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Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills nematodes including diverse species of plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode cytochrome P450 enzymes. Cyprocide fails to kill organisms beyond nematodes, suggesting that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply., (© 2024. The Author(s).)

DNA double-strand breaks (DSBs) are deleterious lesions, which must be repaired precisely to maintain genomic stability. During meiosis, programmed DSBs are repaired via homologous recombination (HR) while repair using the nonhomologous end joining (NHEJ) pathway is inhibited, thereby ensuring crossover formation and accurate chromosome segregation. 1 , 2 How DSB repair pathway choice is implemented during meiosis is unknown. In C. elegans, meiotic DSB repair takes place in the context of the fully formed, highly dynamic zipper-like structure present between homologous chromosomes called the synaptonemal complex (SC). 3 , 4 , 5 , 6 , 7 , 8 , 9 The SC consists of a pair of lateral elements bridged by a central region composed of the SYP proteins in C. elegans. How the structural components of the SC are regulated to maintain the architectural integrity of the assembled SC around DSB repair sites remained unclear. Here, we show that SYP-4, a central region component of the SC, is phosphorylated at Serine 447 in a manner dependent on DSBs and the ATM/ATR DNA damage response kinases. We show that this SYP-4 phosphorylation is critical for preserving the SC structure following exogenous (γ-IR-induced) DSB formation and for promoting normal DSB repair progression and crossover patterning following SPO-11-dependent and exogenous DSBs. We propose a model in which ATM/ATR-dependent phosphorylation of SYP-4 at the S447 site plays important roles both in maintaining the architectural integrity of the SC following DSB formation and in warding off repair via the NHEJ repair pathway, thereby preventing aneuploidy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Accumulation of DNA-RNA hybrids in the form of R-loops can result in replication-transcription conflict that leads to the formation of DNA double strand breaks (DSBs). Using null mutants for the two Caenorhabditis elegans genes encoding for RNaseH1 and RNaseH2, we identify novel effects of R-loop accumulation in the germline. R-loop accumulation leads, as expected, to replication stress, followed by the formation of DSBs. A subset of these DSBs are irreparable. However, unlike irreparable DSBs generated in other systems, which trigger permanent cell cycle arrest, germline irreparable DSBs are propagated to oocytes. Despite DNA damage checkpoint activation in the stem cell niche, the signaling cannot be sustained and nuclei with irreparable DNA damage progress into meiosis. Moreover, unlike other forms of DNA damage that increase germline apoptosis, R-loop-generated DSBs remain undetected by the apoptotic checkpoint. This coincides with attenuation of ATM/ATR signaling in mid-to-late meiotic prophase I. These data altogether indicate that in the germline, DSBs that are generated by R-loops can lead to irreparable DSBs that evade cellular machineries designed for damage recognition. These studies implicate germline R-loops as an especially dangerous driver of germline mutagenesis., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Akirin, a conserved metazoan protein, functions in muscle development in flies and mice. However, this was only tested in the rodent and fly model systems. Akirin was shown to act with chromatin remodeling complexes in transcription and was established as a downstream target of the NFκB pathway. Here we show a role for Caenorhabditis elegans Akirin/AKIR-1 in the muscle and body length regulation through a different pathway. Akirin localizes to somatic tissues throughout the body of C. elegans , including muscle nuclei. In agreement with its role in other model systems, Akirin loss of function mutants exhibit defects in muscle development in the embryo, as well as defects in movement and maintenance of muscle integrity in the C. elegans adult. We also have determined that Akirin acts downstream of the TGF-β Sma/Mab signaling pathway in controlling body size. Moreover, we found that the loss of Akirin resulted in an increase in autophagy markers, similar to mutants in the TGF-β Sma/Mab signaling pathway. In contrast to what is known in rodent and fly models, C. elegans Akirin does not act with the SWI/SNF chromatin-remodeling complex, and is instead involved with the NuRD chromatin remodeling complex in both movement and regulation of body size. Our studies define a novel developmental role (body size) and a new pathway (TGF-β Sma/Mab) for Akirin function, and confirmed its evolutionarily conserved function in muscle development in a new organism., (Copyright © 2020 Bowman et al.)

