancers [stage 1: 5/205, stage 2: 5/205, stage 3: 30/205, stage 4 165/205]. PD-L1 IHC clones included: 22C3 (152/205), 28-8 (21/205) & both (32/205). High PD-L1 expression was observed in 52/205 (25.3%), out of which [37/127 (29.1%) were adenocarcinoma, 13/54 (24%) were squamous cell carcinoma, 2/24 (4.1%) others]. Anti PD-L1 IT was given in 65/205 (31.7%) patients. Anti PD-L1 IT was significantly associated with longer median survival OS (p=0.015) & DFS (p=0.004) (Figure 1). PD-L1 status was significantly associated with OS (p=0. 034) but not DFS (p=0. 076) (Figure 1). High PD-L1 had shorter median survival and higher hazards of death in OS (HR=5.4, CI-1.3-23.1) irrespective of IT. Association between three groups of PD-L1 status when compared with IT was statistically significant (p=0.048, Figure 2). PD-L1 & MSI testing was available in 29 patients & did not show any statistical correlation in this small cohort. No significant difference in survival for those received IT (4/29) vs no IT (25/29) & tested for both PD-L1 & MSI (OS: p= 0.277, DFS: p= 0.107). Conclusions: This study supports the rational approach for PD-L1 therapy. High PD-L1 expression is more commonly seen in adenocarcinoma. Expression of high PD-L1 is associated with worse OS but not DFS. PD-L1 IT is significantly associated with longer median survival, OS & DFS. Larger, prospective studies are needed to support our findings

Prenatal presentation of a rare genetic disorder: a clinical, autopsy and molecular correlation

Walker Warburg syndrome (WWS) lies at the severe end of the spectrum of the congenital muscular dystrophies. WWS is a congenital disorder of the O-glycosylation that disrupts in the post-translation modification of dystroglycan proteins. WWS is characterized by the involvement of the central nervous system and rarely by multisystem involvement. Next-generation sequencing discovered that multiple genes are associated with this disorder. FKTN is the rarest cause of WWS. We describe a clinical-autopsy report of a molecularly- confirmed WWS case presenting with ventriculomegaly, agenesis of the corpus callosum with a novel phenotype of Dandy-Walker malformation and unilateral multi-cystic kidney. The whole-exome sequencing confirmed a homozygous variant (c.411C>A) in the FKTN gene with a premature termination codon. This case emphasizes the importance of detailed postnatal phenotyping through an autopsy in any pregnancy with antenatally identified malformations. Obstetricians, pediatricians as well as fetal medicine experts need to counsel the parents and focus on preserving the appropriate sample for genetic testing. WWS, though rare deserves testing especially in the presence of positive family history. Dandy-Walker malformation is a novel feature and expands the phenotypic spectrum

PARENTAL RNAI SUPPRESSION OF KRUPPEL GENE TO CONTROL HEMIPTERAN PESTS

This disclosure concerns nucleic acid molecules and methods of use thereof for control of hemipteran pests through RNA interference - mediated inhibition of target coding and transcribed non - coding sequences in hemipteran pests. The disclosure also concerns methods for making transgenic plants that express nucleic acid molecules useful for the control of hemipteran pests, and the plant cells and plants obtained thereby

PARENTAL RNAI SUPPRESSION OF HUNCHBACK GENE TO CONTROL HEMIPTERAN PESTS

This disclosure concerns nucleic acid molecules and methods of use thereof for control of hemipteran pests through RNA interference-mediated inhibition of target coding and transcribed non-coding sequences in hemipteran pests. The dis closure also concerns methods for making transgenic plants that express nucleic acid molecules useful for the control of hemipteran pests, and the plant cells and plants obtained thereby