To maintain the integrity of the genome, meiotic DNA double strand breaks (DSBs) need to form by the meiosis-specific nuclease Spo11 and be repaired by homologous recombination. One class of products formed by recombination are crossovers, which are required for proper chromosome segregation in the first meiotic division. The synaptonemal complex (SC) is a protein structure that connects homologous chromosomes during meiotic prophase I. The proper assembly of the SC is important for recombination, crossover formation, and the subsequent chromosome segregation. Here we identify the components of Cullin RING E3 ubiquitin ligase 4 (CRL4) that play a role in SC assembly in Caenorhabditis elegans. Mutants of the CRL4 complex (cul-4, ddb-1, and gad-1) show defects in SC assembly manifested in the formation of polycomplexes (PCs), impaired progression of meiotic recombination, and reduction in crossover numbers. PCs that are formed in cul-4 mutants lack the mobile properties of wild type SC, but are likely not a direct target of ubiquitination. In C. elegans, SC assembly does not require recombination and there is no evidence that PC formation is regulated by recombination as well. However, in one cul-4 mutant PC formation is dependent upon early meiotic recombination, indicating that proper assembly of the SC can be diminished by recombination in some scenarios. Lastly, our studies suggest that CUL-4 deregulation leads to transposition of the Tc3 transposable element, and defects in formation of SPO-11-mediated DSBs. Our studies highlight previously unknown functions of CRL4 in C. elegans meiosis and show that CUL-4 likely plays multiple roles in meiosis that are essential for maintaining genome integrity., Competing Interests: The authors have declared that no competing interests exist.

BACKGROUND Intussusception is defined as the penetration or telescoping of a segment of bowel into a more distal segment. Intussusception is a common cause of small bowel obstruction, especially in children. However, this finding is much less common in adults. Furthermore, when present in adults, intussusception is often found in association with some sort of organic mass, such as a tumor or pancreatic divisum that acts as a lead point, dragging the proximal segment into the distal one. The presence of an intussusception in an adult patient with no obvious lead point is very uncommon. CASE REPORT Here we report a case of ileo-ileo-cecal double intussusception in an adult patient that yielded no lead point on surgical exploration. The patient was a 25-year-old female who presented with symptoms of obstruction and was diagnosed with the intussusception via computed tomography scan. Surgical resection of the bowel was necessary as reduction could not be accomplished. CONCLUSIONS The finding of intussusception in an adult patient is far less common than in children, and even more rare when a lead point is not established. When surgery is required, a thorough exploration should be performed to search any signs of a potential lead point. Laparoscopy is usually preferred to laparotomy; however, in this case the degree of distention determined the surgical approach. Thus, due to severe distention, laparotomy was preferred.

DNA double-strand breaks (DSBs) are toxic lesions that every cell must accurately repair in order to survive. The repair of DSBs is an integral part of a cell life cycle and can lead to lethality if repaired incorrectly. Laser microirradiation is an established technique which has been used in yeast, mammalian cell culture, and Drosophila cell culture to study the regulation of DSB repair. Up to our studies, this method has not been adapted for use in a whole, live, multicellular organism to study this repair in vivo. We have recently shown that this system can be used for study of the recruitment of vital repair proteins to microirradiation-induced breaks in the transparent nematode Caenorhabditis elegans. With the integration of microirradiation and imaging technology, we can precisely induce DSBs in target nuclei and study the recruitment of fluorescently tagged repair proteins from the time of damage induction. Whole, live worms are plated and immobilized for targeting of nuclei, and immediately following induction the targeted region can be imaged for up to an hour and a half post-microirradiation. This method is the first that allows for study of DNA repair protein kinetics in vivo in an intact organism, which can be adapted in numerous ways to allow for study of repair kinetics in various aspects of the repair process.

BACKGROUND Leishmaniasis is a parasitic infection spread by the bite of infected sand flies that are usually present in the Middle East, Africa, and some parts of Asia and Europe. Leishmaniasis manifests in 3 different forms: Visceral (also known as Kala Azar), which is the most serious type; cutaneous, which is the most common type; and mucocutaneous. The symptoms of this infection range from a silent infection to fever, enlargement of the liver and spleen, weight loss, and pancytopenia. CASE REPORT In this case report, we discuss a 73-year-old man known to have chronic lymphocytic leukemia (CLL), presenting with unremitting fever and who to our surprise was found to have Kala Azar. CONCLUSIONS Early diagnosis and treatment are very important in treating visceral leishmaniasis. While the conventional treatment in immunocompromised patients is liposomal amphotericin B, our patient responded to corticosteroids.

Studies of the repair pathways associated with DNA double strand breaks (DSBs) are numerous, and provide evidence for cell-cycle specific regulation of homologous recombination (HR) by the regulation of its associated proteins. Laser microirradiation is a well-established method to examine in vitro kinetics of repair and allows for live-imaging of DSB repair from the moment of induction. Here we apply this method to whole, live organisms, introducing an effective system to analyze exogenous, microirradiation-induced breaks in the Caenorhabditis elegans germline. Through this method we observed the sequential kinetics of the recruitment of ssDNA binding proteins RPA-1 and RAD-51 in vivo. We analyze these kinetics throughout different regions of the germline, and thus throughout a range of developmental stages of mitotic and meiotic nuclei. Our analysis demonstrates a largely conserved timing of recruitment of ssDNA binding proteins to DSBs throughout the germline, with a delay of RAD-51 recruitment at mid-pachytene nuclei. Microirradiated nuclei are viable and undergo a slow kinetics of resolution. We observe RPA-1 and RAD-51 colocalization for hours post-microirradiation throughout the germline, suggesting that there are mixed RPA-1/RAD-51 filaments. Finally, through live imaging analysis we observed RAD-51 foci movement with low frequency of coalescence., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

BACKGROUND Ingested foreign bodies (IFBs) are usually asymptomatic and are excreted uneventfully. IFBs become a major concern in elderly patients due to the increase number of diverticuloses where the foreign body can lodge and cause severe complications. CASE REPORT We report a case of an elderly patient who ingested a chicken bone that caused recurrent diverticulitis. CONCLUSIONS The diagnosis of complicated IFB cases is challenging, requires physician clinical expertise, and must be considered in individuals at risk.

BACKGROUND Among the causes of constipation are bands and adhesions that lead to obstructions at different points in the intestinal tract. These can occur as a consequence of healing following surgery or trauma. However, an entity known as congenital band exists where a band is present from birth. Here we report three such cases of adults with symptoms of intestinal obstruction, in whom a congenital band was discovered through exploratory laparoscopy. CASE REPORT All three of these patients presented lacking a history of any abdominal trauma or previous abdominal surgeries, a fact that is often used to exclude an adhesion as a differential. All three recovered quickly and had relief of their symptoms following surgical intervention. CONCLUSIONS Bands and adhesions are common surgical causes of small bowel obstruction, leading to symptoms such as nausea, vomiting, constipation, and obstipation. These bands almost always result from a prior abdominal surgery or from a recent abdominal trauma. The three cases presented here show a far more unusual picture of a band, one that is congenitally present, as there was an absence of such a history. This is significant because clinical suspicion of a band is often very low due to a lack of distinguishing clinical and diagnostic features, and when the past history is negative., Competing Interests: Conflicts of Interest: None declared Conflicts of interest No conflicts.

Objectives: To evaluate the impact of selecting treatment for nasal obstruction on the basis of a structured physiology-based assessment protocol on patient outcomes., Design: Prospective longitudinal study., Setting: District general hospital., Participants: A population of 71 patients with a mean age of 33 years, containing 36 males, presented with nasal obstruction for consideration of nasal surgery. All patients underwent a structured clinical assessment, skin prick allergy testing and oral-nasal flow-volume loop examination. Fifty-one patients completed the follow-up, and mean follow-up was 11 months., Main Outcome Measures: NOSE, SNOT-22 and NASION scales., Results: Of the 51 patients who completed follow-up, six had conservative treatment, 28 had septal/turbinate surgery, and 17 underwent nasal valve surgery. Mean NOSE score fell from 68 ± 18 to 39 ± 31 following the treatment. Mean SNOT-22 score fell from 47 ± 20 to 29 ± 26 following the treatment. The difference between pre-treatment and post-treatment NOSE and SNOT-22 scores were statistically significant. Success rate of septal/turbinate surgery in patients without nasal allergy was 88%, and this fell to 42% in patients undergoing septal/turbinate surgery who also had nasal allergy. Presence of nasal allergy was the only independent predictor of treatment failure. Patients with nasal valve surgery reported significantly greater symptomatic improvement following surgery. The newly formed NASION scale demonstrated internal consistency with a Cronbach α of 0.9 and excellent change-responsiveness and convergent validity with correlation coefficients of 0.64 and 0.77 against treatment-related changes in SNOT-22 and NOSE scales, respectively., Conclusions: Successful surgical outcomes can be achieved with the use of a structured history, clinical evaluation and physiological testing. Flow-volume loops can help elucidate the cause of nasal obstruction. The newly formed NASION scale is a validated retrospective single time-point patient outcome measure., (© 2015 John Wiley & Sons Ltd.)

The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.

Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.

A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).

Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.

Objective: We a describe technique for correction of internal nasal valve incompetence (INVI) using functional rhinoplasty (FRP) with combined cartilaginous batten and spreader grafts and report the functional and cosmetic outcomes., Design: Prospective series using subjective improvement in nasal airway and quality of life., Setting: Subregional ENT centre, one operating rhinologist., Participants: Twenty-three consecutive adults presenting to ENT department at North Hertfordshire NHS Trust with symptomatic INVI., Main Outcomes Measures: Pre and post-operative symptom scores for nasal obstruction and its impact on overall quality of life using visual analogue scales (1-100mm). Cosmetic outcome graded using subjective scores. Statistical analysis performed using the Wilcoxon signed rank test., Results: We found a median subjective improvement on the visual analogue scale of 55 mm for nasal patency (p<0.001) and of 49 mm for quality of life (p<0.001). Twenty-two patients felt that the appearance of their nose had not changed or had significantly improved post operatively., Conclusion: Combined use of batten and spreader grafts for the correction of INVI in normal or narrow nasal vaults is effective without compromising cosmesis.

p38MAPK has been implicated in the regulation of proinflammatory cytokines and apoptosis in vitro. To understand its role in neurodegeneration, we determined the time course and localization of the dually phosphorylated active form of p38MAPK in hippocampus after global forebrain ischemia. Phosphorylated p38MAPK and mitogen-activated protein kinase-activated protein 2 activity increased over 4 days after ischemia. Phosphorylated p38MAPK immunoreactivity was observed in microglia in regions adjacent to, but not in, the dying CA1 neurons. In contrast, neither c-Jun N-terminal kinase 1 nor p42/p44MAPK activity was altered after ischemia. These results provide the first evidence for localization of activated p38MAPK in the CNS and support a role for p38MAPK in the microglial response to stress.

In vitro studies indicate that p42/p44MAPK phosphorylate both nuclear and cytoplasmic proteins. However, the functional targets of p42/p44MAPK activation in vivo remain unclear. To address this question, we localized activated p42/p44MAPK in hippocampus and cortex and determined their signaling effects after electroconvulsive shock treatment (ECT) in rats. Phosphorylated p42/p44MAPK content increased in the cytoplasm of hippocampal neurons in response to ECT. Consistent with this cytoplasmic localization, inhibition of ECT-induced p42/p44MAPK activation by the extracellular signal-regulated kinase kinase inhibitor PD098059 blocked phosphorylation of the cytoplasmic protein microtubule-associated protein 2c (MAP2c), but failed to inhibit the induction of the nuclear protein c-Fos in response to ECT. In contrast to hippocampal neurons, cortical neurons exhibited an increase in amount of phosphorylated p42/p44MAPK in both the nucleus and cytoplasm after ECT. Accordingly, PD098059 blocked the induction of Fos-like immunoreactivity in the nuclei of cortical neurons as well as MAP2c phosphorylation in the cytoplasm. Our data indicate that both nuclear and cytoplasmic substrates can be activated by p42/p44MAPK in vivo. However, the functional targets of p42/p44MAPK signaling depend on the precise location of p42/p44MAPK within different subcellular compartments of brain regions. These results indicate unique functional pathways of p42/p44MAPK-mediated signal transduction within different brain regions in vivo.